1
|
Liu J, Zhou R, Li Z, Li Y, Li H, Liu M, Xie F. Outcomes of lung transplantation for end stage lung disease with connective tissue disease: a systematic review and meta-analysis. BMC Pulm Med 2025; 25:264. [PMID: 40426174 PMCID: PMC12107806 DOI: 10.1186/s12890-025-03640-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 04/01/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Lung transplantation is the most important treatment for end-stage lung disease. However, the clinical outcomes of lung transplantation in patients with connective tissue disease(CTD) complicated with end-stage pulmonary complications are unclear. Consequently, we performed a systematic review and meta-analysis to compare the survival rates and incidences of adverse events between patients with and without CTD who underwent lung transplantation for end-stage lung disease. METHODS We searched the PubMed, Embase, Web of Science, Cochrane, Wanfang, VIP, CNKI, and CBM databases from their inception until October 18, 2023, for eligible studies. A meta-analysis of each study was performed using State14.0 with a 95% confidence interval (CI). A randomized or fixed-effect model was applied according to the heterogeneity test. The systematic review was registered in PROSPERO (CRD42023483687). RESULTS Our final analysis included 12 publications on 369 patients with CTD and 2,165 without, all of whom underwent lung transplantation. The survival at 1 month (OR = 2.20, 95% CI: 0.75-6.47, P = 0.485), 6 months (OR = 0.61, 95% CI: 0.33-1.14, P = 0.099), 1 year (OR = 1.05, 95% CI: 0.66-1.66, P = 0.982), 2 years (OR = 0.50, 95% CI: 0.23-1.06, P = 0.096), 3 years(OR = 1.11, 95% CI: 0.70-1.78, P = 0.703) and 5 years (OR = 2.08, 95% CI: 1.11-3.91, P = 0.027), grade 3 primary graft dysfunction (PGD) incidence (OR = 1.33, 95% CI: 0.68-2.60, P = 0.184), rejection events incidence (OR = 1.19, 95% CI: 0.61-2.32, P = 0.607) and intensive care unit (ICU) LOS (SMD = 0.54, 95% CI:-0.26-1.34, P = 0.187) were similar between the two groups. Patients with CTD had a greater risk of PGD incidence (OR = 2.91, 95% CI: 1.43-5.95, P = 0.003), a longer post-transplant hospital length of stay (LOS) (SMD = 0.52, 95% CI: 0.09-0.96, P = 0.009) and post-transplant time to extubation (SMD = 0.68, 95% CI: 0.12-1.25, P = 0.023). CONCLUSIONS The survival rate and the incidence of grade 3 PGD in CTD patients after lung transplantation are comparable to those of other patients undergoing lung transplantation for end-stage lung disease. Thus, Lung transplantation should be a strongly considered therapeutic option for patients with CTD who are suffering from end-stage lung disease. Nevertheless, when selecting patients with CTD for lung transplantation, it is crucial to focus on enhancing perioperative management to reduce the burden of hospitalization post-transplantation.
Collapse
Affiliation(s)
- Jihong Liu
- The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
- The First Clinical Medical College of Henan, University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
| | - Rui Zhou
- The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
- The First Clinical Medical College of Henan, University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
| | - Zhan Li
- The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
- The First Clinical Medical College of Henan, University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
| | - Yabin Li
- College of Pulmonary and Critical Care Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Huizhen Li
- The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
- The First Clinical Medical College of Henan, University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, China
| | - Miao Liu
- Department of anti-NBC medicine, graduate school, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Fei Xie
- College of Pulmonary and Critical Care Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
| |
Collapse
|
2
|
Ma M, Chu Z, Quan H, Li H, Zhou Y, Han Y, Li K, Pan W, Wang DY, Yan Y, Shu Z, Qiao Y. Natural products for anti-fibrotic therapy in idiopathic pulmonary fibrosis: marine and terrestrial insights. Front Pharmacol 2025; 16:1524654. [PMID: 40438605 PMCID: PMC12116445 DOI: 10.3389/fphar.2025.1524654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/29/2025] [Indexed: 06/01/2025] Open
Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrotic interstitial lung disease (ILD) of unknown etiology, characterized by increasing incidence and intricate pathogenesis. Current FDA-approved drugs suffer from significant side effects and limited efficacy, highlighting the urgent need for innovative therapeutic agents for IPF. Natural products (NPs), with their multi-target and multifaceted properties, present promising candidates for new drug development. This review delineates the anti-fibrotic pathways and targets of various natural products based on the established pathological mechanisms of IPF. It encompasses over 20 compounds, including flavonoids, saponins, polyphenols, terpenoids, natural polysaccharides, cyclic peptides, deep-sea fungal alkaloids, and algal proteins, sourced from both terrestrial and marine environments. The review explores their potential roles in mitigating pulmonary fibrosis, such as inhibiting inflammatory responses, protecting against lipid peroxidation damage, suppressing mesenchymal cell activation and proliferation, inhibiting fibroblast migration, influencing the synthesis and secretion of pro-fibrotic factors, and regulating extracellular matrix (ECM) synthesis and degradation. Additionally, it covers various in vivo and in vitro disease models, methodologies for analyzing marker expression and signaling pathways, and identifies potential new therapeutic targets informed by the latest research on IPF pathogenesis, as well as challenges in bioavailability and clinical translation. This review aims to provide essential theoretical and technical insights for the advancement of novel anti-pulmonary fibrosis drugs.
Collapse
Affiliation(s)
- Meiting Ma
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| | - Zhengqi Chu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| | - Hongyu Quan
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| | - Hanxu Li
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| | - Yuran Zhou
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, China
| | - Yanhong Han
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| | - Kefeng Li
- Faculty of Applied Sciences, Macao Polytechnic University, Macau, Macao SAR, China
| | - Wenjun Pan
- Department of Oncology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - De-Yun Wang
- Department of Otolaryngology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore
| | - Yan Yan
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, China
| | - Zunpeng Shu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| | - Yongkang Qiao
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, China
| |
Collapse
|
3
|
Li R, Cheng S, Jia Y, Wang H, Li C, Duan W, Wang X, Xiao Q, Liu Y. "Capture and kill" circulating fibrocytes by cisplatin prodrug loaded albumin disrupt the progress of pulmonary fibrosis in mice. J Control Release 2025; 383:113781. [PMID: 40294799 DOI: 10.1016/j.jconrel.2025.113781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/08/2025] [Accepted: 04/24/2025] [Indexed: 04/30/2025]
Abstract
Pulmonary fibrosis (PF) is a progressive chronic disease characterized by a continuous decline in lung function, for which effective therapies remain elusive. Increasing evidence suggests that the recruitment of fibrocytes from the circulatory system to lungs plays a pivotal role in the pathogenesis of PF. Once into the lungs, these fibrocytes differentiate into myofibroblasts, the primary producers of extracellular collagen. Given the difficulty in reversing the disease course, targeting this key mechanism in the early stages of the disease presents a promising therapeutic strategy. To this end, we engineered a plerixafor (CXCR4 antagonist)-modified serum albumin delivery system loaded with a cisplatin prodrug (Cpro@P-SA). This system is specifically designed to target CXCR4-positive circulating fibrocytes after intravenous administration, enhance cellular uptake of Cpro@P-SA, and facilitate the intracellular conversion of cisplatin prodrug to exert its cytotoxic effects, thereby inducing fibrocytes apoptosis. Utilizing a bleomycin-induced PF mouse model, we have demonstrated that Cpro@P-SA maintains prolonged circulation, enabling it to selectively identify and eradicate recruiting fibrocytes with an optimized treatment regimen. Our results confirm that Cpro@P-SA can effectively reduce fibrocyte levels in the circulatory system, thereby mitigating PF symptoms and controlling disease progression, as evidenced by key biochemical markers and histological analyses. Furthermore, the safety of this designed system was validated through multiple evaluations. Consequently, Cpro@P-SA offers a novel and promising therapeutic approach for the treatment of early PF.
Collapse
Affiliation(s)
- Rui Li
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Shihong Cheng
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Yizhen Jia
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Han Wang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Chujie Li
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Wei Duan
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Xiyan Wang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Qicai Xiao
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning 530021, China.
| | - Yang Liu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
| |
Collapse
|
4
|
Wang X, Zhou T, Huang S, Zhou H, Ling Y, Chen T, Zhang S, Wang W, Wu C, Yin W. Screening and validation of active components in Rosa roxburghii Tratt for anti-pulmonary fibrosis based on a spectrum-effect relationship. Int Immunopharmacol 2025; 153:114536. [PMID: 40154178 DOI: 10.1016/j.intimp.2025.114536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 03/09/2025] [Accepted: 03/19/2025] [Indexed: 04/01/2025]
Abstract
Rosa roxburghii Tratt (RRT), a fruit with dual medicinal and nutritional applications, exhibits therapeutic potential against pulmonary fibrosis, yet the specific bioactive constituents underlying this effect remain uncharacterized. This study employed an integrated spectrum-effect relationship to systematically identify RRT's principal anti-pulmonary fibrosis components. Our findings demonstrate that five different polar extracts of RRT (RRTEs) differentially attenuated bleomycin-induced pulmonary fibrosis in murine models, with the ethyl acetate fraction (EAE) showing superior therapeutic efficacy. HPLC-Q-Exactive Orbitrap MS identified 56 compounds, and screened out four active ingredients related to anti-pulmonary fibrosis by spectrum-effect relationship. In vitro experiments revealed that ellagic acid, gallic acid and syringic acid inhibited fibroblast migration, attenuated intracellular ROS overproduction, and downregulated the expression levels of α-SMA and collagen I. In summary, we established for the first time a spectrum-effect relationship between RRT and pulmonary fibrosis, elucidated the key components, and provided a foundation for future clinical applications.
Collapse
Affiliation(s)
- Xiaomeng Wang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Ting Zhou
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Shaolin Huang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Heting Zhou
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yihan Ling
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Tao Chen
- Chengdu Institute of Product Quality Inspection Co., Ltd, Chengdu 610015, China
| | - Shuwen Zhang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Wenxi Wang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Chuan Wu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Wenya Yin
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
| |
Collapse
|
5
|
Xie Y, Yi Q, Xu C, Wang Y, Jiang Y, Feng Y, Wang L, Yang H, Zhang Y, Wang B. Identifying TNFSF4 low-MSCs superiorly treating idiopathic pulmonary fibrosis through Tregs differentiation modulation. Stem Cell Res Ther 2025; 16:194. [PMID: 40254578 PMCID: PMC12010539 DOI: 10.1186/s13287-025-04313-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/04/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis is a progressive lung disorder, presenting clinically with symptoms such as shortness of breath and hypoxemia. Despite its severe prognosis and limited treatment options, the pathogenesis of idiopathic pulmonary fibrosis remains poorly understood. This study aims to investigate the therapeutic potential of mesenchymal stromal cells in treating idiopathic pulmonary fibrosis, focusing on their ability to modulate regulatory T cells through the low tumor necrosis factor superfamily member 4 (TNFSF4) pathway. The goal is to identify mesenchymal stromal cells subtypes with optimal immunomodulatory effects to enhance regulatory T cells functions and ameliorate fibrosis. METHODS We identified the immune characteristics of idiopathic pulmonary fibrosis by mining and analyzing multiple public datasets and detecting regulatory T cells in the blood and lung tissues of idiopathic pulmonary fibrosis patients. An extensive examination followed, including assessing the impact of mesenchymal stromal cells on regulatory T cells proportions in peripheral blood and lung tissue, and exploring the specific role of TNFSF4 expression in regulatory T cells modulation. Whole-genome sequencing and cluster analysis were used to identify mesenchymal stromal cells subtypes with low TNFSF4 expression. RESULTS Mesenchymal stromal cells characterized by TNFSF4 expression (TNFSF4low-MSCs) demonstrated enhanced ability to regulate regulatory T cells subpopulations and exhibited pronounced anti-fibrotic effects in the bleomycin-induced idiopathic pulmonary fibrosis mouse model. These mesenchymal stromal cells increased regulatory T cells proportions, reduced lung fibrosis, and improved survival rates. TNFSF4-tumor necrosis factor receptor superfamily member 4 (TNFRSF4) signaling was identified as a critical pathway influencing regulatory T cells generation and function. CONCLUSIONS Our findings underscore the pivotal role of TNFSF4 in mesenchymal stromal cells mediated regulatory T cells modulation and highlight the therapeutic potential of selecting mesenchymal stromal cells subtypes based on their TNFSF4 expression for treating idiopathic pulmonary fibrosis. This approach may offer a novel avenue for the development of targeted therapies aimed at modulating immune responses and ameliorating fibrosis in idiopathic pulmonary fibrosis. TRIAL REGISTRATION Our study involved collecting 10 mL of peripheral blood from idiopathic pulmonary fibrosis patients, and the Medical Ethics Committee of Nanjing Drum Tower Hospital approved our study protocol with the approval number 2023-675-01.
Collapse
Affiliation(s)
- Yuanyuan Xie
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210009, China
| | - Qing Yi
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210000, China
| | - Congwang Xu
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Clinical Medical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210009, China
| | - Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Clinical Medical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210009, China
| | - Yue Jiang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210009, China
| | - Yirui Feng
- School of Life Science, Nanjing University, Nanjing, Jiangsu, China
| | - Liudi Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210009, China
| | - Hui Yang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210009, China
| | - Yingwei Zhang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210000, China.
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210009, China.
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital, Clinical Medical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210009, China.
- Jiangsu Key Laboratory for Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China.
| |
Collapse
|
6
|
Liu H, Sun Y, Cai S, Zhao C, Xu X, Xu A, Zhou H, Yang C, Gu X, Ai X. Formononetin-Loaded PLGA Large Porous Microparticles via Intratracheal Instillation for Bleomycin-Induced Pulmonary Fibrosis Treatment. AAPS PharmSciTech 2025; 26:112. [PMID: 40246731 DOI: 10.1208/s12249-025-03089-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 03/11/2025] [Indexed: 04/19/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown cause, with few effective therapies available and high mortality rates. Our preceding research indicated that formononetin (FMN) could improve the symptoms of the bleomycin-induced pulmonary fibrosis and be a promising drug against IPF. In this study, an inhalable formononetin-loaded poly(lactic-co-glycolic) acid (PLGA) large porous microspheres (FMN-PLGA-MSs) was prepared by the method of emulsion solvent evaporation. SEM showed that FMN-PLGA-MSs were loose particles existing many pores on the surfaces, and the measured mean geometric diameter was more than 10 µm. The encapsulation efficiency (EE) and drug loading efficiency (DL) were 87.72 ± 6.34% and 4.18 ± 0.30%. FMN in FMN-PLGA-MSs could be rapidly released within 2 h and sustainably released for 21 d. Cell tests and q-RT-PCR tests showed that FMN could inhibit the activation of fibroblasts and the deposition of extracellular matrix (ECM) by acting on the TGF-β1/Smad3 signaling pathway. FMN-PLGA-MSs showed higher antifibrotic effects than free FMN oral administration in the pulmonary fibrosis models of mice, remarkably improving pulmonary function, decreasing hydroxyproline levels, and attenuating lung injuries. By formulating formononetin into microsphere preparations, its solubility can be significantly enhanced, enabling effective pulmonary drug delivery. This approach not only improves lung targeting but also reduces systemic toxicity. Additionally, it facilitates superior lung deposition and extends the retention time of the formononetin within the lungs. Taken together, FMN-PLGA-MSs may be a promising inhaled medication for the treatment of IPF.
Collapse
Affiliation(s)
- Hongting Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Yao Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Shihao Cai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Conglu Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Xiang Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Aiguo Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Honggang Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China.
| | - Xiaoting Gu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China.
| | - Xiaoyu Ai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China.
| |
Collapse
|
7
|
Chen ZY, Ma MM, Wang R, Zhang QQ, Xie ML, Wang YL, Guo YX, Liu K, Cao LF, He FL, Fu L, Jiang YL. Gui-zhi-fu-ling-wan alleviates bleomycin-induced pulmonary fibrosis through inhibiting epithelial-mesenchymal transition and ferroptosis. Front Pharmacol 2025; 16:1552251. [PMID: 40308766 PMCID: PMC12041222 DOI: 10.3389/fphar.2025.1552251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) has a higher morbidity and poor prognosis. Gui-Zhi-Fu-Ling-Wan (GFW) is a traditional Chinese herbal formula which exerts anti-inflammatory and anti-oxidative effects. The goal was to determine the protective effect of GFW on bleomycin (BLM)-induced pulmonary fibrosis. Methods One hundred and twenty-four mice were randomly divided into eight groups, and orally supplemented with GFW (1 g/kg) in 1 week ago and continuing to 1 week later of single BLM intratracheal injection (5.0 mg/kg). Lung tissues were collected in 7 days and 21 days after BLM injection. BEAS-2B cells were pretreated with GFW (100 μg/mL) for three consecutive days before BLM (10 μg/mL) exposure. Cells were harvested in 12 or 24 h after BLM co-culture. Results GFW supplementation alleviated BLM-induced alveolar structure destruction and inflammatory cell infiltration in mice lungs. BLM-incurred collagen deposition was attenuated by GFW. In addition, GFW pretreatment repressed BLM-evoked downregulation of E-cadherin, and elevation of N-cadherin and Vimentin in mouse lungs. Besides, BLM-excited GPX4 reduction, ferritin increases, lipid peroxidation, and free iron overload were significantly relieved by GFW pretreatment in mouse lungs and BEAS-2B cells. Notably, BLM-provoked mitochondrial reactive oxygen species (mtROS) excessive production, elevation of mitochondrial stress markers, such as HSP70 and CLPP, and mitochondrial injury, were all abolished in mouse lungs and BEAS-2B cells by GFW pretreatment. Conclusion GFW supplementation attenuated BLM-evoked lung injury and pulmonary fibrosis partially through repressing EMT and mtROS-mediated ferroptosis in pulmonary epithelial cells.
Collapse
Affiliation(s)
- Zi-Yong Chen
- The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Meng-Meng Ma
- The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Rui Wang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qing-Qing Zhang
- The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Mei-Ling Xie
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Ying-Li Wang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Yong-Xia Guo
- The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Kui Liu
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Li-Fang Cao
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| | - Feng-Lian He
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lin Fu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ya-Lin Jiang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China
| |
Collapse
|
8
|
Luo C, Huang C, Zhu Y, Zhou Y, Qiao Y, Shi C, Gao Y, Guo Y, Wei L. Inhibition of Rho GEFs attenuates pulmonary fibrosis through suppressing myofibroblast activation and reprogramming profibrotic macrophages. Cell Death Dis 2025; 16:278. [PMID: 40216763 PMCID: PMC11992128 DOI: 10.1038/s41419-025-07573-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 02/11/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025]
Abstract
Idiopathic pulmonary fibrosis has a poor prognosis, with existing medications only partially alleviating symptoms, highlighting the urgent need for new therapeutic approaches. The dysregulations of Rho GTPases/ROCK are related with various diseases, including fibrosis. Nevertheless, the development of drugs for pulmonary fibrosis treatment has predominantly concentrated on ROCK inhibitors. Small GTPases have been historically recognized as "undruggable". Here, we explore a novel Rho GEFs inhibitor GL-V9, and find that GL-V9 alleviates bleomycin-induced pulmonary fibrosis in mice by inhibiting myofibroblast activation and reprogramming profibrotic macrophages. Distinct from the mechanisms of the first-line drug Nintedanib, GL-V9 binds to the DH/PH domain of Rho GEFs and block the activation of Rho GTPase signaling. This action subsequently suppresses myofibroblast activation by interfering with Rho GTPase-dependent cytoskeletal reorganization and the activity of MRTF and YAP, and inhibits M2 macrophage polarization by modulating RhoA/STAT3 activity. The discovery of new regulatory mechanisms of GL-V9 suggests that targeting Rho GEFs represents a potent strategy for pulmonary fibrosis treatment.
Collapse
Affiliation(s)
- Chengju Luo
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Chenqi Huang
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China
| | - Yuqi Zhu
- Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, #138 Xianlin Rd, Nanjing, 210023, China
| | - Yuxin Zhou
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China
| | - Yansheng Qiao
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China
| | - Chenxiao Shi
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China
| | - Yuan Gao
- Public Laboratory Platform, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China
| | - Yongjian Guo
- School of Biopharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing, 211198, China.
| | - Libin Wei
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China.
| |
Collapse
|
9
|
Iliakis CS, Crotta S, Wack A. The Interplay Between Innate Immunity and Nonimmune Cells in Lung Damage, Inflammation, and Repair. Annu Rev Immunol 2025; 43:395-422. [PMID: 40036704 DOI: 10.1146/annurev-immunol-082323-031852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
As the site of gas exchange, the lung is critical for organismal survival. It is also subject to continual environmental insults inflicted by pathogens, particles, and toxins. Sometimes, these insults result in structural damage and the initiation of an innate immune response. Operating in parallel, the immune response aims to eliminate the threat, while the repair process ensures continual physiological function of the lung. The inflammatory response and repair processes are thus inextricably linked in time and space but are often studied in isolation. Here, we review the interplay of innate immune cells and nonimmune cells during lung insult and repair. We highlight how cellular cross talk can fine-tune the circuitry of the immune response, how innate immune cells can facilitate or antagonize proper organ repair, and the prolonged changes to lung immunity and physiology that can result from acute immune responses and repair processes.
Collapse
Affiliation(s)
- Chrysante S Iliakis
- Immunoregulation Laboratory, The Francis Crick Institute, London, United Kingdom;
| | - Stefania Crotta
- Immunoregulation Laboratory, The Francis Crick Institute, London, United Kingdom;
| | - Andreas Wack
- Immunoregulation Laboratory, The Francis Crick Institute, London, United Kingdom;
| |
Collapse
|
10
|
Yue M, Luan R, Ding D, Wang Y, Xue Q, Yang J. Identification and validation of biomarkers related to ferroptosis in idiopathic pulmonary fibrosis. Sci Rep 2025; 15:8622. [PMID: 40075162 PMCID: PMC11904244 DOI: 10.1038/s41598-025-93217-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a kind of interstitial lung disease (ILD). It has a high incidence rate and mortality. Its pathogenesis remains unclear. So far, no effective methods have been found for the early diagnosis of IPF. Ferroptosis has been reported to be critical in the initiation and progression of IPF. Therefore, our aim was to identify the hub gene related to ferroptosis co-expressed in the peripheral blood and pulmonary tissue of patients with IPF. Sequencing data were obtained from the Gene Expression Omnibus database. A comprehensive analysis was conducted on the differentially expressed genes (DEGs) to extract ferroptosis-related differentially expressed genes (FRDEGs). The results showed that ferroptosis-related signal paths were highly enriched in IPF, and 10 FRDEGs were identified.The hub gene was predicted through protein-protein interactions (PPI) and Cytoscape. The diagnostic utility of the hub gene was proven by enzyme-linked immunosorbent assay (ELISA) in serum and by immunohistochemistry (IHC) in pulmonary tissues. The results of ELISA indicated that the levels of ATM in the serum of patients with IPF were significantly lower than the normal levels. In contrast, the results of IHC showed that the expression of ATM in the pulmonary tissues of IPF patients exhibited a notably elevated trend. The immune status was assessed by the CIBERSORT method and so was the relevance between ATM and immune cells. These findings unveiled significant differences in various immune cell types in peripheral blood and pulmonary tissue between the IPF group and the control group. Furthermore, ATM was associated with various immune cells. This study suggests that as a ferroptosis-related gene, ATM assumes a pivotal role in the diagnosis and treatment of IPF. This discovery presents a novel approach for the clinical diagnosis and therapy of IPF.
Collapse
Affiliation(s)
- Ming Yue
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, China
| | - Rumei Luan
- Department of Respiratory Medicine, Shandong First Medical University Affiliated Provincial Hospital, Jinan, China
| | - Dongyan Ding
- Department of Respiratory Medicine, The 958 Hospital of Chinese PLA/Jiangbei Campus, The First Affiliated Hospital of Army Medical University, Chongqing, China
| | - Yuhong Wang
- Department of Respiratory Medicine, Jilin Central General Hospital, Jilin, China
| | - Qianfei Xue
- Hospital of Jilin University, Changchun, China.
| | - Junling Yang
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, China.
| |
Collapse
|
11
|
Valand A, Rajasekar P, Wain LV, Clifford RL. Interplay between genetics and epigenetics in lung fibrosis. Int J Biochem Cell Biol 2025; 180:106739. [PMID: 39848439 DOI: 10.1016/j.biocel.2025.106739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 12/15/2024] [Accepted: 01/16/2025] [Indexed: 01/25/2025]
Abstract
Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), is a complex and devastating disease characterised by the progressive scarring of lung tissue leading to compromised respiratory function. Aberrantly activated fibroblasts deposit extracellular matrix components into the surrounding lung tissue, impairing lung function and capacity for gas exchange. Both genetic and epigenetic factors have been found to play a role in the pathogenesis of lung fibrosis, with emerging evidence highlighting the interplay between these two regulatory mechanisms. This review provides an overview of the current understanding of the interplay between genetics and epigenetics in lung fibrosis. We discuss the genetic variants associated with susceptibility to lung fibrosis and explore how epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNA expression contribute to disease. Insights from genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) are integrated to explore the molecular mechanisms underlying lung fibrosis pathogenesis. We also discuss the potential clinical implications of genetics and epigenetics in lung fibrosis, including the development of novel therapeutic targets. Overall, this review highlights the importance of considering both genetic and epigenetic factors in the understanding and management of lung fibrosis.
Collapse
Affiliation(s)
- Anita Valand
- Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, UK; Nottingham NIHR Biomedical Research Centre, Nottingham, UK; Biodiscovery Institute, University Park, University of Nottingham, UK
| | - Poojitha Rajasekar
- Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, UK; Nottingham NIHR Biomedical Research Centre, Nottingham, UK; Biodiscovery Institute, University Park, University of Nottingham, UK
| | - Louise V Wain
- Department of Population Health Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK
| | - Rachel L Clifford
- Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, UK; Nottingham NIHR Biomedical Research Centre, Nottingham, UK; Biodiscovery Institute, University Park, University of Nottingham, UK.
| |
Collapse
|
12
|
St Pierre L, Berhan A, Sung EK, Alvarez JR, Wang H, Ji Y, Liu Y, Yu H, Meier A, Afshar K, Golts EM, Lin GY, Castaldi A, Calvert BA, Ryan A, Zhou B, Offringa IA, Marconett CN, Borok Z. Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167572. [PMID: 39547519 PMCID: PMC11951472 DOI: 10.1016/j.bbadis.2024.167572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 10/14/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.
Collapse
Affiliation(s)
- Laurence St Pierre
- Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Asres Berhan
- Department of Medicine, University of California San Diego, CA 92037, USA
| | - Eun K Sung
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Juan R Alvarez
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Hongjun Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Yanbin Ji
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Yixin Liu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Haoze Yu
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Angela Meier
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92037, USA
| | - Kamyar Afshar
- Department of Medicine, University of California San Diego, CA 92037, USA
| | - Eugene M Golts
- Department of Surgery, University of California, San Diego, La Jolla, CA 92037, USA
| | - Grace Y Lin
- Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA
| | | | - Ben A Calvert
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Amy Ryan
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Beiyun Zhou
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Ite A Offringa
- Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
| | - Crystal N Marconett
- Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Zea Borok
- Department of Medicine, University of California San Diego, CA 92037, USA.
| |
Collapse
|
13
|
Zhang X, Zhang L, Tian J, Li Y, Wu M, Zhang L, Qin X, Gong L. The application and prospects of drug delivery systems in idiopathic pulmonary fibrosis. BIOMATERIALS ADVANCES 2025; 168:214123. [PMID: 39615374 DOI: 10.1016/j.bioadv.2024.214123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/06/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease primarily affecting elderly individuals aged >65 years and has a poor prognosis. No effective treatment is currently available for IPF. The two antipulmonary fibrosis drugs nintedanib and pirfenidone approved by the FDA in the United States have somewhat decelerated IPF progression. However, the side effects of these drugs can lead to poor patient tolerance and compliance with the medications. Researchers have recently developed various methods for IPF treatment, such as gene silencing and pathway inhibitors, which hold great promise in IPF treatment. Nevertheless, the nonselectivity and nonspecificity of drugs often affect their efficacies. Drug delivery systems (DDS) are crucial for delivering drugs to specific target tissues or cells, thereby minimizing potential side effects, enhancing drug bioavailability, and reducing lung deposition. This review comprehensively summarizes the current state of DDS and various delivery strategies for IPF treatment (e.g., nano-delivery, hydrogel delivery, and biological carrier delivery) to completely expound the delivery mechanisms of different drug delivery carriers. Subsequently, the advantages and disadvantages of different DDS are fully discussed. Finally, the challenges and difficulties associated with the use of different DDS are addressed so as to accelerate their rapid clinical translation.
Collapse
Affiliation(s)
- Xi Zhang
- School of Biological Engineering, Zunyi Medical University, Guangdong 519000, China; Department of Clinical Medicine, The Fifth Clinical Institution, Zhuhai Campus of Zunyi Medical University, Guangdong 519000, China
| | - Ling Zhang
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Jiahua Tian
- Department of Clinical Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yunfei Li
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Manli Wu
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Longju Zhang
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Xiaofei Qin
- School of Biological Engineering, Zunyi Medical University, Guangdong 519000, China.
| | - Ling Gong
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China.
| |
Collapse
|
14
|
Shen C, Wang W, Wei D, Yang X, Jiang C, Sheng Y, Chen Y, Sun J, Li X, Li G, Ye S, Chen J. PCR array analysis reveals a novel expression profile of ferroptosis-related genes in idiopathic pulmonary fibrosis. BMC Pulm Med 2025; 25:98. [PMID: 40022042 PMCID: PMC11869717 DOI: 10.1186/s12890-025-03555-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 02/12/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and fatal disease characterized by progressive interstitial lung fibrosis. Given its insidious onset and poor outcome, there is an urgent need to elucidate the molecular mechanisms underlying IPF and identify effective therapeutic targets and diagnosis and prognosis biomarkers. Ferroptosis is an iron-dependent form of programmed cell death that occurs as lipid peroxides accumulate. Growing evidence suggests that ferroptosis is important in IPF. METHODS Human ferroptosis PCR array was performed on IPF and control lung tissue. The differentially expressed ferroptosis-related genes (DE-FRGs) were identified, underwent functional enrichment analyses, protein-protein interaction network construction, and potential drug target prediction. The DE-FRGs were validated and their value as diagnostic and prognostic blood biomarkers were evaluated using the Gene Expression Omnibus dataset GSE28042. RESULTS The array identified 13 DE-FRGs. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the DE-FRGs were mainly related to iron ion transport, blood microparticles, and oxidoreductase activity, and were involved in porphyrin metabolism, necroptosis, and the p53 signaling pathway in addition to ferroptosis. The 13 DE-FRGs were analyzed using the Drug-Gene Interaction Database to explore novel IPF therapeutic agents, yielding 42 potential drugs. Four DE-FRGs (BBC3, STEAP3, EPRS, SLC39A8) in the peripheral blood of IPF patients from the GSE28042 dataset demonstrated the same expression pattern as that observed in the lung tissue array. The receiver operating characteristic analysis demonstrated that the area under the curve of STEAP3 and EPRS were > 0.75. The survival analysis demonstrated that STEAP3 and EPRS were significantly different between the IPF and control groups. CONCLUSIONS The FRG expression profiles in IPF and control lung tissue were characterized. The findings provided valuable ideas to elucidate the role of ferroptosis in IPF and aided the identification of novel IPF therapeutic targets and biomarkers.
Collapse
Affiliation(s)
- Chenyou Shen
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Wei Wang
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Dong Wei
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Xusheng Yang
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Cheng Jiang
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Yating Sheng
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Yuan Chen
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Jie Sun
- Department of Scientific Research, The Affiliated Wuxi People's Hospital of Nanjing Medical, University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Xiaoshan Li
- Organ Donation and Transplant Management Office, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, WuxiJiangsu, 214023, China
| | - Guirong Li
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China.
| | - Shugao Ye
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China.
| | - Jingyu Chen
- Lung Transplant Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China.
| |
Collapse
|
15
|
Tan Y, Qian B, Ma Q, Xiang K, Wang S. Identification and Analysis of Key Immune- and Inflammation-Related Genes in Idiopathic Pulmonary Fibrosis. J Inflamm Res 2025; 18:1993-2009. [PMID: 39959639 PMCID: PMC11829586 DOI: 10.2147/jir.s489210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 12/21/2024] [Indexed: 02/18/2025] Open
Abstract
Background Studies suggest that immune and inflammation processes may be involved in the development of idiopathic pulmonary fibrosis (IPF); however, their roles remain unclear. This study aims to identify key genes associated with immune response and inflammation in IPF using bioinformatics. Methods We identified differentially expressed genes (DEGs) in the GSE93606 dataset and GSE28042 dataset, then obtained differentially expressed immune- and inflammation-related genes (DE-IFRGs) by overlapping DEGs. Two machine learning algorithms were used to further screen key genes. Genes with an area under curve (AUC) of > 0.7 in receiver operating characteristic (ROC) curves, significant expression and consistent trends across datasets were considered key genes. Based on these key genes, we carried out nomogram construction, enrichment and immune analyses, regulatory network mapping, drug prediction, and expression verification. Results 27 DE-IFRGs were identified by intersecting 256 DEGs, 1793 immune-related genes, and 1019 inflammation-related genes. Three genes (RNASE3, S100A12, S100A8) were obtained by crossing two machine algorithms (Boruta and LASSO),which had good diagnostic performance with AUC values. These key genes were all enriched in the same pathways, such as GOCC_azurophil_granule, IL-12 signalling and production in macrophages is the pathway with the strongest role for key genes. Six distinct immune cells, including naive CD4 T cells, T cells CD4 memory resting, T cells regulatory (Tregs), Monocytes, Macrophages M2, Neutrophils were identified. Real-time quantitative polymerase chain reaction (RT-qPCR) results were consistent with the training and validation sets, and the expression of these key genes was significantly upregulated in the IPF samples. Conclusion This study identified three key genes (RNASE3, S100A12 and S100A8) associated with immune response and inflammation in IPF, providing valuable insights into the diagnosis and treatment of IPF.
Collapse
Affiliation(s)
- Yan Tan
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| | - Baojiang Qian
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| | - Qiurui Ma
- Medical School of Kunming University of Science and Technolog, Kunming, People’s Republic of China
| | - Kun Xiang
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| | - Shenglan Wang
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| |
Collapse
|
16
|
Wan R, Liu Y, Yan J, Lin J. Cell therapy: A beacon of hope in the battle against pulmonary fibrosis. FASEB J 2025; 39:e70356. [PMID: 39873972 DOI: 10.1096/fj.202402790r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/28/2024] [Accepted: 01/15/2025] [Indexed: 01/30/2025]
Abstract
Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by abnormal activation of myofibroblasts and pathological remodeling of the extracellular matrix, with a poor prognosis and limited treatment options. Lung transplantation is currently the only approach that can extend the life expectancy of patients; however, its applicability is severely restricted due to donor shortages and patient-specific limitations. Therefore, the search for novel therapeutic strategies is imperative. In recent years, stem cells have shown great promise in the field of regenerative medicine due to their self-renewal capacity and multidirectional differentiation potential, and a growing body of literature supports the efficacy of stem cell therapy in PF treatment. This paper systematically summarizes the research progress of various stem cell types in the treatment of PF. Furthermore, it discusses the primary methods and clinical outcomes of stem cell therapy in PF, based on both preclinical and clinical data. Finally, the current challenges and key factors to consider in stem cell therapy for PF are objectively analyzed, and future directions for improving this therapy are proposed, providing new insights and references for the clinical treatment of PF patients.
Collapse
Affiliation(s)
- Ruyan Wan
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Jingwen Yan
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China
| |
Collapse
|
17
|
Deng X, Yang Y, Gan L, Duan X, Wang X, Zhang J, Wang A, Zhang A, Yuan Z, Chen D, Zheng A. Engineering Lipid Nanoparticles to Enhance Intracellular Delivery of Transforming Growth Factor-Beta siRNA (siTGF-β1) via Inhalation for Improving Pulmonary Fibrosis Post-Bleomycin Challenge. Pharmaceutics 2025; 17:157. [PMID: 40006524 PMCID: PMC11859093 DOI: 10.3390/pharmaceutics17020157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/22/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Transforming Growth Factor-beta (TGFβ1) plays a core role in the process of pulmonary fibrosis (PF). The progression of pulmonary fibrosis can be alleviated by siRNA-based inhibiting TGF-β1. However, the limitations of naked siRNA lead to the failure of achieving therapeutic effect. This study aimed to design lipid nanoparticles (LNPs) that can deliver siTGF-β1 to the lungs for therapeutic purposes. Methods: The cytotoxicity and transfection assay in vitro were used to screen ionizable lipids (ILs). Design of Experiments (DOE) was used to obtain novel LNPs that can enhance resistance to atomization shear forces. Meanwhile, the impact of LNPs encapsulating siTGF-β1 (siTGFβ1-LNPs) on PF was investigated. Results: When DLin-DMA-MC3 (MC3) was used as the ILs, the lipid phase ratio was MC3:DSPC:DMG-PEG2000:cholesterol = 50:10:3:37, and N/P = 3.25; the siTGFβ1-LNPs could be stably delivered to the lungs via converting the siTGFβ1-LNPs solution into an aerosol (atomization). In vitro experiments have confirmed that siTGFβ1-LNPs have high safety, high encapsulation, and can promote cellular uptake and endosomal escape. In addition, siTGFβ1-LNPs significantly reduced inflammatory infiltration and attenuated deposition of extracellular matrix (ECM) and protected the lung tissue from the toxicity of bleomycin (BLM) without causing systemic toxicity. Conclusions: The siTGFβ1-LNPs can be effectively delivered to the lungs, resulting in the silencing of TGF-β1 mRNA and the inhibition of the epithelial-mesenchymal transition pathway, thereby delaying the process of PF, which provides a new method for the treatment and intervention of PF.
Collapse
Affiliation(s)
- Xu Deng
- Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, School of Pharmacy, Yantai University, Yantai 264005, China; (X.D.)
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China (A.Z.)
| | - Yingjie Yang
- Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, School of Pharmacy, Yantai University, Yantai 264005, China; (X.D.)
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China (A.Z.)
| | - Liming Gan
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China (A.Z.)
| | - Xinliu Duan
- Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, School of Pharmacy, Yantai University, Yantai 264005, China; (X.D.)
| | - Xiwei Wang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China (J.Z.)
| | - Jingyan Zhang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China (J.Z.)
| | - Aiping Wang
- Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, School of Pharmacy, Yantai University, Yantai 264005, China; (X.D.)
| | - Anan Zhang
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China (A.Z.)
| | - Zhizhao Yuan
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China (A.Z.)
| | - Daquan Chen
- Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, School of Pharmacy, Yantai University, Yantai 264005, China; (X.D.)
| | - Aiping Zheng
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China (J.Z.)
| |
Collapse
|
18
|
Yu Y, Fang J, Li Y, Wang X, Zhang J, Wang J, Sun B. The Novel Effect and Potential Mechanism of Lactoferrin on Organ Fibrosis Prevention. Nutrients 2025; 17:197. [PMID: 39796631 PMCID: PMC11723014 DOI: 10.3390/nu17010197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/30/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Organ fibrosis is gradually becoming a human health and safety problem, and various organs of the body are likely to develop fibrosis. The ultimate pathological feature of numerous chronic diseases is fibrosis, and few interventions are currently available to specifically target the pathogenesis of fibrosis. The medical detection of organ fibrosis has gradually matured. However, there is currently no effective treatment method for these diseases. Therefore, we need to strive for developing effective and reliable drugs or substances to treat and prevent fibrotic diseases. Lactoferrin (LF) is a multifunctional glycoprotein with many pathological and physiologically active effects, such as antioxidant, anti-inflammatory and antimicrobial effects, and it protects against pathological and physiological conditions in various disease models. This review summarizes the effects and underlying mechanisms of LF in preventing organ fibrosis. As a naturally active substance, LF can be used as a promising and effective drug for the prevention and remission of fibrotic diseases.
Collapse
Affiliation(s)
| | | | | | | | - Jingjie Zhang
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, China-Canada Joint Lab of Food Nutrition and Health, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Beijing Technology and Business University, Beijing 100048, China; (Y.Y.); (J.F.); (Y.L.); (X.W.); (B.S.)
| | - Jing Wang
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, China-Canada Joint Lab of Food Nutrition and Health, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Beijing Technology and Business University, Beijing 100048, China; (Y.Y.); (J.F.); (Y.L.); (X.W.); (B.S.)
| | | |
Collapse
|
19
|
Keith R, Nambiar AM. Potential of phosphodiesterase 4B inhibition in the treatment of progressive pulmonary fibrosis. Ther Adv Respir Dis 2025; 19:17534666241309795. [PMID: 39745090 DOI: 10.1177/17534666241309795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is often regarded as the archetypal progressive fibrosing interstitial lung disease (ILD). The term "progressive pulmonary fibrosis" (PPF) generally describes progressive lung fibrosis in an individual with an ILD other than IPF. Both IPF and PPF are associated with loss of lung function, worsening dyspnea and quality of life, and premature death. Current treatments slow the decline in lung function but have side effects that may deter the initiation or continuation of treatment. There remains a high unmet need for additional therapies that can be used alone or in combination with current therapies to preserve lung function in patients with IPF and PPF. Phosphodiesterase-4 (PDE4) is an enzyme involved in the regulation of inflammatory processes. Pre-clinical studies have shown that preferential inhibition of PDE4B has anti-inflammatory and antifibrotic effects and a lower potential for gastrointestinal adverse events than pan-PDE4 inhibition. The preferential PDE4B inhibitor nerandomilast demonstrated efficacy in preserving lung function in a phase II trial in patients with IPF and is under investigation in phase III trials as a treatment for IPF and PPF.
Collapse
Affiliation(s)
- Rebecca Keith
- National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
| | - Anoop M Nambiar
- University of Texas Health San Antonio and the South Texas Veterans Health Care System, San Antonio, TX, USA
| |
Collapse
|
20
|
Cassidy N, Fox L, Love M, Byrne I, Doyle AM, Korn B, Shanagher D, Shone T, Cullen M, Cullen T, Mullaney P, O'Carroll N, O'Dowd G, O'Sullivan T, Russell AM. Fibrotic interstitial lung disease - palliative care needs: a World-Café qualitative study. BMJ Support Palliat Care 2024; 14:e2649-e2656. [PMID: 34635541 PMCID: PMC11672070 DOI: 10.1136/bmjspcare-2021-003249] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 09/11/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVES The importance of palliative care in those with advanced fibrotic interstitial lung diseases (F-ILD) is recognised, but the palliative care requirements of patients and caregivers affected by F-ILD regardless of disease course are not established. We set out to explore this and identify optimal solutions in meeting the needs of a F-ILD population in Ireland. METHODS Implementing a World-Café qualitative research approach, we captured insights evolving, iteratively in interactive small group discussions in response to six predefined topics on palliative care and planning for the future. Thirty-nine stakeholders participated in the World-Café including 12 patients, 13 caregivers, 9 healthcare professionals, 4 industry representatives and 1 representative of the clergy. RESULTS Palliative care emerged as fundamental to the care and treatment of F-ILDs, regardless of disease progression. Unmet palliative care needs were identified as psychological and social support, disease education, inclusion of caregivers and practical/legal advice for disease progression and end-of-life planning. Participants identified diagnosis as a particularly distressing time for patients and families. They called for the introduction of palliative care discussions at this early-stage alongside improvements in integrated care, specifically increasing the involvement of primary care practitioners in referrals to palliative services. CONCLUSION Patients and caregivers need discussions on palliative care associated with F-ILD to be included at the point of diagnosis. This approach may address persisting inadequacies in service provision previously identified over the course of the last decade in the UK, Ireland and European F-ILD patient charters.
Collapse
Affiliation(s)
| | - Lynn Fox
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Maria Love
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Irene Byrne
- Mater Misericordiae University Hospital, Dublin, Ireland
| | | | - Bettina Korn
- Hospice Friendly Hospitals Programme, St. James's Hospital, Dublin, Ireland
| | | | | | - Matt Cullen
- Irish Lung Fibrosis Association, Dublin, Ireland
| | | | | | | | - Gemma O'Dowd
- Irish Lung Fibrosis Association, Dublin, Ireland
| | | | - Anne-Marie Russell
- University of Exeter, Exeter, UK
- Imperial College Health Care Trust, London, UK
| |
Collapse
|
21
|
Yang J, Lu D, Sun Y, Qiu M, Zhao T, Yan B, Wang S, Shao Z, Wang D, Li T, Xiao Q, Fu T. Cell Membrane Hybrid Liposome-Targeted Delivery of the Heat Shock Protein 90 C-Terminal Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis. ACS Pharmacol Transl Sci 2024; 7:4083-4095. [PMID: 39698274 PMCID: PMC11651165 DOI: 10.1021/acsptsci.4c00524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/24/2024] [Accepted: 10/28/2024] [Indexed: 12/20/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) represents a grave challenge as it is characterized by high fatality rates and irreversible progression without effective clinical interventions available at present. Previous studies have demonstrated that inhibition of heat shock protein 90 (HSP90) by an N-terminal inhibitor disrupts its interaction with TGFβRII, leading to the instability of TGFβRII, thus blocking the role of transforming growth factor-β1 (TGF-β1), which could potentially ameliorate IPF symptoms. However, given that the broad spectrum of HSP90 N-terminal inhibitors may lead to unanticipated side effects, we hypothesize that C-terminal inhibitors of HSP90 can interfere with TGFβRII while minimizing adverse reactions. In this study, silybin, a C-terminal inhibitor of HSP90, was separated into monomers, and silybin A was screened for its superior efficacy against TGFβRII. To facilitate targeted therapy for treating IPF, a cell membrane hybrid liposome loaded with silybin A (Cm-A-Lip) was developed to deliver silybin A to lung fibroblasts through pulmonary drug delivery. A bleomycin-induced IPF mouse model was used to evaluate the efficacy of Cm-A-Lip. By examination of lung hydroxyproline content, wet weight, histology, and inflammatory factor expression, the results showed that pulmonary delivery of Cm-A-Lip could increase the drug retention time in lung tissue compared with intravenous injection. Furthermore, Cm-A-Lip exhibited superior antifibrotic activity relative to conventional liposmomes loaded with silybin A (A-Lip) while concurrently mitigating systemic inflammatory responses associated with silybin A administration, thus enhancing the overall safety profile.
Collapse
Affiliation(s)
| | | | - Yuping Sun
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Mengmeng Qiu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Tianlong Zhao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Baofei Yan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Siting Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhitao Shao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Demei Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ting Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Qingqing Xiao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Tingming Fu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| |
Collapse
|
22
|
Wang H, Sun K, Peng H, Wang Y, Zhang L. Emerging roles of noncoding RNAs in idiopathic pulmonary fibrosis. Cell Death Discov 2024; 10:443. [PMID: 39433746 PMCID: PMC11494106 DOI: 10.1038/s41420-024-02170-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 10/23/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with limited treatment options and efficacy. Evidence suggests that IPF arises from genetic, environmental, and aging-related factors. The pathogenic mechanisms of IPF primarily involve dysregulated repeated microinjuries to epithelial cells, abnormal fibroblast/myofibroblast activation, and extracellular matrix (ECM) deposition, but thus far, the exact etiology remains unclear. Noncoding RNAs (ncRNAs) play regulatory roles in various biological processes and have been implicated in the pathophysiology of multiple fibrotic diseases, including IPF. This review summarizes the roles of ncRNAs in the pathogenesis of IPF and their potential as diagnostic and therapeutic targets.
Collapse
Affiliation(s)
- Haitao Wang
- Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Kai Sun
- Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Hao Peng
- Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Yi Wang
- Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
| | - Lei Zhang
- Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
- Xianning Medical College, Hubei University of Science & Technology, Xianning, 437000, Hubei, China.
| |
Collapse
|
23
|
Göksu AY, Dirol H, Kocanci FG. Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model. Pharmacol Res Perspect 2024; 12:e70018. [PMID: 39360479 PMCID: PMC11447456 DOI: 10.1002/prp2.70018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 07/26/2024] [Accepted: 09/06/2024] [Indexed: 10/04/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.
Collapse
Affiliation(s)
- Azize Yasemin Göksu
- Department of Histology and EmbryologyAkdeniz University, School of MedicineAntalyaTurkey
- Department of Gene and Cell TherapyAkdeniz University, School of MedicineAntalyaTurkey
| | - Hulya Dirol
- Department of Chest DiseasesAkdeniz University, School of MedicineAntalyaTurkey
| | - Fatma Gonca Kocanci
- Vocational High School of Health Services, Department of Medical Laboratory TechniquesAlanya Alaaddin Keykubat UniversityAlanyaTurkey
| |
Collapse
|
24
|
Xu J, Zhou L, Chen H, He Y, Zhao G, Li L, Efferth T, Ding Z, Shan L. Aerosol inhalation of total ginsenosides repairs acute lung injury and inhibits pulmonary fibrosis through SMAD2 signaling-mediated mechanism. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155871. [PMID: 39098168 DOI: 10.1016/j.phymed.2024.155871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 06/24/2024] [Accepted: 07/08/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a progressive lung disease caused by previous acute lung injury (ALI), but there is currently no satisfactory therapy available. Aerosol inhalation of medicine is an effective way for treating PF. Total ginsenosides (TG) shows potential for the treatment of ALI and PF, but the effects of inhaled TG remain unclear. PURPOSE To determine the therapeutic effects of TG in ALI and PF, to assess the superiority of the inhaled form of TG over the routine form, and to clarify the mechanism of action of inhaled TG. METHODS Ultrahigh-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry (UPLC-QE-MS) was applied to determine the chemoprofile of TG. A mouse model of ALI and PF was established to evaluate the effects of inhaled TG by using bronchoalveolar lavage fluid (BALF) analysis, histopathological observation, hydroxyproline assay, and immunohistochemical analysis. Primary mouse lung fibroblasts (MLF) and human lung fibroblast cell line (HFL1) were applied to determine the in vitro effects and mechanism of TG by using cell viability assay, quantitative real time PCR (qPCR) assay, and western blot (WB) analysis. RESULTS The UPLC-QE-MS results revealed the main types of ginsenosides in TG, including Re (14.15 ± 0.42%), Rd (8.42 ± 0.49%), Rg1 (6.22 ± 0.42%), Rb3 (3.28 ± 0.01%), Rb2 (3.09 ± 0.00%), Rc (2.33 ± 0.01%), Rg2 (2.09 ± 0.04%), Rb1 (1.43 ± 0.24%), and Rf (0.13 ± 0.06%). Inhaled TG, at dosages of 10, 20, and 30 mg/kg significantly alleviated both ALI and PF in mice. Analyses of BALF and HE staining revealed that TG modulated the levels of IFN-γ, IL-1β, and TGF-β1, reduced inflammatory cell infiltration, and restored the alveolar architecture of the lung tissues. Furthermore, HE and Masson's trichrome staining demonstrated that TG markedly decreased fibroblastic foci and collagen fiber deposition, evidenced by the reduction of blue-stained collagen fibers. Hydroxyproline assay and immunohistochemical analyses indicated that TG significantly decreased hydroxyproline level and down-regulated the expression of Col1a1, Col3a1, and α-sma. The inhaled administration of TG demonstrated enhanced efficacy over the oral route when comparable doses were used. Additionally, inhaled TG showed superior safety and therapeutic profiles compared to pirfenidone, as evidenced by a CCK8 assay, which confirmed that TG concentrations ranging from 20 to 120 μg/ml were non-cytotoxic. qPCR and WB analyses revealed that TG, at concentrations of 25, 50, and 100 μg/ml, significantly suppressed the phosphorylation of smad2 induced by TGF-β1 and down-regulated the expression of fibrotic genes and proteins, including α-sma, Col1a1, Col3a1, and FN1, suggesting an anti-fibrotic mechanism mediated by the smad2 signaling pathway. In vitro, TG's safety and efficacy were also found to be superior to those of pirfenidone. CONCLUSIONS This study demonstrates, for the first time, the therapeutic efficacy of inhaled TG in treating ALI and PF. Inhaled TG effectively inhibits inflammation and reduces collagen deposition, with a particular emphasis on its role in modulating the Smad2 signaling pathway, which is implicated in the anti-fibrotic mechanism of TG. The study also highlights the superiority of inhaled TG over the oral route and its favorable safety profile in comparison to pirfenidone, positioning it as an ideal alternative for ALI and PF therapy.
Collapse
Affiliation(s)
- Jiaan Xu
- Fuyang Academy of Research, Zhejiang Chinese Medical University, Hangzhou 310053, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Li Zhou
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310053, China
| | - Huixin Chen
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yuzhou He
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital of Zhejiang Province), Hangzhou 310053, China
| | - Guoping Zhao
- Fuyang Academy of Research, Zhejiang Chinese Medical University, Hangzhou 310053, China; CAS Key Laboratory of Synthetic Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lan Li
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310053, China
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, 55128 Mainz, Germany.
| | - Zhishan Ding
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Letian Shan
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital of Zhejiang Province), Hangzhou 310053, China.
| |
Collapse
|
25
|
Han X, Zhang A, Meng Z, Wang Q, Liu S, Wang Y, Tan J, Guo L, Li F. Bioinformatics analysis based on extracted ingredients combined with network pharmacology, molecular docking and molecular dynamics simulation to explore the mechanism of Jinbei oral liquid in the therapy of idiopathic pulmonary fibrosis. Heliyon 2024; 10:e38173. [PMID: 39364246 PMCID: PMC11447332 DOI: 10.1016/j.heliyon.2024.e38173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/05/2024] Open
Abstract
Objective Jinbei oral liquid (JBOL), which is derived from a traditional hospital preparation, is frequently utilized to treat idiopathic pulmonary fibrosis (IPF) and has shown efficacy in clinical therapy. However, there are now several obstacles facing the mechanism inquiry, including target proteins, active components, and the binding affinity between crucial compounds and target proteins. To gain additional insight into the mechanisms underlying JBOL in anti-IPF, this study used bioinformation technologies, including network pharmacology, molecular docking, and molecular dynamic simulation, with a substantial amount of data based on realistic constituents. Methods Using network pharmacology, we loaded 118 realistic compounds into the SwissTargetPrediction and SwissADME databases and screened the active compounds and target proteins. IPF-related targets were collected from the OMIM, DisGeNET, and GeneCards databases, and the network of IPF-active constituents was built with Cytoscape 3.10.1. The GO and KEGG pathway enrichment analyses were carried out using Metascape, and the protein-protein interaction (PPI) network was constructed to screen the key targets with the STRING database. Finally, the reciprocal affinity between the active molecules and the crucial targets was assessed through the use of molecular docking and molecular dynamics simulation. Results A total of 122 targets and 34 tested active compounds were summarized in this investigation. Among these, kaempferol, apigenin, baicalein were present in high degree. PPI networks topological analysis identified eight key target proteins. AGE-RAGE, EGFR, and PI3K-Akt signaling pathways were found to be regulated during the phases of cell senescence, inflammatory response, autophagy, and immunological response in anti-IPF of JBOL. It was verified by molecular docking and molecular dynamics simulation that the combining way and binding energy between active ingredients and selected targets. Conclusions This work forecasts the prospective core ingredients, targets, and signal pathways of JBOL in anti-IPF, which has confirmed the multiple targets and pathways of JBOL in anti-IPF and provided the first comprehensive assessment with bioinformatic approaches. With empirical backing and an innovative approach to the molecular mechanism, JBOL is being considered as a potential new medication.
Collapse
Affiliation(s)
- Xinru Han
- Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Pharmacy, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Aijun Zhang
- Shandong University of Traditional Chinese Medicine, Jinan, China
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Zhaoqing Meng
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Qian Wang
- Department of Pharmacy, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Song Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunjia Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiaxin Tan
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lubo Guo
- Department of Pharmacy, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Feng Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| |
Collapse
|
26
|
Rautajoki T, Rantala HA, Sutinen E, Saarto T, Rajala K, Pesonen I, Hollmen M, Myllärniemi M, Lehto JT. Health-related quality of life measured with K-BILD is associated with survival in patients with idiopathic pulmonary fibrosis. BMC Pulm Med 2024; 24:480. [PMID: 39350048 PMCID: PMC11443770 DOI: 10.1186/s12890-024-03303-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Health-related quality of life (HRQoL) assessments and estimates of prognosis are needed for comprehensive care and planning of subsequent treatment in patients with idiopathic pulmonary fibrosis (IPF). We investigated HRQoL and its association with survival using a disease-specific tool in patients with IPF. METHODS The patients were recruited from the real-life FinnishIPF study in 2015. HRQoL was assessed with the King's Brief Interstitial Lung Disease (K-BILD) questionnaire every six months for 2.5 years. Dyspnoea was assessed with the modified Medical Research Council (mMRC) dyspnoea scale. Survival was registered until 31 December 2022. Patient survival according to the K-BILD total score was evaluated using the Kaplan‒Meier method. The Friedman test was used to compare the K-BILD total scores longitudinally, and the Mann‒Whitney U test was used to compare the mMRC groups. P values < 0.05 were considered statistically significant. RESULTS The median K-BILD total score (n = 245) was 51.6. At baseline, patients in the highest HRQoL quartile (K-BILD scores 58.9-100) had a longer median survival time (5.3 years) than did those with scores of 51.7-58.8 (3.1 years), 45.7-51.6 (2.3 years), and 0.0-45.6 (1.8 years). A decrease in the K-BILD total score of ≥ 5 units in the preceding 12 or 24 months showed a trend towards poorer survival, although statistical significance was not reached. Ninety-four patients survived more than 2.5 years and had available K-BILD data at all time points. The K-BILD total score remained higher in patients with a baseline mMRC of 0-1 than in those with a mMRC of 2-4, and the total score decreased only modestly in both groups (median of 3.3 and 4.8 units in patients with mMRC scores of 0-1 and 2-4, respectively). CONCLUSIONS In IPF, a reduced HRQoL is associated with impaired survival. A K-BILD total score less than approximately 50 units is associated with a median survival of approximately two years. In addition to assessing the treatment needs of patients with IPF using K-BILD, a decreased score may be useful for facilitating advance care planning and transplantation assessment.
Collapse
Affiliation(s)
- Tuuli Rautajoki
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
| | - Heidi A Rantala
- Department of Respiratory Medicine, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
| | - Eva Sutinen
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Tiina Saarto
- University of Helsinki, Helsinki, Finland
- Palliative Care Center, HUS Comprehensive Cancer Centre, Helsinki, Finland
| | - Kaisa Rajala
- Wellbeing Services of Vantaa and Kerava, Vantaa, Finland
| | - Ida Pesonen
- Respiratory Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Maria Hollmen
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Marjukka Myllärniemi
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Juho T Lehto
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Palliative Care Centre, Tampere University Hospital, Tampere, Finland
| |
Collapse
|
27
|
Fu C, Tian X, Wu S, Chu X, Cheng Y, Wu X, Yang W. Role of telomere dysfunction and immune infiltration in idiopathic pulmonary fibrosis: new insights from bioinformatics analysis. Front Genet 2024; 15:1447296. [PMID: 39346776 PMCID: PMC11427275 DOI: 10.3389/fgene.2024.1447296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/29/2024] [Indexed: 10/01/2024] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by unexplained irreversible pulmonary fibrosis. Although the etiology of IPF is unclear, studies have shown that it is related to telomere length shortening. However, the prognostic value of telomere-related genes in IPF has not been investigated. Methods We utilized the GSE10667 and GSE110147 datasets as the training set, employing differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen for disease candidate genes. Then, we used consensus clustering analysis to identify different telomere patterns. Next, we used summary data-based mendelian randomization (SMR) analysis to screen core genes. We further evaluated the relationship between core genes and overall survival and lung function in IPF patients. Finally, we performed immune infiltration analysis to reveal the changes in the immune microenvironment of IPF. Results Through differential expression analysis and WGCNA, we identified 35 significant telomere regulatory factors. Consensus clustering analysis revealed two distinct telomere patterns, consisting of cluster A (n = 26) and cluster B (n = 19). Immune infiltration analysis revealed that cluster B had a more active immune microenvironment, suggesting its potential association with IPF. Using GTEx eQTL data, our SMR analysis identified two genes with potential causal associations with IPF, including GPA33 (PSMR = 0.0013; PHEIDI = 0.0741) and MICA (PSMR = 0.0112; PHEIDI = 0.9712). We further revealed that the expression of core genes is associated with survival time and lung function in IPF patients. Finally, immune infiltration analysis revealed that NK cells were downregulated and plasma cells and memory B cells were upregulated in IPF. Further correlation analysis showed that GPA33 expression was positively correlated with NK cells and negatively correlated with plasma cells and memory B cells. Conclusion Our study provides a new perspective for the role of telomere dysfunction and immune infiltration in IPF and identifies potential therapeutic targets. Further research may reveal how core genes affect cell function and disease progression, providing new insights into the complex mechanisms of IPF.
Collapse
Affiliation(s)
- Chenkun Fu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xin Tian
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Shuang Wu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaojuan Chu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yiju Cheng
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Respiratory and Critical Care Medicine, The Fourth People’s Hospital of Guiyang, Guiyang, China
| | - Xiao Wu
- Department of Critical Care Medicine, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Wengting Yang
- Department of Critical Care Medicine, The Second People’s Hospital of Guiyang, Guiyang, China
| |
Collapse
|
28
|
Soltanmohammadi F, Gharehbaba AM, Zangi AR, Adibkia K, Javadzadeh Y. Current knowledge of hybrid nanoplatforms composed of exosomes and organic/inorganic nanoparticles for disease treatment and cell/tissue imaging. Biomed Pharmacother 2024; 178:117248. [PMID: 39098179 DOI: 10.1016/j.biopha.2024.117248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024] Open
Abstract
Exosome-nanoparticle hybrid nanoplatforms, can be prepared by combining exosomes with different types of nanoparticles. The main purpose of combining exosomes with nanoparticles is to overcome the limitations of using each of them as drug delivery systems. Using nanoparticles for drug delivery has some limitations, such as high immunogenicity, poor cellular uptake, low biocompatibility, cytotoxicity, low stability, and rapid clearance by immune cells. However, using exosomes as drug delivery systems also has its own drawbacks, such as poor encapsulation efficiency, low production yield, and the inability to load large molecules. These limitations can be addressed by utilizing hybrid nanoplatforms. Additionally, the use of exosomes allows for targeted delivery within the hybrid system. Exosome-inorganic/organic hybrid nanoparticles may be used for both therapy and diagnosis in the future. This may lead to the development of personalized medicine using hybrid nanoparticles. However, there are a few challenges associated with this. Surface modifications, adding functional groups, surface charge adjustments, and preparing nanoparticles with the desired size are crucial to the possibility of preparing exosome-nanoparticle hybrids. Additional challenges for the successful implementation of hybrid platforms in medical treatments and diagnostics include scaling up the manufacturing process and ensuring consistent quality and reproducibility across various batches. This review focuses on various types of exosome-nanoparticle hybrid systems and also discusses the preparation and loading methods for these hybrid nanoplatforms. Furthermore, the potential applications of these hybrid nanocarriers in drug/gene delivery, disease treatment and diagnosis, and cell/tissue imaging are explained.
Collapse
Affiliation(s)
- Fatemeh Soltanmohammadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Adel Mahmoudi Gharehbaba
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Rajabi Zangi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khosro Adibkia
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yousef Javadzadeh
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
29
|
Mora-Cuesta VM, Martínez-Meñaca A, González-Fernández Á, Iturbe-Fernández D, Tello-Mena S, Izquierdo-Cuervo S, Fernández-Rozas S, Alonso-Lecue P, Cifrián-Martínez JM. The impact of time from ILD diagnosis to referral to the transplant center on the probability of inclusion in the transplant waiting list. Heart Lung 2024; 67:92-99. [PMID: 38735159 DOI: 10.1016/j.hrtlng.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/14/2024]
Abstract
BACKGROUND Lung transplant is a therapeutic option for patients with progressive interstitial lung disease (ILD). OBJECTIVES The objective of this study was to determine whether time from ILD diagnosis to referral to a transplant center influences the probability of being included in the transplant waiting list. METHODS We performed a retrospective cohort study including all ILD patients evaluated as lung transplantation (LT) candidates at a lung transplant center between 01/01/2017 and 31/12/2022. The primary endpoint was the probability of being included in the lung transplant waiting list according to the time elapsed from diagnosis to referral to the transplant center. RESULTS A total of 843 lung transplant requests were received, of which 367 (43.5%) were associated with ILD. Thirteen patients were excluded because they did not attend the first visit, whereas another 11 were excluded because some information was missing. As a result, our final sample was composed of 343 patients. The median time from diagnosis to referral was 29.4 (10.9 - 61.1) months. The overall probability of inclusion in the waiting list was 29.7%. By time from diagnosis to referral, the probability of inclusion in the waiting list was 48.1% for the patients referred 〈 6 months from diagnosis; 27.5% for patients referred 6 to 24 months from diagnosis; and 25.8% for patients referred 〉 24 months from diagnosis (p = 0.007). CONCLUSIONS Early referral to a lung transplant center seemed to increase the probability of being included in the lung transplant waiting list. Further research is needed in this topic.
Collapse
Affiliation(s)
- Víctor M Mora-Cuesta
- Respiratory Department, Lung Transplant Unit, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n. 39008, Santander, Spain.
| | - Amaya Martínez-Meñaca
- Respiratory Department. ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Spain
| | | | - David Iturbe-Fernández
- Respiratory Department, Lung Transplant Unit, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n. 39008, Santander, Spain
| | - Sandra Tello-Mena
- Respiratory Department, Lung Transplant Unit, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n. 39008, Santander, Spain
| | - Sheila Izquierdo-Cuervo
- Respiratory Department, Lung Transplant Unit, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n. 39008, Santander, Spain
| | - Sonia Fernández-Rozas
- Respiratory Department. ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Spain
| | | | - José M Cifrián-Martínez
- Respiratory Department, Lung Transplant Unit, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n. 39008, Santander, Spain
| |
Collapse
|
30
|
Milman Krentsis I, Zheng Y, Rosen C, Shin SY, Blagdon C, Shoshan E, Qi Y, Wang J, Yadav SK, Bachar Lustig E, Shetzen E, Dickey BF, Karmouty-Quintana H, Reisner Y. Lung cell transplantation for pulmonary fibrosis. SCIENCE ADVANCES 2024; 10:eadk2524. [PMID: 39178253 PMCID: PMC11343030 DOI: 10.1126/sciadv.adk2524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 07/19/2024] [Indexed: 08/25/2024]
Abstract
Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors expanded to form numerous donor-derived patches comprising AT1 and AT2 alveolar cells, as well as donor-derived mesenchymal and endothelial cells. This lung chimerism was associated with attenuation of fibrosis, as demonstrated histologically, biochemically, by computed tomography imaging, and by lung function measurements. Our study provides a strong rationale for the treatment of lung fibrosis using lung cell transplantation.
Collapse
Affiliation(s)
- Irit Milman Krentsis
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Yangxi Zheng
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Chava Rosen
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
- Department of Neonatology, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer, Israel
| | - Sarah Y. Shin
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Christa Blagdon
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Einav Shoshan
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Yuan Qi
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer, Houston, TX, USA
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer, Houston, TX, USA
| | - Sandeep K. Yadav
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Esther Bachar Lustig
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Elias Shetzen
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| | - Burton F. Dickey
- Department of Pulmonary Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Divisions of Critical Care, Pulmonary and Sleep Medicine, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yair Reisner
- Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
31
|
Wang S, Yang G, Zhang K, Chen Z, Qiu M, Hou S, Zheng T, Wu Z, Ma Q, Zhang F, Gao G, Huang YY, Zhou Q, Luo HB, Wu D. Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis. Bioorg Chem 2024; 149:107474. [PMID: 38805909 DOI: 10.1016/j.bioorg.2024.107474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/06/2024] [Accepted: 05/16/2024] [Indexed: 05/30/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.
Collapse
Affiliation(s)
- Sen Wang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Guofeng Yang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Kai Zhang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; School of Life and Health Sciences, Hainan University, Haikou 570228, China
| | - Zhexin Chen
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Meiying Qiu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Siyu Hou
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Tiansheng Zheng
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Zongmin Wu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Qinjiang Ma
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Furong Zhang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; School of Life and Health Sciences, Hainan University, Haikou 570228, China
| | - Ge Gao
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Yi-You Huang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Qian Zhou
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
| | - Hai-Bin Luo
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
| | - Deyan Wu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
| |
Collapse
|
32
|
Aghajani Mir M. Illuminating the pathogenic role of SARS-CoV-2: Insights into competing endogenous RNAs (ceRNAs) regulatory networks. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2024; 122:105613. [PMID: 38844190 DOI: 10.1016/j.meegid.2024.105613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/20/2024] [Accepted: 05/31/2024] [Indexed: 06/10/2024]
Abstract
The appearance of SARS-CoV-2 in 2019 triggered a significant economic and health crisis worldwide, with heterogeneous molecular mechanisms that contribute to its development are not yet fully understood. Although substantial progress has been made in elucidating the mechanisms behind SARS-CoV-2 infection and therapy, it continues to rank among the top three global causes of mortality due to infectious illnesses. Non-coding RNAs (ncRNAs), being integral components across nearly all biological processes, demonstrate effective importance in viral pathogenesis. Regarding viral infections, ncRNAs have demonstrated their ability to modulate host reactions, viral replication, and host-pathogen interactions. However, the complex interactions of different types of ncRNAs in the progression of COVID-19 remains understudied. In recent years, a novel mechanism of post-transcriptional gene regulation known as "competing endogenous RNA (ceRNA)" has been proposed. Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and viral ncRNAs function as ceRNAs, influencing the expression of associated genes by sequestering shared microRNAs. Recent research on SARS-CoV-2 has revealed that disruptions in specific ceRNA regulatory networks (ceRNETs) contribute to the abnormal expression of key infection-related genes and the establishment of distinctive infection characteristics. These findings present new opportunities to delve deeper into the underlying mechanisms of SARS-CoV-2 pathogenesis, offering potential biomarkers and therapeutic targets. This progress paves the way for a more comprehensive understanding of ceRNETs, shedding light on the intricate mechanisms involved. Further exploration of these mechanisms holds promise for enhancing our ability to prevent viral infections and develop effective antiviral treatments.
Collapse
Affiliation(s)
- Mahsa Aghajani Mir
- Deputy of Research and Technology, Babol University of Medical Sciences, Babol, Iran.
| |
Collapse
|
33
|
Ge Z, Chen Y, Ma L, Hu F, Xie L. Macrophage polarization and its impact on idiopathic pulmonary fibrosis. Front Immunol 2024; 15:1444964. [PMID: 39131154 PMCID: PMC11310026 DOI: 10.3389/fimmu.2024.1444964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lung disease that worsens over time, causing fibrosis in the lungs and ultimately resulting in respiratory failure and a high risk of death. Macrophages play a crucial role in the immune system, showing flexibility by transforming into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages when exposed to different stimuli, ultimately impacting the development of IPF. Recent research has indicated that the polarization of macrophages is crucial in the onset and progression of IPF. M1 macrophages secrete inflammatory cytokines and agents causing early lung damage and fibrosis, while M2 macrophages support tissue healing and fibrosis by releasing anti-inflammatory cytokines. Developing novel treatments for IPF relies on a thorough comprehension of the processes involved in macrophage polarization in IPF. The review outlines the regulation of macrophage polarization and its impact on the development of IPF, with the goal of investigating the possible therapeutic benefits of macrophage polarization in the advancement of IPF.
Collapse
Affiliation(s)
- Zhouling Ge
- Department of Respiratory Medicine, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, China
| | - Yong Chen
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Leikai Ma
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangjun Hu
- Department of Respiratory Medicine, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, China
| | - Lubin Xie
- Department of Respiratory Medicine, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
34
|
Koh SY, Lee JH, Park H, Goo JM. Value of CT quantification in progressive fibrosing interstitial lung disease: a deep learning approach. Eur Radiol 2024; 34:4195-4205. [PMID: 38085286 DOI: 10.1007/s00330-023-10483-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/23/2023] [Accepted: 10/27/2023] [Indexed: 06/29/2024]
Abstract
OBJECTIVES To evaluate the relationship of changes in the deep learning-based CT quantification of interstitial lung disease (ILD) with changes in forced vital capacity (FVC) and visual assessments of ILD progression, and to investigate their prognostic implications. METHODS This study included ILD patients with CT scans at intervals of over 2 years between January 2015 and June 2021. Deep learning-based texture analysis software was used to segment ILD findings on CT images (fibrosis: reticular opacity + honeycombing cysts; total ILD extent: ground-glass opacity + fibrosis). Patients were grouped according to the absolute decline of predicted FVC (< 5%, 5-10%, and ≥ 10%) and ILD progression assessed by thoracic radiologists, and their quantification results were compared among these groups. The associations between quantification results and survival were evaluated using multivariable Cox regression analysis. RESULTS In total, 468 patients (239 men; 64 ± 9.5 years) were included. Fibrosis and total ILD extents more increased in patients with larger FVC decline (p < .001 in both). Patients with ILD progression had higher fibrosis and total ILD extent increases than those without ILD progression (p < .001 in both). Increases in fibrosis and total ILD extent were significant prognostic factors when adjusted for absolute FVC declines of ≥ 5% (hazard ratio [HR] 1.844, p = .01 for fibrosis; HR 2.484, p < .001 for total ILD extent) and ≥ 10% (HR 2.918, p < .001 for fibrosis; HR 3.125, p < .001 for total ILD extent). CONCLUSION Changes in ILD CT quantification correlated with changes in FVC and visual assessment of ILD progression, and they were independent prognostic factors in ILD patients. CLINICAL RELEVANCE STATEMENT Quantifying the CT features of interstitial lung disease using deep learning techniques could play a key role in defining and predicting the prognosis of progressive fibrosing interstitial lung disease. KEY POINTS • Radiologic findings on high-resolution CT are important in diagnosing progressive fibrosing interstitial lung disease. • Deep learning-based quantification results for fibrosis and total interstitial lung disease extents correlated with the decline in forced vital capacity and visual assessments of interstitial lung disease progression, and emerged as independent prognostic factors. • Deep learning-based interstitial lung disease CT quantification can play a key role in diagnosing and prognosticating progressive fibrosing interstitial lung disease.
Collapse
Affiliation(s)
- Seok Young Koh
- Department of Radiology, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Jong Hyuk Lee
- Department of Radiology, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Hyungin Park
- Department of Radiology, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Jin Mo Goo
- Department of Radiology, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
- Department of Radiology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
- Institute of Radiation Medicine, Seoul National University Medical Research Center, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
- Cancer Research Institute, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
| |
Collapse
|
35
|
He Y, Han Y, Zou L, Yao T, Zhang Y, Lv X, Jiang M, Long L, Li M, Cheng X, Jiang G, Peng Z, Tao L, Meng J, Xie W. Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis. Sci Rep 2024; 14:14376. [PMID: 38909094 PMCID: PMC11193722 DOI: 10.1038/s41598-024-64844-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/13/2024] [Indexed: 06/24/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.
Collapse
Affiliation(s)
- Yijun He
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Yuanyuan Han
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Lijun Zou
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Tingting Yao
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Yan Zhang
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Xin Lv
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Mao Jiang
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Lingzhi Long
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Mengyu Li
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Xiaoyun Cheng
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Guoliang Jiang
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Zhangzhe Peng
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- National International Collaborative Research Center for Medical Metabolomics, Changsha, China
| | - Lijian Tao
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- National International Collaborative Research Center for Medical Metabolomics, Changsha, China
| | - Jie Meng
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China.
- National International Collaborative Research Center for Medical Metabolomics, Changsha, China.
| | - Wei Xie
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
36
|
Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
Collapse
Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
37
|
Wang Y, Huang R, Lu Y, Liu M, Mo R. Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation. Nat Commun 2024; 15:5176. [PMID: 38890279 PMCID: PMC11189436 DOI: 10.1038/s41467-024-49135-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 05/24/2024] [Indexed: 06/20/2024] Open
Abstract
The longevity of grafts remains a major challenge in allogeneic transplantation due to immune rejection. Systemic immunosuppression can impair graft function and can also cause severe adverse effects. Here, we report a local immuno-protective strategy to enhance post-transplant persistence of allografts using a mesenchymal stem cell membrane-derived vesicle (MMV)-crosslinked hydrogel (MMV-Gel). MMVs are engineered to upregulate expression of Fas ligand (FasL) and programmed death ligand 1 (PD-L1). The MMVs are retained within the hydrogel by crosslinking. The immuno-protective microenvironment of the hydrogel protects allografts by presenting FasL and PD-L1. The binding of these ligands to T effector cells, the dominant contributors to graft destruction and rejection, results in apoptosis of T effector cells and generation of regulatory T cells. We demonstrate that implantation with MMV-Gel prolongs the survival and function of grafts in mouse models of allogeneic pancreatic islet cells and skin transplantation.
Collapse
Affiliation(s)
- Yuqian Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Renqi Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Yougong Lu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Mingqi Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Ran Mo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
| |
Collapse
|
38
|
Ren L, Chang YF, Jiang SH, Li XH, Cheng HP. DNA methylation modification in Idiopathic pulmonary fibrosis. Front Cell Dev Biol 2024; 12:1416325. [PMID: 38915445 PMCID: PMC11194555 DOI: 10.3389/fcell.2024.1416325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/22/2024] [Indexed: 06/26/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease with a prognosis worse than lung cancer. It is a fatal lung disease with largely unknown etiology and pathogenesis, and no effective therapeutic drugs render its treatment largely unsuccessful. With continuous in-depth research efforts, the epigenetic mechanisms in IPF pathogenesis have been further discovered and concerned. As a widely studied mechanism of epigenetic modification, DNA methylation is primarily facilitated by DNA methyltransferases (DNMTs), resulting in the addition of a methyl group to the fifth carbon position of the cytosine base, leading to the formation of 5-methylcytosine (5-mC). Dysregulation of DNA methylation is intricately associated with the advancement of respiratory disorders. Recently, the role of DNA methylation in IPF pathogenesis has also received considerable attention. DNA methylation patterns include methylation modification and demethylation modification and regulate a range of essential biological functions through gene expression regulation. The Ten-Eleven-Translocation (TET) family of DNA dioxygenases is crucial in facilitating active DNA demethylation through the enzymatic conversion of the modified genomic base 5-mC to 5-hydroxymethylcytosine (5-hmC). TET2, a member of TET proteins, is involved in lung inflammation, and its protein expression is downregulated in the lungs and alveolar epithelial type II cells of IPF patients. This review summarizes the current knowledge of pathologic features and DNA methylation mechanisms of pulmonary fibrosis, focusing on the critical roles of abnormal DNA methylation patterns, DNMTs, and TET proteins in impacting IPF pathogenesis. Researching DNA methylation will enchance comprehension of the fundamental mechanisms involved in IPF pathology and provide novel diagnostic biomarkers and therapeutic targets for pulmonary fibrosis based on the studies involving epigenetic mechanisms.
Collapse
Affiliation(s)
- Lu Ren
- Clinical Nursing Teaching and Research Section, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yan-Fen Chang
- Medicine School, Zhengzhou University of Industrial Technology, Zhengzhou, China
| | - Shi-He Jiang
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao-Hong Li
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hai-Peng Cheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
39
|
Ma L, Liu C, Zhao Y, Liu M, Liu Y, Zhang H, Yang S, An J, Tian Y, Cao Y, Qu G, Song S, Cao Q. Anti-pulmonary fibrosis activity analysis of methyl rosmarinate obtained from Salvia castanea Diels f. tomentosa Stib. using a scalable process. Front Pharmacol 2024; 15:1374669. [PMID: 38895626 PMCID: PMC11183283 DOI: 10.3389/fphar.2024.1374669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/15/2024] [Indexed: 06/21/2024] Open
Abstract
Pulmonary fibrosis is a progressive, irreversible, chronic interstitial lung disease associated with high morbidity and mortality rates. Current clinical drugs, while effective, do not reverse or cure pulmonary fibrosis and have major side effects, there are urgent needs to develop new anti-pulmonary fibrosis medicine, and corresponding industrially scalable process as well. Salvia castanea Diels f. tomentosa Stib., a unique herb in Nyingchi, Xizang, China, is a variant of S. castanea. and its main active ingredient is rosmarinic acid (RA), which can be used to prepare methyl rosmarinate (MR) with greater drug potential. This study presented an industrially scalable process for the preparation of MR, which includes steps such as polyamide resin chromatography, crystallization and esterification, using S. castanea Diels f. tomentosa Stib. as the starting material and the structure of the product was verified by NMR technology. The anti-pulmonary fibrosis effects of MR were further investigated in vivo and in vitro. Results showed that this process can easily obtain high-purity RA and MR, and MR attenuated bleomycin-induced pulmonary fibrosis in mice. In vitro, MR could effectively inhibit TGF-β1-induced proliferation and migration of mouse fibroblasts L929 cells, promote cell apoptosis, and decrease extracellular matrix accumulation thereby suppressing progressive pulmonary fibrosis. The anti-fibrosis effect of MR was stronger than that of the prodrug RA. Further study confirmed that MR could retard pulmonary fibrosis by down-regulating the phosphorylation of the TGF-β1/Smad and MAPK signaling pathways. These results suggest that MR has potential therapeutic implications for pulmonary fibrosis, and the establishment of this scalable preparation technology ensures the development of MR as a new anti-pulmonary fibrosis medicine.
Collapse
Affiliation(s)
- Li Ma
- Binzhou Medical University, Shandong, China
| | | | | | - Mengke Liu
- Binzhou Medical University, Shandong, China
| | - Yunyi Liu
- Binzhou Medical University, Shandong, China
| | | | - Shude Yang
- Department of Edible Mushrooms, School of Agriculture, Ludong University, Shandong, China
| | - Jing An
- Division of Infectious Diseases and Global Health, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, United States
| | | | | | - Guiwu Qu
- Binzhou Medical University, Shandong, China
| | - Shuling Song
- Binzhou Medical University, Shandong, China
- Shandong Engineering Research Center for Functional Crop Germplasm Innovation and Cultivation Utilization, Shandong, China
| | - Qizhi Cao
- Binzhou Medical University, Shandong, China
| |
Collapse
|
40
|
Chen X, Lin X, Xu L, Liu Y, Liu X, Zhang C, Xie B. Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice. Open Life Sci 2024; 19:20220860. [PMID: 38840894 PMCID: PMC11151390 DOI: 10.1515/biol-2022-0860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/16/2024] [Accepted: 03/18/2024] [Indexed: 06/07/2024] Open
Abstract
The aim of this study is to observe the changes in autophagy activities in lung tissues of mice with different degrees of pulmonary fibrosis (PF), and explore the association between PF and autophagy activity. The PF model was established by bleomycin (BLM, 25 and 35 mg/kg) atomization inhalation in C57BL/6 mice, samples were collected on the 7, 14, and 28 days after BLM administration. Hematoxylin-eosin staining was used to observe the pathological changes in lung tissues. Masson staining was utilized to assess areas of blue collagen fiber deposition in lung tissues. Quantitative real time polymerase chain reaction was used to detect the mRNA expressions of autophagy-related genes, including Atg5, Atg7, and Atg10 in lung tissues. Western blot was used to detect the protein expressions of autophagy-related genes, including p62 and LC3II/LC3I in lung tissues. Compared with control group, BLM dose-dependently decreased PaO2, mRNA expressions of Atg5, Atg7, Atg10, and LC3II/LC3I, while increased lung wet weight, lung coefficient, PF score, the blue area of collagen fibers, and p62 protein on the 7th, 14th, and 28th days. In conclusion, the more severe the PF induced by BLM, the lower the autophagy activity.
Collapse
Affiliation(s)
- Xiulan Chen
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, China
- Department of Respiratory and Critical Care Medicine, Fujian Provincial Geriatric Hospital, Fuzhou, Fujian 350009, China
| | - Xin Lin
- Department of Respiratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China
| | - Lihuan Xu
- Department of Internal Medicine, Fujian Provincial Hospital, Fuzhou, Fujian 350013, China
| | - Yu Liu
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, China
- Department of Respiratory and Critical Care Medicine, Fujian Provincial Geriatric Hospital, Fuzhou, Fujian 350009, China
| | - Xin Liu
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, China
- Department of Respiratory and Critical Care Medicine, Fujian Provincial Geriatric Hospital, Fuzhou, Fujian 350009, China
| | - Chunhui Zhang
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, China
- Department of Respiratory and Critical Care Medicine, Fujian Provincial Geriatric Hospital, Fuzhou, Fujian 350009, China
| | - Baosong Xie
- Department of Respiratory and Critical Care Medicine, Fujian Provincial Hospital, No. 134 East Street, Fuzhou, Fujian 350013, China
| |
Collapse
|
41
|
Yao F, Xu M, Dong L, Shen X, Shen Y, Jiang Y, Zhu T, Zhang C, Yu G. Sinomenine attenuates pulmonary fibrosis by downregulating TGF-β1/Smad3, PI3K/Akt and NF-κB signaling pathways. BMC Pulm Med 2024; 24:229. [PMID: 38730387 PMCID: PMC11088103 DOI: 10.1186/s12890-024-03050-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 05/07/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Since COVID-19 became a global epidemic disease in 2019, pulmonary fibrosis (PF) has become more prevalent among persons with severe infections, with IPF being the most prevalent form. In traditional Chinese medicine, various disorders are treated using Sinomenine (SIN). The SIN's strategy for PF defense is unclear. METHODS Bleomycin (BLM) was used to induce PF, after which inflammatory factors, lung histological alterations, and the TGF-/Smad signaling pathway were assessed. By administering various dosages of SIN and the TGF- receptor inhibitor SB-431,542 to human embryonic lung fibroblasts (HFL-1) and A549 cells, we were able to examine proliferation and migration as well as the signaling molecules implicated in Epithelial-Mesenchymal Transition (EMT) and Extra-Cellular Matrix (ECM). RESULTS In vivo, SIN reduced the pathological changes in the lung tissue induced by BLM, reduced the abnormal expression of inflammatory cytokines, and improved the weight and survival rate of mice. In vitro, SIN inhibited the migration and proliferation by inhibiting TGF-β1/Smad3, PI3K/Akt, and NF-κB pathways, prevented the myofibroblasts (FMT) of HFL-1, reversed the EMT of A549 cells, restored the balance of matrix metalloenzymes, and reduced the expression of ECM proteins. CONCLUSION SIN attenuated PF by down-regulating TGF-β/Smad3, PI3K/Akt, and NF-κB signaling pathways, being a potential effective drug in the treatment of PF.
Collapse
Affiliation(s)
- Fuqiang Yao
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Minghao Xu
- School of Medicine, ShaoXing University, Shaoxing, Zhejiang, China
| | - Lingjun Dong
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Xiao Shen
- School of Medicine, ShaoXing University, Shaoxing, Zhejiang, China
| | - Yujie Shen
- School of Medicine, ShaoXing University, Shaoxing, Zhejiang, China
| | - Yisheng Jiang
- School of Medicine, ShaoXing University, Shaoxing, Zhejiang, China
| | - Ting Zhu
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Chu Zhang
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Guangmao Yu
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
| |
Collapse
|
42
|
Bando M, Homma S, Date H, Kishi K, Yamauchi H, Sakamoto S, Miyamoto A, Goto Y, Nakayama T, Azuma A, Kondoh Y, Johkoh T, Nishioka Y, Fukuoka J, Miyazaki Y, Yoshino I, Suda T. Japanese guidelines for the treatment of idiopathic pulmonary fibrosis 2023:Revised edition. Respir Investig 2024; 62:402-418. [PMID: 38484504 DOI: 10.1016/j.resinv.2024.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/08/2024] [Accepted: 02/22/2024] [Indexed: 04/20/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an unknown cause that generally progresses to pulmonary fibrosis and leads to irreversible tissue alteration. The "Guidelines for the treatment of idiopathic pulmonary fibrosis 2017," specializing in the treatment of IPF for the first time in Japan and presenting evidence-based standard treatment methods suited to the state of affairs in Japan, was published in 2017, in line with the 2014 version of "Formulation procedure for Minds Clinical Practice Guidelines." Because new evidence had accumulated, we formulated the "Guidelines for the treatment of Idiopathic Pulmonary Fibrosis 2023 (revised 2nd edition)." While keeping the revision consistent with the ATS/ERS/JRS/ALAT IPF treatment guidelines, new clinical questions (CQs) on pulmonary hypertension were added to the chronic stage, in addition to acute exacerbation and comorbid lung cancer, which greatly affect the prognosis but are not described in the ATS/ERS/JRS/ALAT IPF guidelines. Regarding the advanced stages, we additionally created expert consensus-based advice for palliative care and lung transplantation. The number of CQs increased from 17 in the first edition to 24. It is important that these guidelines be used not only by respiratory specialists but also by general practitioners, patients, and their families; therefore, we plan to revise them appropriately in line with ever-advancing medical progress.
Collapse
Affiliation(s)
- Masashi Bando
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
| | - Sakae Homma
- Department of Respiratory Medicine, Toho University Omori Medical Center, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Kazuma Kishi
- Department of Respiratory Medicine, Toho University Omori Medical Center, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Hiroyoshi Yamauchi
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Susumu Sakamoto
- Department of Respiratory Medicine, Toho University Omori Medical Center, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Atsushi Miyamoto
- Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yoshihito Goto
- Clinical Research Center, National Hospital Organization Kyoto Medical Center, 1-1, Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto, Kyoto, 612-8555, Japan
| | - Takeo Nakayama
- Department of Health Informatics, Graduate School of Medicine and School of Public Health, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, Kyoto, 606-8501, Japan
| | - Arata Azuma
- Pulmonary Medicine, Tokorozawa Mihara General Hospital, 2-2934-3 Mihara-cho, Tokorozawa-shi, Saitama, 359-0045, Japan; Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Yasuhiro Kondoh
- Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwake-cho, Seto, Aichi, 489-8642, Japan
| | - Takeshi Johkoh
- Department of Radiology, Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki, Hyogo, 660-8511, Japan
| | - Yasuhiko Nishioka
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Junya Fukuoka
- Department of Pathology Informatics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yasunari Miyazaki
- Department of Respiratory Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Ichiro Yoshino
- Department of Thoracic Surgery, International University of Health and Welfare Narita Hospital, 852 Hatakeda, Narita City, Chiba, 286-8520, Japan; Department of General Thoracic Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatus, 431-3192, Japan
| |
Collapse
|
43
|
Zhu Y, Meng X, Zhu X, Zhang J, Lv H, Wang F, Wang J, Chen C, Chen M, Wang D, Jin W, Tian R, Wang R. Circular RNA MKLN1 promotes epithelial-mesenchymal transition in pulmonary fibrosis by regulating the miR-26a/b-5p/CDK8 axis in human alveolar epithelial cells and mice models. Arch Toxicol 2024; 98:1399-1413. [PMID: 38460002 PMCID: PMC10965569 DOI: 10.1007/s00204-024-03700-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/31/2024] [Indexed: 03/11/2024]
Abstract
Pulmonary fibrosis involves destruction of the lung parenchyma and extracellular matrix deposition. Effective treatments for pulmonary fibrosis are lacking and its pathogenesis is still unclear. Studies have found that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) plays an important role in progression of pulmonary fibrosis. Thus, an in-depth exploration of its mechanism might identify new therapeutic targets. In this study, we revealed that a novel circular RNA, MKLN1 (circMKLN1), was significantly elevated in two pulmonary fibrosis models (intraperitoneally with PQ, 50 mg/kg for 7 days, and intratracheally with BLM, 5 mg/kg for 28 days). Additionally, circMKLN1 was positively correlated with the severity of pulmonary fibrosis. Inhibition of circMKLN1 expression significantly reduced collagen deposition and inhibited EMT in AECs. EMT was aggravated after circMKLN1 overexpression in AECs. MiR-26a-5p/miR-26b-5p (miR-26a/b), the targets of circMKLN1, were confirmed by luciferase reporter assays. CircMKLN1 inhibition elevated miR-26a/b expression. Significantly decreased expression of CDK8 (one of the miR-26a/b targets) was observed after inhibition of circMKLN1. EMT was exacerbated again, and CDK8 expression was significantly increased after circMKLN1 inhibition and cotransfection of miR-26a/b inhibitors in AECs. Our research indicated that circMKLN1 promoted CDK8 expression through sponge adsorption of miR-26a/b, which regulates EMT and pulmonary fibrosis. This study provides a theoretical basis for finding new targets or biomarkers in pulmonary fibrosis.
Collapse
Affiliation(s)
- Yong Zhu
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Xiaoxiao Meng
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Xian Zhu
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Jiaxiang Zhang
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Hui Lv
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Feiyao Wang
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Jinfeng Wang
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Cheng Chen
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Mengting Chen
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China
| | - Dapeng Wang
- Department of Intensive Care Medicine, Wuxi People's Hospital, Nanjing Medical University, Wuxi, 214021, Jiangsu, China
| | - Wei Jin
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China.
| | - Rui Tian
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China.
| | - Ruilan Wang
- Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China.
| |
Collapse
|
44
|
Qian W, Yang L, Li T, Li W, Zhou J, Xie S. RNA modifications in pulmonary diseases. MedComm (Beijing) 2024; 5:e546. [PMID: 38706740 PMCID: PMC11068158 DOI: 10.1002/mco2.546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 02/26/2024] [Accepted: 03/14/2024] [Indexed: 05/07/2024] Open
Abstract
Threatening public health, pulmonary disease (PD) encompasses diverse lung injuries like chronic obstructive PD, pulmonary fibrosis, asthma, pulmonary infections due to pathogen invasion, and fatal lung cancer. The crucial involvement of RNA epigenetic modifications in PD pathogenesis is underscored by robust evidence. These modifications not only shape cell fates but also finely modulate the expression of genes linked to disease progression, suggesting their utility as biomarkers and targets for therapeutic strategies. The critical RNA modifications implicated in PDs are summarized in this review, including N6-methylation of adenosine, N1-methylation of adenosine, 5-methylcytosine, pseudouridine (5-ribosyl uracil), 7-methylguanosine, and adenosine to inosine editing, along with relevant regulatory mechanisms. By shedding light on the pathology of PDs, these summaries could spur the identification of new biomarkers and therapeutic strategies, ultimately paving the way for early PD diagnosis and treatment innovation.
Collapse
Affiliation(s)
- Weiwei Qian
- Emergency Department of Emergency MedicineLaboratory of Emergency Medicine, West China Hospital, And Disaster Medical, Sichuan UniversityChengduSichuanChina
- Emergency DepartmentShangjinnanfu Hospital, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Lvying Yang
- The Department of Respiratory and Critical Care MedicineThe First Veterans Hospital of Sichuan ProvinceChengduSichuanChina
| | - Tianlong Li
- Department of Critical Care Medicine Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina
| | - Wanlin Li
- National Clinical Research Center for Infectious Disease, Shenzhen Third People's HospitalShenzhenGuangdongChina
| | - Jian Zhou
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National‐Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical SchoolShenzhenChina
- Department of ImmunologyInternational Cancer Center, Shenzhen University Health Science CenterShenzhenGuangdongChina
| | - Shenglong Xie
- Department of Thoracic SurgerySichuan Provincial People's Hospital, University of Electronic Science and Technology of ChinaChengduSichuanChina
| |
Collapse
|
45
|
Patel M, Post Y, Hill N, Sura A, Ye J, Fisher T, Suen N, Zhang M, Cheng L, Pribluda A, Chen H, Yeh WC, Li Y, Baribault H, Fletcher RB. A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model. Respir Res 2024; 25:153. [PMID: 38566174 PMCID: PMC10985870 DOI: 10.1186/s12931-024-02786-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/23/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Wnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies. METHODS Using our antibody-based platform of Wnt/β-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures. RESULTS A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo. CONCLUSIONS Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/β-catenin pathway modulation for the treatment of pulmonary fibrosis.
Collapse
Affiliation(s)
- Mehaben Patel
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Yorick Post
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Natalie Hill
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Asmiti Sura
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Jay Ye
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Trevor Fisher
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Nicholas Suen
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Mengrui Zhang
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Leona Cheng
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Ariel Pribluda
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Hui Chen
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Wen-Chen Yeh
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Yang Li
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Hélène Baribault
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA
| | - Russell B Fletcher
- Surrozen, Inc., 171 Oyster Point Blvd, Suite 400, South San Francisco, CA, 94080, USA.
| |
Collapse
|
46
|
Vajter J, Holubova G, Novysedlak R, Svorcova M, Vachtenheim J, Vymazal T, Lischke R. Anaesthesiologic Considerations for Intraoperative ECMO Anticoagulation During Lung Transplantation: A Single-Centre, Retrospective, Observational Study. Transpl Int 2024; 37:12752. [PMID: 38585623 PMCID: PMC10996050 DOI: 10.3389/ti.2024.12752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 03/06/2024] [Indexed: 04/09/2024]
Abstract
Background: Extracorporeal membrane oxygenation (ECMO) is frequently used during lung transplantation. Unfractionated heparin (UFH) is mainly used as part of ECMO support for anticoagulation. One of the most common perioperative complications is bleeding, which high-dose UFH can aggravate. Methods: We retrospectively analyzed (n = 141) patients who underwent lung transplantation between 2020 and 2022. All subjects (n = 109) underwent central cannulated VA ECMO with successful intraoperative ECMO weaning. Patients on ECMO bridge, postoperative ECMO, heart-lung transplants and transplants without ECMO were excluded. The dose of UFH for the entire surgical procedure, blood loss and consumption of blood derivatives intraoperatively and 48 h after ICU admission were recorded. Surgical revision for postoperative bleeding were analyzed. Thrombotic complications, mortality and long-term survival were evaluated. Results: Lower doses of UFH administered for intraoperative ECMO anticoagulation contribute to a reduction in intraoperative blood derivates consumption and blood loss with no thrombotic complications related to the patient or the ECMO circuit. Lower doses of UFH may lead to a decreased incidence of surgical revision for hemothorax. Conclusion: Lower doses of UFH as part of intraoperative ECMO anticoagulation might reduce the incidence of complications and lead to better postoperative outcomes.
Collapse
Affiliation(s)
- Jaromir Vajter
- Department of Anaesthesiology, Resuscitation, and Intensive Care Medicine, Second Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| | - Gabriela Holubova
- Department of Anaesthesiology, Resuscitation, and Intensive Care Medicine, Second Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| | - Rene Novysedlak
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| | - Monika Svorcova
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| | - Jiri Vachtenheim
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| | - Tomas Vymazal
- Department of Anaesthesiology, Resuscitation, and Intensive Care Medicine, Second Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| | - Robert Lischke
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University, University Hospital in Motol, Prague, Czechia
| |
Collapse
|
47
|
Li C, Feng X, Li S, He X, Luo Z, Cheng X, Yao J, Xiao J, Wang X, Wen D, Liu D, Li Y, Zhou H, Ma L, Lin T, Cai X, Lin Y, Guo L, Yang M. Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model. Mol Ther 2024; 32:766-782. [PMID: 38273656 PMCID: PMC10928155 DOI: 10.1016/j.ymthe.2024.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/05/2023] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.
Collapse
Affiliation(s)
- Chen Li
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Xiaorong Feng
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Songhang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xing He
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China
| | - Zeli Luo
- Department of Pulmonary and Critical Care Medicine, Wenjiang Hospital of Sichuan Provincial People's, Chengdu 611138, China
| | - Xia Cheng
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Jie Yao
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Jie Xiao
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Xiaofei Wang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dingke Wen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Duanya Liu
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Yanfei Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Hong Zhou
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610056, China
| | - Lu Ma
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tongyu Lin
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; College of Biomedical Engineering, Sichuan University, Chengdu 610041, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; College of Biomedical Engineering, Sichuan University, Chengdu 610041, China.
| | - Lu Guo
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
| | - Mu Yang
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China.
| |
Collapse
|
48
|
Liu YM, Zhang J, Wu JJ, Guo WW, Tang FS. Strengthening pharmacotherapy research for COVID-19-induced pulmonary fibrosis. World J Clin Cases 2024; 12:875-879. [PMID: 38414600 PMCID: PMC10895630 DOI: 10.12998/wjcc.v12.i5.875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/26/2023] [Accepted: 01/15/2024] [Indexed: 01/31/2024] Open
Abstract
The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis (PF), an irreversible lung injury. This condition can manifest within a short interval following the onset of pneumonia symptoms, sometimes even within a few days. While lung transplantation is a potentially lifesaving procedure, its limited availability, high costs, intricate surgeries, and risk of immunological rejection present significant drawbacks. The optimal timing of medication administration for coronavirus disease 2019 (COVID-19)-induced PF remains controversial. Despite this, it is crucial to explore pharmacotherapy interventions, involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF. Additionally, studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors. Genetic mutations may also impact therapeutic efficacy. Enhancing research efforts on pharmacotherapy interventions, while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration, will lead to enhanced, personalized, and fair treatment for individuals impacted by COVID-19-related PF. These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients' quality of life.
Collapse
Affiliation(s)
- Yan-Miao Liu
- The First Clinical Institute, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Jing Zhang
- Department of Respiratory Medicine, Central Hospital in Jinchang City, Jinchang 737102, Gansu Province, China
| | - Jing-Jing Wu
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Wei-Wei Guo
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Fu-Shan Tang
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| |
Collapse
|
49
|
Wu X, Xiao X, Fang H, He C, Wang H, Wang M, Lan P, Wang F, Du Q, Yang H. Elucidating shared biomarkers in gastroesophageal reflux disease and idiopathic pulmonary fibrosis: insights into novel therapeutic targets and the role of angelicae sinensis radix. Front Pharmacol 2024; 15:1348708. [PMID: 38414734 PMCID: PMC10897002 DOI: 10.3389/fphar.2024.1348708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 01/31/2024] [Indexed: 02/29/2024] Open
Abstract
Background: The etiological underpinnings of gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remain elusive, coupled with a scarcity of effective therapeutic interventions for IPF. Angelicae sinensis radix (ASR, also named Danggui) is a Chinese herb with potential anti-fibrotic properties, that holds promise as a therapeutic agent for IPF. Objective: This study seeks to elucidate the causal interplay and potential mechanisms underlying the coexistence of GERD and IPF. Furthermore, it aims to investigate the regulatory effect of ASR on this complex relationship. Methods: A two-sample Mendelian randomization (TSMR) approach was employed to delineate the causal connection between gastroesophageal reflux disease and IPF, with Phennoscanner V2 employed to mitigate confounding factors. Utilizing single nucleotide polymorphism (SNPs) and publicly available microarray data, we analyzed potential targets and mechanisms related to IPF in GERD. Network pharmacology and molecular docking were employed to explore the targets and efficacy of ASR in treating GERD-related IPF. External datasets were subsequently utilized to identify potential diagnostic biomarkers for GERD-related IPF. Results: The IVW analysis demonstrated a positive causal relationship between GERD and IPF (IVW: OR = 1.002, 95%CI: 1.001, 1.003; p < 0.001). Twenty-five shared differentially expressed genes (DEGs) were identified. GO functional analysis revealed enrichment in neural, cellular, and brain development processes, concentrated in chromosomes and plasma membranes, with protein binding and activation involvement. KEGG analysis unveiled enrichment in proteoglycan, ERBB, and neuroactive ligand-receptor interaction pathways in cancer. Protein-protein interaction (PPI) analysis identified seven hub genes. Network pharmacology analysis demonstrated that 104 components of ASR targeted five hub genes (PDE4B, DRD2, ERBB4, ESR1, GRM8), with molecular docking confirming their excellent binding efficiency. GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF (ESR1: AUCGERD = 0.762, AUCIPF = 0.725; GRM8: AUCGERD = 0.717, AUCIPF = 0.908). GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF, validated in external datasets. Conclusion: This study establishes a causal link between GERD and IPF, identifying five key targets and two potential diagnostic biomarkers for GERD-related IPF. ASR exhibits intervention efficacy and favorable binding characteristics, positioning it as a promising candidate for treating GERD-related IPF. The potential regulatory mechanisms may involve cell responses to fibroblast growth factor stimulation and steroidal hormone-mediated signaling pathways.
Collapse
Affiliation(s)
- Xuanyu Wu
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiang Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hanyu Fang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Cuifang He
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hanyue Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Miao Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peishu Lan
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fei Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Quanyu Du
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Han Yang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
50
|
Ikrama M, Usama M, Israr S, Humayon M. Pulmonary fibrosis: Is stem cell therapy the way forward? J Taibah Univ Med Sci 2024; 19:82-89. [PMID: 37876594 PMCID: PMC10590845 DOI: 10.1016/j.jtumed.2023.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/15/2023] [Accepted: 09/30/2023] [Indexed: 10/26/2023] Open
Abstract
Pulmonary fibrosis, a chronic and fatal lung disease affecting millions of people worldwide, is characterized by the scarring of lung tissue, thereby impairing oxygen exchange between the lungs and blood. The etiology of pulmonary fibrosis is multifactorial, involving environmental exposures, comorbidities, and genetic mutations. Current pharmacological treatments can only slow the disease progression, and lung transplantation is limited by donor availability and complications. Stem cell therapy has emerged as a potential alternative treatment for pulmonary fibrosis, in which stem cells modulate the inflammatory response, differentiate into lung epithelial cells, secrete growth factors and extracellular matrix components, and enhance vascularization and tissue regeneration. Various sources of stem cells, such as endogenous lung stem cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells, have been investigated in animal models and human trials. Various delivery routes, such as intravenous injection, intratracheal instillation, and inhalation, have been tested for safety and efficacy. However, several challenges and limitations remain to be overcome, such as high costs, ethical issues, immunological compatibility, cell survival and homing, and long-term outcomes. Further research is needed to optimize the protocols and parameters in stem cell therapy for pulmonary fibrosis, and to evaluate the clinical benefits and risks for patients.
Collapse
Affiliation(s)
- Muhammad Ikrama
- Services Institute of Medical Sciences, Department of Medicine, Lahore, Pakistan
| | - Muhammad Usama
- Services Institute of Medical Sciences, Department of Medicine, Lahore, Pakistan
| | - Shifa Israr
- Services Institute of Medical Sciences, Department of Medicine, Lahore, Pakistan
| | - Maryam Humayon
- Services Institute of Medical Sciences, Department of Medicine, Lahore, Pakistan
| |
Collapse
|