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Humphries SM, Adegunsoye A, Demoruelle MK, Wei Kam ML, Amigues I, Bang TJ, Teague SD, Lynch DA, Chung JH, Strek ME, Swigris JJ, Solomon JJ. Quantitative CT Scan Analysis in Rheumatoid Arthritis-Related Interstitial Lung Disease. Chest 2025; 167:1428-1439. [PMID: 39528110 DOI: 10.1016/j.chest.2024.10.052] [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: 01/25/2023] [Revised: 09/18/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Quantitative CT imaging may be a useful predictor of outcome in rheumatoid arthritis-related interstitial lung disease (RA-ILD). RESEARCH QUESTION What is the utility of deep learning-based lung fibrosis quantitation on CT imaging in assessing disease severity, predicting mortality, and identifying progression in RA-ILD? STUDY DESIGN AND METHODS CT scans on a primary cohort of 289 patients and a validation cohort of 50 individuals with RA-ILD were assessed quantitatively by using the data-driven texture analysis (DTA) method. We examined associations between quantitative scores for extent of lung fibrosis and pulmonary function and survival. RESULTS DTA fibrosis score at baseline showed moderate negative correlation with FVC percent predicted (primary cohort rho = -0.55; validation cohort rho = -0.50; both, P < .001), and diffusing capacity for carbon monoxide percent predicted (primary cohort rho = -0.67; validation cohort rho = -0.65; both, P < .001). Longitudinal change in DTA fibrosis score was associated with changes in FVC and diffusing capacity for carbon monoxide in the primary cohort (rho = -0.46 and rho = -0.43, respectively; both, P < .001). Cox multivariable models adjusted for potentially influential variables showed that the baseline DTA fibrosis score was significantly associated with mortality risk (primary cohort hazard ratio [HR], 1.04 [95% CI, 1.03-1.05; P < .001]; validation cohort HR, 1.06 [95% CI, 1.01-1.11; P = .026]). In the primary cohort, the increase in DTA fibrosis score on sequential scans was associated with increased risk of mortality (HR, 1.04; 95% CI, 1.01-1.06; P = .003) independent of baseline DTA extent. INTERPRETATION In 2 cohorts of patients with RA-ILD, quantitative assessment of lung fibrosis on CT imaging was associated with worse lung function at baseline and risk of mortality. Increase in DTA-derived lung fibrosis score on sequential scans was associated with subsequent risk of mortality. Quantitative CT imaging should be considered for use as a clinical and research outcome assessment tool in RA-ILD.
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Affiliation(s)
| | | | | | - Michelle Li Wei Kam
- Center for Interstitial Lung Disease, National Jewish Health, Denver, CO; Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore
| | | | - Tami J Bang
- Department of Radiology, National Jewish Health, Denver, CO
| | - Shawn D Teague
- Department of Radiology, National Jewish Health, Denver, CO
| | - David A Lynch
- Department of Radiology, National Jewish Health, Denver, CO
| | | | | | - Jeffrey J Swigris
- Center for Interstitial Lung Disease, National Jewish Health, Denver, CO
| | - Joshua J Solomon
- Center for Interstitial Lung Disease, National Jewish Health, Denver, CO.
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Jo YS, Song JW. Air Pollution and Interstitial Lung Disease. Tuberc Respir Dis (Seoul) 2025; 88:45-55. [PMID: 39542009 PMCID: PMC11704737 DOI: 10.4046/trd.2024.0116] [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: 08/03/2024] [Revised: 10/11/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024] Open
Abstract
This review article explores the multifaceted relationship between air pollution and interstitial lung diseases (ILDs), particularly focusing on idiopathic pulmonary fibrosis, the most severe form of fibrotic ILD. Air pollutants are mainly composed of particulate matter, ozone (O3), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2). They are recognized as risk factors for several respiratory diseases. However, their specific effects on ILDs and related mechanisms have not been thoroughly studied yet. Emerging evidence suggests that air pollutants may contribute to the development and acute exacerbation of ILDs. Longitudinal studies have indicated that air pollution can adversely affect the prognosis of disease by decreasing lung function and increasing mortality. Lots of in vitro, in vivo , and epidemiologic studies have proposed possible mechanisms linking ILDs to air pollution, including inflammation and oxidative stress induced by exposure to air pollutants, which may induce mitochondrial dysfunction, promote cellular senescence, and disrupt normal epithelial repair processes. Despite these findings, effective interventions to mitigate effects of air pollution on ILD are not well established yet. This review emphasizes the urgent need to address air pollution as a key environmental risk factor for ILDs and calls for further studies to clarify its effects and develop preventive and therapeutic strategies.
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Affiliation(s)
- Yong Suk Jo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Woo Song
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Zhao J, Yu W, Zhou D, Liu Y, Wei J, Bi L, Zhao S, He J, Liu J, Su J, Jin H, Liu Y, Shan H, Li M, Zhang Y, Li Y. Delineating, Imaging, and Assessing Pulmonary Fibrosis Remodeling via Collagen Hybridization. ACS NANO 2024; 18:27997-28011. [PMID: 39361472 DOI: 10.1021/acsnano.4c06139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening disease with no early detection, few treatments, and dismal outcomes. Although collagen overdeposition is a hallmark of lung fibrosis, current research mostly focuses on the cellular aspect, leaving collagen, particularly its dynamic remodeling (i.e., degradation and turnover), largely unexplored. Here, using a collagen hybridizing peptide (CHP) that specifically binds unfolded collagen chains, we reveal vast collagen denaturation in human IPF lungs and delineate the spatiotemporal progression of collagen denaturation three-dimensionally within fibrotic lungs in mice. Transcriptomic analyses support that lung collagen denaturation is strongly associated with up-regulated collagen catabolism in mice and patients. We thus show that CHP probing differentiates remodeling responses to antifibrotics and highlights the resolution of established fibrosis by agents up-regulating collagen catabolism. We further develop a radioactive CHP that detects fibrosis in vivo in mice as early as 7 days postlung-injury (Ashcroft score: 2-3) by positron emission tomography (PET) imaging and ex vivo in clinical lung specimens. These findings establish collagen denaturation as a promising marker of fibrotic remodeling for the investigation, diagnosis, and therapeutic development of pulmonary fibrosis.
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Affiliation(s)
- Jie Zhao
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Wenjun Yu
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Department of Radiology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Daoning Zhou
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Yinghua Liu
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Jingyue Wei
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Biobank and Department of Information Technology and Data Center, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Lei Bi
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Suwen Zhao
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Jianzhong He
- Department of Pathology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Jing Liu
- Department of Pulmonary and Critical Care Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Jin Su
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China
| | - Hongjun Jin
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Ye Liu
- Department of Pathology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Hong Shan
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Department of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Man Li
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Biobank and Department of Information Technology and Data Center, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Yaqin Zhang
- Department of Radiology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Yang Li
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
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Aribindi K, Liu GY, Albertson TE. Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF). Expert Rev Clin Pharmacol 2024; 17:817-835. [PMID: 39192604 PMCID: PMC11441789 DOI: 10.1080/17512433.2024.2396121] [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: 05/29/2024] [Accepted: 08/20/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function. AREAS COVERED Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents. EXPERT OPINION New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.
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Affiliation(s)
- Katyayini Aribindi
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
- Department of Medicine, Department of Veterans Affairs Northern California Health Care System, Mather, CA, USA
| | - Gabrielle Y Liu
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
| | - Timothy E Albertson
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
- Department of Medicine, Department of Veterans Affairs Northern California Health Care System, Mather, CA, USA
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Figueiredo RG, Duarte NFV, Campos DCB, de Jesus Diaz Verduzco M, Márquez ÁA, de Araujo GTB, Rubin AS. Improving Accessibility to Patients with Interstitial Lung Disease (ILD): Barriers to Early Diagnosis and Timely Treatment in Latin America. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2024; 21:647. [PMID: 38791861 PMCID: PMC11121643 DOI: 10.3390/ijerph21050647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024]
Abstract
Delayed initiation of effective antifibrotic therapy in patients with interstitial lung diseases (ILD) may influence the progression and outcome of the disease. This study analyzes the differences in the journey of patients with ILD in the Brazilian and Mexican health systems. An evaluative study was conducted in reference centers for interstitial lung diseases in Brazil and Mexico with a panel of four specialists. The patient's journey in both countries begins when the patient seeks medical care after observing a chronic respiratory symptom. In both countries, due to diagnostic complexity, these patients arrive at ILD referral centers at an advanced stage of the disease. Once diagnosis is established, the treatment onset differs between Mexico and Brazil. In Brazil, access to antifibrotic drugs through the public health system has been a significant challenge, and their cost makes them unaffordable for most people. This situation forces medical specialists to provide only supportive care to patients until these drugs can be accessed. In Mexico, antifibrotics have been available in health sectors since 2018. Brazil and Mexico have several similarities regarding the initial journey of the patient due to diagnosis difficulties. Still, the outcome tends to be different due to a difference in access to treatment with antifibrotics. For this reason, advancing health policies that ensure proper treatment for patients with ILD is crucial for the sustainability and reliability of the health system.
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Affiliation(s)
- Ricardo G. Figueiredo
- Programa de Pós-Graduação em Saúde Coletiva, Universidade Estadual de Feira de Santana (UEFS), Feira de Santana 44036-900, Brazil
| | | | | | - Manuel de Jesus Diaz Verduzco
- Hospital Regional “Dr. Manuel Cardenas de la Vega”, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Culiacán Rosales 80230, Mexico;
| | - Ángel Alemán Márquez
- Hospital Naval de Especialidades de Veracruz, Hospital Español Veracruz, Universidad del Valle de México (UVM), UNAM Campus Veracruz, Veracruz 91700, Mexico;
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Yuan Z, Lei W, Xing X, He X, Huang X, Wei L, Lv Y, Qiu S, Yuan Z, Wang J, Yang M. Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients. BMC Pulm Med 2024; 24:163. [PMID: 38570751 PMCID: PMC10993445 DOI: 10.1186/s12890-024-02974-2] [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: 12/16/2023] [Accepted: 03/19/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.
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Affiliation(s)
- Ziheng Yuan
- Department of Clinical Laboratory, Yunnan Molecular Diagnostic Center, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wanyang Lei
- Department of Clinical Laboratory, Yunnan Molecular Diagnostic Center, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xiqian Xing
- Department of Respiratory and Critical Care, Affiliated Hospital of Yunnan University, Kunming, China
| | - Xiaohua He
- Department of Respiratory and Critical Care, Affiliated Hospital of Yunnan University, Kunming, China
| | - Xiaoxian Huang
- Department of Respiratory and Critical Care, Affiliated Hospital of Yunnan University, Kunming, China
| | - Li Wei
- Department of Respiratory and Critical Care, Affiliated Hospital of Yunnan University, Kunming, China
| | - Yuanyuan Lv
- Department of Respiratory and Critical Care, Affiliated Hospital of Yunnan University, Kunming, China
| | - Shuyi Qiu
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ziyu Yuan
- Department of Clinical Laboratory Medicine, Yunnan Cancer Hospital, Yunnan Cancer Center, The Third Affiliated Hospital of Kunming Medical University, 650118, Kunming, China
| | - Jiyang Wang
- Department of Cardiovascular Surgery, Affiliated Hospital of Yunnan University, Kunming, China.
| | - Mei Yang
- Department of Respiratory and Critical Care, Affiliated Hospital of Yunnan University, Kunming, China.
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Liu B, Zhang X, Liu Z, Pan H, Yang H, Wu Q, Lv Y, Shen T. A novel model for predicting prognosis in patients with idiopathic pulmonary fibrosis based on endoplasmic reticulum stress-related genes. Cell Biol Int 2024; 48:483-495. [PMID: 38238919 DOI: 10.1002/cbin.12121] [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: 06/09/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 03/13/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of unknown pathogenic origin. Endoplasmic reticulum (ER) stress refers to the process by which cells take measures to ER function when the morphology and function of the reticulum are changed. Recent studies have demonstrated that the ER was involved in the evolution and progression of IPF. In this study, we obtained transcriptome data and relevant clinical information from the Gene Expression Omnibus database and conducted bioinformatics analysis. Among the 544 ER stress-related genes (ERSRGs), 78 were identified as differentially expressed genes (DEGs). These DEGs were primarily enriched in response to ER stress, protein binding, and protein processing. Two genes (HTRA2 and KTN1) were included for constructing an accurate molecular signature. The overall survival of patients was remarkably worse in the high-risk group than in the low-risk group. We further analyzed the difference in immune cells between high-risk and low-risk groups. M0 and M2 macrophages were significantly increased in the high-risk group. Our results suggested that ERSRGs might play a critical role in the development of IPF by regulating the immune microenvironment in the lungs, which provide new insights on predicting the prognosis of patients with IPF.
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Affiliation(s)
- Bin Liu
- Department of Medical Aspects of Specifc Environments, School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Xiang Zhang
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Zikai Liu
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Haihong Pan
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Hongxu Yang
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Qing Wu
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Yan Lv
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Tong Shen
- Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, China
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Sofia C, Comes A, Sgalla G, Richeldi L. Promising advances in treatments for the management of idiopathic pulmonary fibrosis. Expert Opin Pharmacother 2024; 25:717-725. [PMID: 38832823 DOI: 10.1080/14656566.2024.2354460] [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: 02/27/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
INTRODUCTION Following the INPULSIS and ASCEND studies, leading to the first two approved antifibrotic therapies for patients with IPF, ongoing investigations are firmly exploring novel agents for a targeted effective and better tolerated therapy able to improve the natural history of the disease. AREAS COVERED This review aims to analyze recent advances in pharmacological research of IPF, discussing the currently available treatments and the novel drugs under investigation in phase 3 trials, with particular emphasis on BI 1015550 and inhaled treprostinil. The literature search utilized Medline and Clinicaltrials.org databases. Critical aspects of clinical trial design in IPF are discussed in light of recently completed phase III studies. EXPERT OPINION While randomized clinical trials in IPF are currently underway, future objectives should explore potential synergistic benefits when combining novel molecules with the existing therapies and identify more specific molecular targets. Moreover, refining the study design represent another crucial goal. The aim of the pharmacological research will be not only stabilizing but also potentially reversing the fibrotic changes in IPF.
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Affiliation(s)
- Carmelo Sofia
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessia Comes
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Richeldi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Xu F, Tong Y, Yang W, Cai Y, Yu M, Liu L, Meng Q. Identifying a survival-associated cell type based on multi-level transcriptome analysis in idiopathic pulmonary fibrosis. Respir Res 2024; 25:126. [PMID: 38491375 PMCID: PMC10941445 DOI: 10.1186/s12931-024-02738-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/19/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a five-year survival rate of less than 40%. There is significant variability in survival time among IPF patients, but the underlying mechanisms for this are not clear yet. METHODS AND RESULTS We collected single-cell RNA sequence data of 13,223 epithelial cells taken from 32 IPF patients and bulk RNA sequence data from 456 IPF patients in GEO. Based on unsupervised clustering analysis at the single-cell level and deconvolution algorithm at bulk RNA sequence data, we discovered a special alveolar type 2 cell subtype characterized by high expression of CCL20 (referred to as ATII-CCL20), and found that IPF patients with a higher proportion of ATII-CCL20 had worse prognoses. Furthermore, we uncovered the upregulation of immune cell infiltration and metabolic functions in IPF patients with a higher proportion of ATII-CCL20. Finally, the comprehensive decision tree and nomogram were constructed to optimize the risk stratification of IPF patients and provide a reference for accurate prognosis evaluation. CONCLUSIONS Our study by integrating single-cell and bulk RNA sequence data from IPF patients identified a special subtype of ATII cells, ATII-CCL20, which was found to be a risk cell subtype associated with poor prognosis in IPF patients. More importantly, the ATII-CCL20 cell subtype was linked with metabolic functions and immune infiltration.
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Affiliation(s)
- Fei Xu
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yun Tong
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Wenjun Yang
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yiyang Cai
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Meini Yu
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Lei Liu
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
| | - Qingkang Meng
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
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Boente RD, Schacht S, Borton R, Vincent J, Golzarri-Arroyo L, Rattray N. Assessing the acceptability and feasibility of remote spirometric monitoring for rural patients with interstitial lung disease: a multimethod approach. Respir Res 2024; 25:92. [PMID: 38378645 PMCID: PMC10877761 DOI: 10.1186/s12931-024-02735-z] [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: 01/11/2024] [Accepted: 02/14/2024] [Indexed: 02/22/2024] Open
Abstract
INTRODUCTION Interstitial lung disease encompasses a group of rare lung conditions causing inflammation and scarring of lung tissue. The typical method of monitoring disease activity is through pulmonary function tests performed in a hospital setting. However, accessing care can be difficult for rural patients due to numerous barriers. This study assesses the feasibility and acceptability of home spirometry telemonitoring using MIR-Spirometers and the patientMpower home-monitoring platform for rural patients with interstitial lung disease. METHODS Unblinded, uncontrolled, prospective, multiple-methods study of the feasibility and utility of remote monitoring of 20 rural subjects with interstitial lung disease. Study assessments include adherence to twice weekly spirometry for 3 months in addition to mMRC dyspnea and EQ-5D-5L health-related quality of life questionnaires with each spirometry maneuver. Upon completion, subjects were encouraged to complete an 11-question satisfaction survey and participate in semi-structured qualitative interviews to further explore expectations and perceptions of rural patients to telehealth and remote patient monitoring. RESULTS 19 subjects completed the 3-month study period. Adherence to twice weekly spirometry was mean 53% ± 38%, with participants on average performing 2.26 ± 1.69 maneuvers per week. The median (Range) number of maneuvers per week was 2.0 (0.0, 7.0). The majority of participants responded favorably to the patient satisfaction survey questions. Themes regarding barriers to access included: lack of local specialty care, distance to center with expertise, and time, distance, and high cost associated with travel. Remote monitoring was well perceived amongst subjects as a way to improve access and overcome barriers. CONCLUSIONS Remote spirometry monitoring through web-based telehealth is acceptable and feasible for rural patients. Perceived benefits include overcoming access barriers like time, distance, and travel costs. However, cost, reimbursement, and internet access must be addressed before implementing it widely. Future studies are needed to ensure long-term feasibility and to compare outcomes with usual care.
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Affiliation(s)
- Ryan D Boente
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy, Sleep and Occupational Medicine, Indiana University School of Medicine, 1120 W. Michigan St, Gatch Hall, CL 290B, Indianapolis, IN, 46202, USA.
- Roudebush VA Medical Center, Center for Health Information and Communication, Indianapolis, IN, USA.
| | - Sydney Schacht
- Department of Medicine, Division of Pulmonary, Critical Care, Allergy, Sleep and Occupational Medicine, Indiana University School of Medicine, 1120 W. Michigan St, Gatch Hall, CL 290B, Indianapolis, IN, 46202, USA
| | | | | | - Lilian Golzarri-Arroyo
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health, Bloomington, IN, USA
| | - Nicholas Rattray
- Roudebush VA Medical Center, Center for Health Information and Communication, Indianapolis, IN, USA
- Regenstrief Institute, Inc., Indianapolis, IN, USA
- Department of Medicine, Indiana School of Medicine, Indianapolis, IN, USA
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11
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Sofia C, Comes A, Sgalla G, Richeldi L. An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis: a look towards 2023 and beyond. Expert Opin Emerg Drugs 2023; 28:283-296. [PMID: 37953604 DOI: 10.1080/14728214.2023.2281416] [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: 07/13/2023] [Accepted: 11/06/2023] [Indexed: 11/14/2023]
Abstract
INTRODUCTION Currently approved drug treatments for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, have been shown to slow lung function decline and improve clinical outcomes. Since significant advances in the understanding of pathogenetic mechanisms in IPF, novel potential agents are being tested to identify new targeted and better tolerated therapeutic strategies. AREAS COVERED This review describes the evidence from IPF phase II and III clinical trials that have been completed or are ongoing in recent years. The literature search was performed using Medline and Clinicaltrials.org databases. Particular attention is paid to the new inhibitor of phosphodiesterase 4B (BI 1015550), being studied in a more advanced research phase. Some emerging critical issues of the pharmacological research are highlighted considering the recent outstanding failures of several phase III trials. EXPERT OPINION An exponential number of randomized clinical trials are underway testing promising new molecules to increase treatment choices for patients with IPF and improve patients' quality of life. The next goals should aim at a deeper understanding of the pathogenic pathways of the disease with the challenging goal of being able not only to stabilize but also to reverse the ongoing fibrotic process in patients with IPF.
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Affiliation(s)
- Carmelo Sofia
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alessia Comes
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giacomo Sgalla
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Richeldi
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
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12
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Blanco I, Hernández-González F, García A, Torres-Castro R, Barberà JA. Management of Pulmonary Hypertension Associated with Chronic Lung Disease. Semin Respir Crit Care Med 2023; 44:826-839. [PMID: 37487524 DOI: 10.1055/s-0043-1770121] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Pulmonary hypertension (PH) is a common complication of chronic lung diseases, particularly in chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD) and especially in advanced disease. It is associated with greater mortality and worse clinical course. Given the high prevalence of some respiratory disorders and because lung parenchymal abnormalities might be present in other PH groups, the appropriate diagnosis of PH associated with respiratory disease represents a clinical challenge. Patients with chronic lung disease presenting symptoms that exceed those expected by the pulmonary disease should be further evaluated by echocardiography. Confirmatory right heart catheterization is indicated in candidates to surgical treatments, suspected severe PH potentially amenable with targeted therapy, and, in general, in those conditions where the result of the hemodynamic assessment will determine treatment options. The treatment of choice for these patients who are hypoxemic is long-term oxygen therapy and pulmonary rehabilitation to improve symptoms. Lung transplant is the only curative therapy and can be considered in appropriate cases. Conventional vasodilators or drugs approved for pulmonary arterial hypertension (PAH) are not recommended in patients with mild-to-moderate PH because they may impair gas exchange and their lack of efficacy shown in randomized controlled trials. Patients with severe PH (as defined by pulmonary vascular resistance >5 Wood units) should be referred to a center with expertise in PH and lung diseases and ideally included in randomized controlled trials. Targeted PAH therapy might be considered in this subset of patients, with careful monitoring of gas exchange. In patients with ILD, inhaled treprostinil has been shown to improve functional ability and to delay clinical worsening.
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Affiliation(s)
- Isabel Blanco
- Department of Pulmonary Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic-University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Spain
| | - Fernanda Hernández-González
- Department of Pulmonary Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic-University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Spain
| | - Agustín García
- Department of Pulmonary Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic-University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Spain
| | - Rodrigo Torres-Castro
- Department of Pulmonary Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic-University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Spain
| | - Joan A Barberà
- Department of Pulmonary Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic-University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Spain
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13
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Behr J, Nathan SD, Costabel U, Albera C, Wuyts WA, Glassberg MK, Haller H, Alvaro G, Gilberg F, Samara K, Lancaster L. Efficacy and Safety of Pirfenidone in Advanced Versus Non-Advanced Idiopathic Pulmonary Fibrosis: Post-Hoc Analysis of Six Clinical Studies. Adv Ther 2023; 40:3937-3955. [PMID: 37391667 PMCID: PMC10427557 DOI: 10.1007/s12325-023-02565-3] [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: 04/06/2023] [Accepted: 05/18/2023] [Indexed: 07/02/2023]
Abstract
INTRODUCTION In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis (IPF). This analysis compared the efficacy and safety of pirfenidone in advanced IPF versus non-advanced IPF. METHODS Data were included from the following studies of pirfenidone: ASCEND (NCT01366209); CAPACITY (004 [NCT00287716] and 006 [NCT00287729]); RECAP (NCT00662038; advanced IPF defined as percent predicted forced vital capacity [%FVC] < 50% and/or percent predicted carbon monoxide diffusing capacity [%DLco] < 35% at baseline); PASSPORT (NCT02699879; advanced IPF defined as baseline %FVC < 50%); and SP-IPF (NCT02951429; patients with advanced IPF [defined as %DLco ≤ 40% at screening] at risk of group 3 pulmonary hypertension). RESULTS In the pooled ASCEND/CAPACITY studies, the annual mean rate of FVC decline from baseline to Week 52 was significantly lower for pirfenidone versus placebo in advanced (p = 0.0035) and non-advanced IPF (p = 0.0001). Rate of all-cause mortality over 52 weeks was numerically lower for pirfenidone versus placebo in advanced and non-advanced IPF. In RECAP, the mean annual rate of FVC decline from baseline to Week 180 of pirfenidone treatment was similar in patients with advanced (- 141.5 mL) and non-advanced IPF (- 153.5 mL). In SP-IPF, the mean annual rate of FVC decline and rate of all-cause mortality from baseline to Week 52 in patients treated with placebo + pirfenidone were - 93.0 mL and 20.2%, respectively. No new safety signals were identified, and the safety profile of pirfenidone in patients with advanced IPF was generally consistent with that of non-advanced IPF. CONCLUSIONS These results highlight the benefit of pirfenidone treatment in patients with advanced and non-advanced IPF. As such, the indication for pirfenidone in the EU has now been updated to include the treatment of adult patients with advanced IPF. TRIAL REGISTRATIONS ASCEND (NCT01366209), CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), RECAP (NCT00662038), PASSPORT (NCT02699879), and SP-IPF (NCT02951429).
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Affiliation(s)
- Jürgen Behr
- Department of Medicine V, University Hospital, LMU Munich and Asklepios Fachkliniken Gauting, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
| | - Steven D Nathan
- Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Ulrich Costabel
- Center for Interstitial and Rare Lung Diseases, Pneumology Department, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Carlo Albera
- Department of Medical Sciences, School of Medicine, University of Turin, Turin, Italy
| | - Wim A Wuyts
- Department of Pulmonary Medicine, Unit for Interstitial Lung Diseases, University Hospitals Leuven, Leuven, Belgium
| | | | | | | | | | | | - Lisa Lancaster
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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14
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Neely ML, Hellkamp AS, Bender S, Todd JL, Liesching T, Luckhardt TR, Oldham JM, Raj R, White ES, Palmer SM. Lung function trajectories in patients with idiopathic pulmonary fibrosis. Respir Res 2023; 24:209. [PMID: 37612608 PMCID: PMC10463468 DOI: 10.1186/s12931-023-02503-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 08/01/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function. We evaluated trajectories of forced vital capacity (FVC) and diffusing capacity (DLco) in a cohort of patients with IPF. METHODS Patients with IPF that was diagnosed or confirmed at the enrolling centre in the previous 6 months were enrolled into the IPF-PRO Registry between June 2014 and October 2018. Patients were followed prospectively, with lung function data collected as part of routine clinical care. Mean trajectories of FVC and DLco % predicted in all patients and in subgroups by characteristics assessed at enrolment were estimated using a joint model that accounted for factors such as disease severity and visit patterns. RESULTS Of 1002 patients in the registry, 941 had ≥ 1 FVC and/or DLco measurement after enrolment. The median (Q1, Q3) follow-up period was 35.1 (18.9, 47.2) months. Overall, mean estimated declines in FVC and DLco % predicted were 2.8% and 2.9% per year, respectively. There was no evidence that the mean trajectories of FVC or DLco had a non-linear relationship with time at the population level. Patients who were male, white, had a family history of ILD, were using oxygen, or had prior/current use of antifibrotic therapy at enrolment had greater rates of decline in FVC % predicted. Patients who were male or white had greater rates of decline in DLco % predicted. CONCLUSIONS Data from the IPF-PRO Registry suggest a constant rate of decline in lung function over a prolonged period, supporting the inexorably progressive nature of IPF. A graphical abstract summarising the data in this manuscript is available at: https://www.usscicomms.com/respiratory/IPF-PRORegistry_LungFunctionTrajectories . TRIAL REGISTRATION NCT01915511.
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Affiliation(s)
- Megan L Neely
- Duke Clinical Research Institute, Durham, NC, USA.
- Duke University Medical Center, Durham, NC, USA.
| | - Anne S Hellkamp
- Duke Clinical Research Institute, Durham, NC, USA
- Duke University Medical Center, Durham, NC, USA
| | - Shaun Bender
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Jamie L Todd
- Duke Clinical Research Institute, Durham, NC, USA
- Duke University Medical Center, Durham, NC, USA
| | | | - Tracy R Luckhardt
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Justin M Oldham
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rishi Raj
- Stanford University School of Medicine, Stanford, CA, USA
| | - Eric S White
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Scott M Palmer
- Duke Clinical Research Institute, Durham, NC, USA
- Duke University Medical Center, Durham, NC, USA
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15
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Moshkovitz N, Epstein Shochet G, Shitrit D. Prostaglandin E2 (PGE2) and Roflumilast Involvement in IPF Progression. Int J Mol Sci 2023; 24:12393. [PMID: 37569768 PMCID: PMC10418473 DOI: 10.3390/ijms241512393] [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: 06/29/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a platform for testing drug candidates. Here, we tested the involvement of a PGE2 and PDE4 inhibitor, Roflumilast, in the IPF-CM system. Primary normal/IPF tissue-derived human lung fibroblasts (N/IPF-HLFs) were cultured on Matrigel and then removed to create the IPF-CM. N-HLFs were exposed to the IPF-CM/N-CM with/without PGE2 (1 nM) and Roflumilast (1 µM) for 24 h. The effect of the IPF-CM on cell phenotype and pro-fibrotic gene expression was tested. In addition, electronic records of 107 patients with up to 15-year follow-up were retrospectively reviewed. Patients were defined as slow/rapid progressors using forced vital capacity (FVC) annual decline. Medication exposure was examined. N-HLFs cultured on IPF-CM were arranged in large aggregates as a result of increased proliferation, migration and differentiation. A PGE2 and Roflumilast combination blocked the large aggregate formation induced by the IPF-CM (p < 0.001) as well as cell migration, proliferation, and pro-fibrotic gene expression. A review of patient records showed that significantly more slow-progressing patients were exposed to NSAIDs (p = 0.003). PGE2/PDE4 signaling may be involved in IPF progression. These findings should be further studied.
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Affiliation(s)
- Noa Moshkovitz
- Pulmonary Department, Meir Medical Center, Kfar Saba 44281, Israel; (N.M.); (G.E.S.)
| | - Gali Epstein Shochet
- Pulmonary Department, Meir Medical Center, Kfar Saba 44281, Israel; (N.M.); (G.E.S.)
| | - David Shitrit
- Pulmonary Department, Meir Medical Center, Kfar Saba 44281, Israel; (N.M.); (G.E.S.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
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16
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Shapanis A, Jones MG, Schofield J, Skipp P. Topological data analysis identifies molecular phenotypes of idiopathic pulmonary fibrosis. Thorax 2023; 78:682-689. [PMID: 36808085 PMCID: PMC10314053 DOI: 10.1136/thorax-2022-219731] [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: 10/10/2022] [Accepted: 01/19/2023] [Indexed: 02/22/2023]
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive disease with a median survival time of 3-5 years. Diagnosis remains challenging and disease progression varies greatly, suggesting the possibility of distinct subphenotypes. METHODS AND RESULTS We analysed publicly available peripheral blood mononuclear cell expression datasets for 219 IPF, 411 asthma, 362 tuberculosis, 151 healthy, 92 HIV and 83 other disease samples, totalling 1318 patients. We integrated the datasets and split them into train (n=871) and test (n=477) cohorts to investigate the utility of a machine learning model (support vector machine) for predicting IPF. A panel of 44 genes predicted IPF in a background of healthy, tuberculosis, HIV and asthma with an area under the curve of 0.9464, corresponding to a sensitivity of 0.865 and a specificity of 0.89. We then applied topological data analysis to investigate the possibility of subphenotypes within IPF. We identified five molecular subphenotypes of IPF, one of which corresponded to a phenotype enriched for death/transplant. The subphenotypes were molecularly characterised using bioinformatic and pathway analysis tools identifying distinct subphenotype features including one which suggests an extrapulmonary or systemic fibrotic disease. CONCLUSIONS Integration of multiple datasets, from the same tissue, enabled the development of a model to accurately predict IPF using a panel of 44 genes. Furthermore, topological data analysis identified distinct subphenotypes of patients with IPF which were defined by differences in molecular pathobiology and clinical characteristics.
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Affiliation(s)
- Andrew Shapanis
- Biological Sciences, University of Southampton, Southampton, Hampshire, UK
| | - Mark G Jones
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Paul Skipp
- Biological Sciences, University of Southampton, Southampton, Hampshire, UK
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17
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Yamazaki R, Nishiyama O, Yoshikawa K, Tohda Y, Matsumoto H. Prognostic value of the qSOFA in patients with acute exacerbation of idiopathic pulmonary fibrosis. Respir Investig 2023; 61:339-346. [PMID: 36933282 DOI: 10.1016/j.resinv.2023.02.006] [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: 09/16/2022] [Revised: 01/09/2023] [Accepted: 02/05/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Patients with idiopathic pulmonary fibrosis (IPF) have a slowly progressive clinical course, although some develop acute exacerbations (AEs). An easily obtained composite score is desirable for predicting the survival rate in patients with AE of IPF (AE-IPF). We investigated the quick sequential organ failure assessment (qSOFA), originally developed to identify sepsis, as a predictor of mortality in patients with AE-IPF and compared it to other composite assessments. METHODS Consecutive patients with IPF admitted for their first AE between 2008 and 2019 were recruited retrospectively. The association between the qSOFA score obtained at admission and mortality was investigated. RESULTS During the study period, 97 patients with AE-IPF were hospitalized. The hospital mortality was 30.9%. Multivariate logistic regression analysis revealed that both the qSOFA and the Japanese Association for Acute Medicine (JAAM)-disseminated intravascular coagulation (DIC) scores were significant predictors of hospital mortality (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.43-10.3; p = 0.007 and OR 2.71, 95% CI 1.56-4.67; p = 0.0004; respectively). Kaplan-Meier survival curves showed that both scores were consistently associated with survival. Furthermore, the sum of the two scores was a more effective predictor than the individual scores. CONCLUSIONS The qSOFA score of patients admitted with AE-IPF was associated with both in-hospital and long-term mortality, which was also true for the JAAM-DIC score. The qSOFA score plus the JAAM-DIC score should be determined during the diagnostic evaluation of a patient with AE-IPF. Both scores combined may be more effective at predicting outcomes than individual scores.
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Affiliation(s)
- Ryo Yamazaki
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Osamu Nishiyama
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan.
| | - Kazuya Yoshikawa
- Department of Respiratory Medicine and Allergology, Kindai University Nara Hospital, Ikoma, Nara 630-0293, Japan
| | - Yuji Tohda
- Kindai University Hospital, Osakasayama, Osaka 589-8511, Japan
| | - Hisako Matsumoto
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
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18
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Clinical Profile of Patients with Idiopathic Pulmonary Fibrosis in Real Life. J Clin Med 2023; 12:jcm12041669. [PMID: 36836204 PMCID: PMC9959732 DOI: 10.3390/jcm12041669] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
OBJECTIVE The objective of this study is to define the real-life clinical profile and therapeutic management of patients with idiopathic pulmonary fibrosis using artificial intelligence. METHODS We have conducted an observational, retrospective, non-interventional study using data from the Castilla-La Mancha Regional Healthcare Service (SESCAM) in Spain between January 2012 and December 2020. The Savana Manager 3.0 artificial intelligence platform was used to collect information from electronic medical records by applying natural language processing. RESULTS Our study includes 897 subjects whose diagnosis was compatible with idiopathic pulmonary fibrosis; 64.8% were men, with a mean age of 72.9 years (95% CI 71.9-73.8), and 35.2% were women, with a mean age of 76.8 years (95% CI 75.5-78). Patients who had a family history of IPF (98 patients; 12%) were younger and predominantly female (53.1%). Regarding treatment, 45% of patients received antifibrotic therapy. Patients who had undergone lung biopsy, chest CT, or bronchoscopy were younger than the patient population in whom these studies were not completed. CONCLUSIONS This study has used artificial intelligence techniques to analyze a large population over a 9-year period and determine the situation of IPF in standard clinical practice by identifying the patient clinical profile, use of diagnostic tests and therapeutic management.
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Doğan S, Güldiken GS, Alpaslan B, Barış SA, Doğan NÖ. Impact of COVID-19 pneumonia on interstitial lung disease: semi-quantitative evaluation with computed tomography. Eur Radiol 2023:10.1007/s00330-023-09441-2. [PMID: 36764951 PMCID: PMC9918400 DOI: 10.1007/s00330-023-09441-2] [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: 07/14/2022] [Revised: 01/04/2023] [Accepted: 01/14/2023] [Indexed: 02/12/2023]
Abstract
OBJECTIVES To evaluate the CT scores and fibrotic pattern changes in interstitial lung disease (ILD) patients, with and without previous COVID-19 pneumonia. METHODS Patients with ILD (idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD)) were retrospectively enrolled in the study which consisted of patients who had COVID-19 pneumonia while the control group had not. All patients had two CT scans, initial and follow-up, which were evaluated semi-quantitatively for severity, extent, and total CT scores, fibrosis patterns, and traction bronchiectasis. RESULTS A total of 102 patients (pneumonia group n = 48; control group n = 54) were enrolled in the study. For both groups, baseline characteristics were similar and CT scores were increased. While there was a 4.5 ± 4.6 point change in the total CT score of the COVID-19 group, there was a 1.2 ± 2.7 point change in the control group (p < 0.001). In the IPF subgroup, the change in total CT score was 7.0 points (95% CI: 4.1 to 9.9) in the COVID-19 group and 2.1 points (95% CI: 0.8 to 3.4) in the control group. Seven patients (14.6%) in the COVID-19 group progressed to a higher fibrosis pattern, but none in the control group. CONCLUSIONS Semi-quantitative chest CT scores in ILD patients demonstrated a significant increase after having COVID-19 pneumonia compared to ILD patients who had not had COVID-19 pneumonia. The increase in CT scores was more prominent in the IPF subgroup. There was also a worsening in the fibrosis pattern in the COVID-19 group. KEY POINTS • The impact of COVID-19 pneumonia on existing interstitial lung diseases and fibrosis is unclear. • COVID-19 pneumonia may worsen existing interstitial lung involvement with direct lung damage and indirect inflammatory effect. • COVID-19 pneumonia may affect existing lung fibrosis by triggering inflammatory pathways.
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Affiliation(s)
- Sevtap Doğan
- Department of Radiology, Faculty of Medicine, Kocaeli University, 41380, Kocaeli, Turkey.
| | - Gözde Selvi Güldiken
- grid.411105.00000 0001 0691 9040Department of Pulmonary Diseases, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Burcu Alpaslan
- grid.411105.00000 0001 0691 9040Department of Radiology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey
| | - Serap Argun Barış
- grid.411105.00000 0001 0691 9040Department of Pulmonary Diseases, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Nurettin Özgür Doğan
- grid.411105.00000 0001 0691 9040Department of Emergency Medicine, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
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20
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Real-World Clinical Outcomes Based on Body Mass Index and Annualized Weight Change in Patients with Idiopathic Pulmonary Fibrosis. Adv Ther 2023; 40:691-704. [PMID: 36481866 PMCID: PMC9898398 DOI: 10.1007/s12325-022-02382-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/14/2022] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Identification of clinical characteristics associated with prognosis for idiopathic pulmonary fibrosis (IPF) may help to guide management decisions. This analysis utilized data from the Pulmonary Fibrosis Foundation Patient Registry to examine the relationships between clinical outcomes and both body mass index (BMI) at study enrollment (hereafter referred to as baseline BMI) and annualized percent change in body weight in patients with IPF in a real-world setting. METHODS The following outcomes over 24 months were stratified by baseline BMI and annualized percent change in body weight: all-cause mortality; annualized change in percent predicted forced vital capacity (%FVC), percent predicted diffusing capacity for carbon monoxide, and 6-min walk distance; all-cause and respiratory-related hospitalizations; and acute exacerbations. RESULTS Overall, 600 patients with IPF were included (baseline BMI: < 25 kg/m2, n = 120; 25 to < 30 kg/m2, n = 242; ≥ 30 kg/m2, n = 238; annualized percent change in body weight: no loss, n = 95; > 0% to < 5% loss, n = 425; ≥ 5% loss, n = 80). Enrollment demographics and characteristics were generally similar across subgroups. There was no association between mortality and BMI. All-cause mortality was lower among patients who experienced no annualized weight loss versus those with ≥ 5% (OR [95% CI] 3.28 [1.15, 10.95]) or > 0 to < 5% weight loss (OR [95% CI] 2.83 [1.14, 8.62]) over 24 months. Patients with baseline BMI < 25 kg/m2 had a significantly greater estimated annualized decline in %FVC versus patients with baseline BMI ≥ 30 kg/m2 (difference [95% CI] 1.47 [0.01, 2.93]). No relationship was observed between %FVC and weight loss. Other clinical outcomes were generally similar across subgroups. CONCLUSIONS Some clinical outcomes may be worse in patients with IPF who have a low BMI (< 25 kg/m2) or who experience weight loss over 24 months, but the causation for these relationships is unknown. These results may help to inform management decisions for patients with IPF. CLINICALTRIALS GOV IDENTIFIER NCT02758808.
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21
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Alonso-Gonzalez A, Tosco-Herrera E, Molina-Molina M, Flores C. Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine. Front Med (Lausanne) 2023; 10:1152211. [PMID: 37181377 PMCID: PMC10172674 DOI: 10.3389/fmed.2023.1152211] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/03/2023] [Indexed: 05/16/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.
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Affiliation(s)
- Aitana Alonso-Gonzalez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Universidad de Santiago de Compostela, Santiago de Compostela, Spain
| | - Eva Tosco-Herrera
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Maria Molina-Molina
- Servei de Pneumologia, Laboratori de Pneumologia Experimental, IDIBELL, Barcelona, Spain
- Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Flores
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
- Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
- *Correspondence: Carlos Flores,
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22
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Patel H, Shah JR, Patel DR, Avanthika C, Jhaveri S, Gor K. Idiopathic pulmonary fibrosis: Diagnosis, biomarkers and newer treatment protocols. Dis Mon 2022:101484. [DOI: 10.1016/j.disamonth.2022.101484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Yamazaki R, Nishiyama O, Yoshikawa K, Tohda Y, Matsumoto H. Outcome of patients who were incidentally diagnosed with idiopathic pulmonary fibrosis: How early in the disease should we identify patients? Respir Med 2022; 201:106933. [PMID: 35930918 DOI: 10.1016/j.rmed.2022.106933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 11/29/2022]
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Nagel DJ, Rackow AR, Ku WY, Bell TJ, Sime PJ, Kottmann RM. Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis. Cells 2022; 11:2540. [PMID: 36010617 PMCID: PMC9406836 DOI: 10.3390/cells11162540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis.
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Affiliation(s)
- David J. Nagel
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Ashley R. Rackow
- Laboratory Medicine, Department of Pathology, Division of Clinical Chemistry, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Wei-Yao Ku
- BMW of North America, Woodcliff Lake, NJ 07675, USA
| | - Tyler J. Bell
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - Patricia J. Sime
- Department of Medicine, Virginia Commonwealth University Health System, Richmond, VA 23298, USA
| | - Robert Matthew Kottmann
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
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Nikkho SM, Richter MJ, Shen E, Abman SH, Antoniou K, Chung J, Fernandes P, Hassoun P, Lazarus HM, Olschewski H, Piccari L, Psotka M, Saggar R, Shlobin OA, Stockbridge N, Vitulo P, Vizza CD, Wort SJ, Nathan SD. Clinical significance of pulmonary hypertension in interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's innovative drug development initiative-Group 3 pulmonary hypertension. Pulm Circ 2022; 12:e12127. [PMID: 36016668 PMCID: PMC9395696 DOI: 10.1002/pul2.12127] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/18/2022] [Accepted: 08/09/2022] [Indexed: 11/18/2022] Open
Abstract
Pulmonary hypertension (PH) has been linked to worse outcomes in chronic lung diseases. The presence of PH in the setting of underlying Interstitial Lung Disease (ILD) is strongly associated with decreased exercise and functional capacity, an increased risk of hospitalizations and death. Examining the scope of this issue and its impact on patients is the first step in trying to define a roadmap to facilitate and encourage future research in this area. The aim of our working group is to strengthen the communities understanding of PH due to lung diseases and to improve the care and quality of life of affected patients. This introductory statement provides a broad overview and lays the foundation for further in-depth papers on specific topics pertaining to PH-ILD.
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Affiliation(s)
| | - Manuel J. Richter
- Department of Internal Medicine Pulmonary Hypertension DivisionUniversities of Giessen and Marburg Lung Center (UGMLC)GiessenGermany
| | - Eric Shen
- Global Medical AffairsUnited Therapeutics CorporationSilver SpringMarylandUSA
| | - Steven H. Abman
- School of Medicine and Children's HospitalUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
| | - Katerina Antoniou
- Department of Thoracic MedicineUniversity of Crete School of MedicineHeraklionCreteGreece
| | - Jonathan Chung
- Department of RadiologyThe University of Chicago MedicineChicagoIllinoisUSA
| | - Peter Fernandes
- Regulatory, Safety and Quality DepartmentBellerophon Therapeutics IncWarrenNew JerseyUSA
| | - Paul Hassoun
- Department of Medicine, Division of Pulmonary and Critical Care MedicineJohns Hopkins UniversityBaltimoreMarylandUSA
| | | | - Horst Olschewski
- Division of Pulmonology, Department of Internal MedicineMedical University of GrazGrazSteiermarkAustria
| | - Lucilla Piccari
- Department of Pulmonary MedicineHospital del Mar, Pulmonary Hypertension UnitBarcelonaCatalunyaSpain
| | - Mitchell Psotka
- Inova Heart and Vascular InstituteFalls ChurchVirginiaUSA
- Division of Cardiology and NephrologyFood and Drug AdministrationSilver SpringMarylandUSA
| | - Rajan Saggar
- Lung & Heart‐Lung Transplant and Pulmonary Hypertension ProgramsUniversity of California Los Angeles David Geffen School of MedicineLos AngelesCaliforniaUSA
| | - Oksana A. Shlobin
- Advanced Lung Disease and Transplant ProgramInova Heart and Vascular InstituteFalls ChurchVirginiaUSA
| | - Norman Stockbridge
- Division of Cardiology and NephrologyUS Food and Drug AdministrationSilver SpringMarylandUSA
| | - Patrizio Vitulo
- Therapies, Department of Pulmonary MedicineIRCCS Mediterranean Institute for Transplantation and Advanced SpecializedPalermoSiciliaItaly
| | | | - Stephen J. Wort
- National Pulmonary Hypertension Service at Royal Brompton HospitalLondonUK
- National Heart and Lung Institute, Imperial CollegeLondonUK
| | - Steven D. Nathan
- Advanced Lung Disease and Transplant ProgramInova Heart and Vascular InstituteFalls ChurchVirginiaUSA
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Dudhat K, Patel H. Preparation and evaluation of pirfenidone loaded chitosan nanoparticles pulmonary delivery for idiopathic pulmonary fibrosis. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-022-00419-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disorder caused by abnormal extracellular matrix deposition, which results in increasing dyspnea and loss of pulmonary function. Pirfenidone (PFD) has antifibrotic properties that have been approved by the US FDA for the treatment of IPF. Pirfenidone is currently delivered orally, which has drawbacks like reduced bioavailability in the presence of food, gastrointestinal (dyspepsia and anorexia), and dermatological (photosensitivity) side-effects, large amount of dose, and elimination half-life of 2.4 h. This study aimed was to prepare inhalable powders containing PFD-loaded chitosan nanoparticles for sustained delivery of the drug to the lung.
Result
The quasi-solvent diffusion method was used with optimized 100 mg PFD and 100 mg chitosan (CS). An in-vitro drug release research found that increasing the amount of chitosan reduced the rate of drug release from nanoparticles. Entrapment of PFD into chitosan nanoparticles decreased with the increased concentration of stabilizer concentration. All batches produced nanoparticles with a spherical morphology confirmed by SEM and sizes ranging from 239.3 ± 1.8 to 928.7 ± 4.6 nm. The optimized nanoparticles exhibited a mean particle size of 467.33 ± 7.8 nm with a polydispersity index of 0.127 ± 0.022, zeta potential of + 34.8 ± 1.6 mV, % entrapment efficiency (39.45 ± 4.63%), % drug release after 12 h (94.78 ± 2.88%), and in-vitro deposition (81.49%). Results showed that the obtained powders had different aerosolization properties. The particle size of nanoparticles reduced, and the process yield, extra-fine particle fraction, geometric standard diameter, and fine particle fraction increased significantly. Stability study showed, there are no aggregation observed and stable for six month study.
Conclusion
Prepared pirfenidone-loaded chitosan nanoparticles can be result of 6 months of stability studies that give details that there was no significant aggregation of PFD-loaded CS NPs and the spherical shape particle with smooth surface as per SEM studies. Hence, PFD-loaded CS NPs can be a suitable alternative to the currently available therapy.
Graphical abstract
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27
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Chung C, Kim J, Cho HS, Kim HC. Baseline serum Krebs von den Lungen-6 as a biomarker for the disease progression in idiopathic pulmonary fibrosis. Sci Rep 2022; 12:8564. [PMID: 35595812 PMCID: PMC9123161 DOI: 10.1038/s41598-022-12399-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 05/06/2022] [Indexed: 11/09/2022] Open
Abstract
Disease progression (DP) is an important parameter for the prognosis of idiopathic pulmonary fibrosis (IPF). This study aimed to evaluate the baseline serum biomarkers for predicting the DP in IPF. Seventy-four patients who were diagnosed with IPF and had their serum Krebs von den Lungen-6 (KL-6) and monocyte count, which might be associated with prognosis of IPF, checked more than twice were included. KL-6 ≥ 1000 U/mL and monocyte ≥ 600/μL were arbitrarily set as the cut-off values for DP. The DP was defined as a 10% reduction in forced vital capacity, a 15% reduction in diffusing capacity of the lung for carbon monoxide relative to the baseline, or disease-related mortality. Of the 74 patients, 18 (24.3%) were defined as having DP. The baseline KL-6 level was significantly increased in the DP group compared to the stable disease group (median, 1228.0 U/mL vs. 605.5 U/mL, P = 0.019). Multivariate Cox analyses demonstrated that a high KL-6 level (KL-6 ≥ 1000 U/mL; hazard ratio, 2.761 or 2.845; P = 0.040 or 0.045) was independently associated with DP in each model. The baseline serum KL-6 level might be a useful biomarker for DP in IPF.
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Affiliation(s)
- Chiwook Chung
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Jiwon Kim
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Hyo Sin Cho
- University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ho Cheol Kim
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
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Cao Y, Rudrakshala J, Williams R, Rodriguez S, Sorkhdini P, Yang AX, Mundy M, Yang D, Palmisciano A, Walsh T, Delcompare C, Caine T, Tomasi L, Shea BS, Zhou Y. CRTH2 Mediates Pro-fibrotic Macrophage Differentiation and Promotes Lung Fibrosis. Am J Respir Cell Mol Biol 2022; 67:201-214. [PMID: 35585756 DOI: 10.1165/rcmb.2021-0504oc] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis with unknown reason. In patients with IPF, high serum and lung levels of CHI3L1 can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 to stimulate pro-fibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 on pro-fibrotic macrophage differentiation and fibrosis development, and primary human PBMC cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between IPF patients and normal controls. Our results showed that null mutation or small molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from IPF patients appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting CHI3L1-CRTH2 pathway as a promising therapeutic approach in IPF and that the sensitivity of blood monocytes to CHI3L1-induced pro-fibrotic differentiation may serve as a biomarker that predicts responsiveness to CHI3L1 or CRTH2 based interventions.
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Affiliation(s)
- Yueming Cao
- Brown University, 6752, Providence, Rhode Island, United States
| | | | - River Williams
- Brown University, 6752, Providence, Rhode Island, United States
| | - Shade Rodriguez
- Brown University, 6752, Providence, Rhode Island, United States
| | | | - Alina X Yang
- Brown University, 6752, Providence, Rhode Island, United States
| | - Miles Mundy
- Brown University, 6752, Providence, Rhode Island, United States
| | - Dongqin Yang
- Brown University, 6752, Providence, Rhode Island, United States
| | - Amy Palmisciano
- Rhode Island Hospital, Pulmonary, Critical Care and Sleep, Providence, Rhode Island, United States
| | - Thomas Walsh
- Rhode Island Hospital, 23325, Providence, Rhode Island, United States
| | - Cesar Delcompare
- Rhode Island Hospital, Pulmonary, Critical Care and Sleep, Providence, Rhode Island, United States
| | - Tanis Caine
- Rhode Island Hospital, Pulmonary, Critical Care and Sleep, Providence, Rhode Island, United States
| | - Luca Tomasi
- Rhode Island Hospital, Pulmonary, Critical Care and Sleep, Providence, Rhode Island, United States
| | - Barry S Shea
- Rhode Island Hospital, Pulmonary, Critical Care and Sleep, Providence, Rhode Island, United States
| | - Yang Zhou
- Brown University, Molecular Microbiology and Immunology, Providence, Rhode Island, United States;
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29
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Tseng CM, Chen MY, Kao CY, Tao CW. Investigation of clinical predictors of survival in idiopathic pulmonary fibrosis patients: A cohort study in Taiwan. J Chin Med Assoc 2022; 85:578-583. [PMID: 35353790 DOI: 10.1097/jcma.0000000000000719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Two antifibrotic medications, pirfenidone and nintedanib, have been approved as treatments for idiopathic pulmonary fibrosis (IPF)-a life-threatening interstitial lung disease. However, there are insufficient current data regarding clinical predictors of survival for patients with IPF in the era of antifibrotics. METHODS We retrospectively analyzed the medical records of patients with IPF treated between April 2017 and May 2020. Univariate and multivariate Cox proportional hazard models were used to identify independent predictors of mortality among these patients with IPF. RESULTS A total of 40 patients with IPF (average age, 75.58 ± 8.34 years) were included in the study, 27 (67.5%) of whom were treated with antifibrotic drugs. In the entire cohort, 14 (35%) patients died, and the overall survival of the study population was 48.52 ± 5 months (median, not applicable [NA] [29-NA] months). The univariate and multivariate Cox proportional hazard models indicated that chest tightness, finger clubbing, acute exacerbation after medication, decreased percentage forced vital capacity (%FVC), and decreased percentage 1-second forced expiratory volume were clinical factors linked to all-cause mortality among all patients, although without statistical significance at the multivariate level. Meanwhile, only finger clubbing was a significant mortality predictor among patients who received antifibrotic medications. A mortality scoring system was built upon the aforementioned risk factors, with the exclusion of %FVC, whose individual mortality score was nearly zero. CONCLUSION Chest tightness, finger clubbing, acute exacerbation after medication, and decreased %FVC were clinical factors associated with mortality in patients with IPF, although without statistical significance. A scoring system including these factors can be used to predict all-cause mortality in patients with IPF. The mere intake of antifibrotic medications was not a significant mortality predictor in this study. This might be owed to the retrospective nature of the study, where many patients started the medications after the deterioration of their pulmonary function rather than from the start.
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Affiliation(s)
- Ching-Min Tseng
- Division of Chest Medicine, Department of Internal Medicine, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Mei-Yin Chen
- Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan, ROC
| | - Chen-Yu Kao
- Department of Internal Medicine, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
| | - Chi-Wei Tao
- Department of Internal Medicine, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
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30
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Glass DS, Grossfeld D, Renna HA, Agarwala P, Spiegler P, DeLeon J, Reiss AB. Idiopathic pulmonary fibrosis: Current and future treatment. THE CLINICAL RESPIRATORY JOURNAL 2022; 16:84-96. [PMID: 35001525 PMCID: PMC9060042 DOI: 10.1111/crj.13466] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 10/21/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022]
Abstract
Objectives Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease characterized by dry cough, fatigue, and progressive exertional dyspnea. Lung parenchyma and architecture is destroyed, compliance is lost, and gas exchange is compromised in this debilitating condition that leads inexorably to respiratory failure and death within 3–5 years of diagnosis. This review discusses treatment approaches to IPF in current use and those that appear promising for future development. Data Source The data were obtained from the Randomized Controlled Trials and scientific studies published in English literature. We used search terms related to IPF, antifibrotic treatment, lung transplant, and management. Results Etiopathogenesis of IPF is not fully understood, and treatment options are limited. Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. The mainstay therapies are the oral antifibrotic drugs pirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression. Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy. Conclusion Clearly, there is an unmet need for accelerated research into IPF mechanisms so that progress can be made in therapeutics toward the goals of increasing life expectancy, alleviating symptoms, and improving well‐being.
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Affiliation(s)
- Daniel S Glass
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
| | - David Grossfeld
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
| | - Heather A Renna
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
| | - Priya Agarwala
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
| | - Peter Spiegler
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
| | - Joshua DeLeon
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
| | - Allison B Reiss
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, New York, USA
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31
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Wang E, Wang Y, Zhou S, Xia X, Han R, Fei G, Zeng D, Wang R. Identification of three hub genes related to the prognosis of idiopathic pulmonary fibrosis using bioinformatics analysis. Int J Med Sci 2022; 19:1417-1429. [PMID: 36035368 PMCID: PMC9413564 DOI: 10.7150/ijms.73305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 08/09/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by peripheral distribution of bilateral pulmonary fibrosis that is more pronounced at the base. IPF has a short median survival time and a poor prognosis. Therefore, it is necessary to identify effective prognostic indicators to guide the treatment of patients with IPF. Methods: We downloaded microarray data of bronchoalveolar lavage cells from the Gene Expression Omnibus (GEO), containing 176 IPF patients and 20 controls. The top 5,000 genes in the median absolute deviation were classified into different color modules using weighted gene co-expression network analysis (WGCNA), and the modules significantly associated with both survival time and survival status were identified as prognostic modules. We used Lasso Cox regression and multivariate Cox regression to search for hub genes related to prognosis from the differentially expressed genes (DEGs) in the prognostic modules and constructed a risk model and nomogram accordingly. Moreover, based on the risk model, we divided IPF patients into high-risk and low-risk groups to determine the biological functions and immune cell subtypes associated with the prognosis of IPF using gene set enrichment analysis and immune cell infiltration analysis. Results: A total of 153 DEGs located in the prognostic modules, three (TPST1, MRVI1, and TM4SF1) of which were eventually defined as prognostic hub genes. A risk model was constructed based on the expression levels of the three hub genes, and the accuracy of the model was evaluated using time-dependent receiver operating characteristic (ROC) curves. The areas under the curve for 1-, 2-, and 3-year survival rates were 0.862, 0.885, and 0.833, respectively. The results of enrichment analysis showed that inflammation and immune processes significantly affected the prognosis of patients with IPF. The degree of mast and natural killer (NK) cell infiltration also increases the prognostic risk of IPF. Conclusions: We identified three hub genes as independent molecular markers to predict the prognosis of patients with IPF and constructed a prognostic model that may be helpful in promoting therapeutic gains for IPF patients.
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Affiliation(s)
- Enze Wang
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Yue Wang
- Department of Infectious Diseases, Hefei second people's hospital, Hefei 230001, China
| | - Sijing Zhou
- Department of occupational medicine, Hefei third clinical college of Anhui Medical University, Hefei 230022, China
| | - Xingyuan Xia
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Rui Han
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Guanghe Fei
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
| | - Daxiong Zeng
- Department of pulmonary and critical care medicine, Suzhou Dushu Lake Hospital, Suzhou, 215006, China.,Department of pulmonary and critical care medicine, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou, 215006, China
| | - Ran Wang
- Department of respiratory and critical care medicine, the first affiliated hospital of Anhui medical university, Hefei 230022, China
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32
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Lyu Y, Guo C, Zhang H. Fatty acid metabolism-related genes in bronchoalveolar lavage fluid unveil prognostic and immune infiltration in idiopathic pulmonary fibrosis. Front Endocrinol (Lausanne) 2022; 13:1001563. [PMID: 36267568 PMCID: PMC9576944 DOI: 10.3389/fendo.2022.1001563] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 09/21/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition with an unfavorable prognosis. A recent study has demonstrated that IPF patients exhibit characteristic alterations in the fatty acid metabolism in their lungs, suggesting an association with IPF pathogenesis. Therefore, in this study, we have explored whether the gene signature associated with fatty acid metabolism could be used as a reliable biological marker for predicting the survival of IPF patients. METHODS Data on the fatty acid metabolism-related genes (FAMRGs) were extracted from databases like Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, and Reactome pathway. The GSE70866 dataset with information on IPF patients was retrieved from the Gene Expression Omnibus (GEO). Next, the consensus clustering method was used to identify novel molecular subgroups. Gene Set Enrichment Analysis (GSEA) was performed to understand the mechanisms involved. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the level of immune cell infiltration in the identified subgroups based on gene expression signatures of immune cells. Finally, the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression analysis were performed to develop a prognostic risk model. RESULTS The gene expression signature associated with fatty acid metabolism was used to create two subgroups with significantly different prognoses. GSEA reveals that immune-related pathways were significantly altered between the two subgroups, and the two subgroups had different metabolic characteristics. High infiltration of immune cells, mainly activated NK cells, monocytes, and activated mast cells, was observed in the subgroup with a poor prognosis. A risk model based on FAMRGs had an excellent ability to predict the prognosis of IPF. The nomogram constructed using the clinical features and the risk model could accurately predict the prognosis of IPF patients. CONCLUSION The fatty acid metabolism-related gene expression signature could be used as a potential biological marker for predicting clinical outcomes and the level of infiltration of immune cells. This could eventually enhance the accuracy of the treatment of IPF patients.
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Affiliation(s)
- Yin Lyu
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chen Guo
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hao Zhang
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- *Correspondence: Hao Zhang,
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Chandran RR, Xie Y, Gallardo-Vara E, Adams T, Garcia-Milian R, Kabir I, Sheikh AQ, Kaminski N, Martin KA, Herzog EL, Greif DM. Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis. Nat Commun 2021; 12:7179. [PMID: 34893592 PMCID: PMC8664937 DOI: 10.1038/s41467-021-27499-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 11/19/2021] [Indexed: 12/11/2022] Open
Abstract
During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β+ cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β+ cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β+ cells transition into myofibroblasts. In contrast to PDGFR-β+ cells, KLF4 reduction in α-smooth muscle actin (SMA)+ cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β+ cells via a Forkhead box M1 to C-C chemokine ligand 2-receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β+ cells and SMA+ cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types.
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Affiliation(s)
- Rachana R Chandran
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Yi Xie
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Eunate Gallardo-Vara
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Taylor Adams
- Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Rolando Garcia-Milian
- Bioinformatics Support Program, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Inamul Kabir
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Abdul Q Sheikh
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Pfizer, 610 Main Street, Cambridge, MA, 02139, USA
| | - Naftali Kaminski
- Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Kathleen A Martin
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Erica L Herzog
- Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Daniel M Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA.
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Wu KK. Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite. Front Pharmacol 2021; 12:759199. [PMID: 34858185 PMCID: PMC8632247 DOI: 10.3389/fphar.2021.759199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/28/2021] [Indexed: 12/23/2022] Open
Abstract
Tissue fibrosis causes debilitating human diseases such as liver cirrhosis, heart failure, chronic kidney disease and pulmonary insufficiency. It is a dynamic process orchestrated by specific subsets of monocyte-macrophages, fibroblasts, pericytes and hepatic stellate cells. Fibrosis is linked to tissue inflammation. Pro-inflammatory macrophages promote fibrosis by driving myofibroblast differentiation and macrophage myofibroblast transition. Myofibroblasts express α-smooth muscle cell actin (α-SMA) and secrete extracellular matrix (ECM) proteins notably collagen I and III. Deposition of ECM proteins at injury sites and interstitial tissues distorts normal structure and impairs vital functions. Despite advances in the mechanisms of fibrosis at cellular, molecular and genetic levels, prevention and treatment of fibrotic diseases remain poorly developed. Recent reports suggest that 5-methoxytryptophan (5-MTP) is effective in attenuating injury-induced liver, kidney, cardiac and pulmonary fibrosis. It inhibits macrophage activation and blocks fibroblast differentiation to myofibroblasts. Furthermore, it inhibits hepatic stellate cell differentiation into myofibroblasts. As 5-MTP is an endogenous molecule derived from tryptophan catabolism via tryptophan hydroxylase pathway, it is well-suited as a lead compound for developing new anti-fibrotic drugs. This article provides an overview of 5-MTP synthesis, and a critical review of its anti-fibrotic activities. Its mechanisms of actions and potential therapeutic value will be discussed.
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Affiliation(s)
- Kenneth K Wu
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.,Institute of Biotechnology, College of Life Science, National Tsing-Hua University, Hsinchu, Taiwan
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35
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Li M, Wang K, Zhang Y, Fan M, Li A, Zhou J, Yang T, Shi P, Li D, Zhang G, Chen M, Ren H. Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis. Front Med (Lausanne) 2021; 8:693959. [PMID: 34671612 PMCID: PMC8520927 DOI: 10.3389/fmed.2021.693959] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/31/2021] [Indexed: 01/02/2023] Open
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and unfavorable prognosis. Ferroptosis is a form of regulated cell death with an iron-dependent way that is involved in the development of various diseases. Whereas the prognostic value of ferroptosis-related genes (FRGs) in IPF remains uncertain and needs to be further elucidated. Methods: The FerrDb database and the previous studies were screened to explore the FRGs. The data of patients with IPF were obtained from the GSE70866 dataset. Wilcoxon's test and univariate Cox regression analysis were applied to identify the FRGs that are differentially expressed between normal and patients with IPF and associated with prognosis. Next, a multigene signature was constructed by the least absolute shrinkage and selection operator (LASSO)-penalized Cox model in the training cohort and evaluated by using calibration and receiver operating characteristic (ROC) curves. Then, 30% of the dataset samples were randomly selected for internal validation. Finally, the potential function and pathways that might be affected by the risk score-related differently expressed genes (DEGs) were further explored. Results: A total of 183 FRGs were identified by the FerrDb database and the previous studies, and 19 of them were differentially expressed in bronchoalveolar lavage fluid (BALF) between IPF and healthy controls and associated with prognosis (p < 0.05). There were five FRGs (aconitase 1 [ACO1], neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS], Ectonucleotide pyrophosphatase/phosphodiesterase 2 [ENPP2], Mucin 1 [MUC1], and ZFP36 ring finger protein [ZFP36]) identified as risk signatures and stratified patients with IPF into the two risk groups. The overall survival rate in patients with high risk was significantly lower than that in patients with low risk (p < 0.001). The calibration and ROC curve analysis confirmed the predictive capacity of this signature, and the results were further verified in the validation group. Risk score-related DEGs were found enriched in ECM-receptor interaction and focal adhesion pathways. Conclusion: The five FRGs in BALF can be used for prognostic prediction in IPF, which may contribute to improving the management strategies of IPF.
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Affiliation(s)
- Meng Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.,Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Ke Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Yanpeng Zhang
- Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.,Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.,Department of Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Meng Fan
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Anqi Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Jiejun Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Tian Yang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Puyu Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Dan Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Guangjian Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Mingwei Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Hui Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.,Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
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Caminati A, Madotto F, Conti S, Cesana G, Mantovani L, Harari S. The natural history of idiopathic pulmonary fibrosis in a large European population: the role of age, sex and comorbidities. Intern Emerg Med 2021; 16:1793-1802. [PMID: 33586036 DOI: 10.1007/s11739-021-02651-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 01/21/2021] [Indexed: 02/08/2023]
Abstract
Placebo arms of clinical trials provide an opportunity to investigate the natural history of idiopathic pulmonary fibrosis (IPF) but these patients are not representative of the real life IPF population. Objective of this article is to evaluate patients' characteristics of incident IPF cases and their impact on mortality and hospitalizations risk. We conducted a retrospective cohort study using data from administrative databases from 2000 to 2010. Based on different algorithms reported in literature, incident IPF cases were identified. We applied Cox proportional hazards models to assess relationship between patients' characteristics, mortality and hospitalization. According to three case definitions, we identified 2338, 460 and 1704 incident IPF cases. Mean age at diagnosis was about 72 years, the proportion of male varied between 59 and 62% and patients with at least one chronic disease were between 70 and 74%. Age, male sex and comorbidities were associated to worse outcomes. Congestive heart failure (CHF), diabetes and cancer were conditions associated to mortality, while those associated to hospitalization were CHF and chronic obstructive pulmonary disease. Our data source provided one of the largest samples of unselected patients with a long follow-up period. Using different algorithms proposed and validated in literature, we observed that mortality and hospitalization rate are high in patients with IPF and age, sex and comorbidities significantly affect clinical outcomes. Females show a significant survival advantage over males, even after adjusting for age and comorbidities. Patients with pre-existing diseases, especially those with pulmonary and cardiovascular diseases are at higher risk.
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Affiliation(s)
- Antonella Caminati
- U.O. di Pneumologia e Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare. Ospedale San Giuseppe, MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, MI, Italy.
| | - Fabiana Madotto
- Value-based Healthcare Unit, IRCCS MultiMedica, Via Milanese 300, Sesto San Giovanni, 20099, Milan, Italy
- Research Centre on Public Health, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Monza e Brianza, Italy
| | - Sara Conti
- Research Centre on Public Health, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Monza e Brianza, Italy
| | - Giancarlo Cesana
- Research Centre on Public Health, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Monza e Brianza, Italy
| | - Lorenzo Mantovani
- Value-based Healthcare Unit, IRCCS MultiMedica, Via Milanese 300, Sesto San Giovanni, 20099, Milan, Italy
- Research Centre on Public Health, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Monza e Brianza, Italy
| | - Sergio Harari
- U.O. di Pneumologia e Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare. Ospedale San Giuseppe, MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, MI, Italy
- Clinica Medica, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
- Dipartimento di Scienze Cliniche e di Comunità, Università di Milano, Milan, Italy
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37
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Kang J, Song JW. Effect of sildenafil added to antifibrotic treatment in idiopathic pulmonary fibrosis. Sci Rep 2021; 11:17824. [PMID: 34497295 PMCID: PMC8426395 DOI: 10.1038/s41598-021-97396-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/19/2021] [Indexed: 01/15/2023] Open
Abstract
Sildenafil is a phosphodiesterase-5 inhibitor used to treat idiopathic pulmonary arterial hypertension; however, its benefits are unclear in patients with advanced idiopathic pulmonary fibrosis (IPF). We aimed to evaluate its effect as an add-on to antifibrotic agents on clinical outcomes of real-world IPF patients. Among a total of 607 IPF patients treated with antifibrotic agent, 66 concurrently received sildenafil. Propensity score matching was performed to adjust for differences in age, sex, body mass index, forced vital capacity (FVC), and diffusing capacity (DLCO) between the sildenafil and no-sildenafil groups. The outcomes of these groups in terms of FVC decline rate, all-cause mortality, hospitalization, and acute exacerbation were compared. Propensity score matching identified 51 matched pairs. The mean age of the patients was 69.5 years and 80.4% were male. Mean FVC and DLCO were 51.7% and 29.5% of the predicted values, respectively. The FVC decline rates did not differ significantly (p = 0.714) between the sildenafil (− 101 mL/year) and no-sildenafil (− 117 mL/year) groups. In multivariable analyses adjusted for comorbidities and presence of pulmonary hypertension, sildenafil had no significant impact on all-cause mortality, hospitalization, or acute exacerbation. Sildenafil add-on to antifibrotic treatment had no significant effects on the clinical outcomes of IPF patients.
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Affiliation(s)
- Jieun Kang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Jin Woo Song
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
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Huan C, Xu W, Liu Y, Ruan K, Shi Y, Cheng H, Zhang X, Ke Y, Zhou J. Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway. Front Mol Biosci 2021; 8:683267. [PMID: 34422900 PMCID: PMC8377751 DOI: 10.3389/fmolb.2021.683267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 06/16/2021] [Indexed: 11/13/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-β (TGF-β) superfamily involves bone morphogenetic proteins (BMPs) and TGF-β, and the balance between the activation of TGF-β-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for fibrosis process. GREM2, initially identified as a TGF-β-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricellular proteins, its role in lung fibrosis is not clear. Here, we identified Gremlin2 as a key regulator of fibroblast activation. Gremlin2 was highly expressed in the serum and lung tissues in IPF patients. Bleomycin-induced lung fibrosis model exhibited high expression of Gremlin2 in the bronchoalveolar lavage fluid (BALF) and lung tissue. Isolation of primary cells from bleomycin-induced fibrosis lung showed a good correlation of Gremlin2 and Acta2 (α-SMA) expressions. Overexpression of Gremlin2 in human fetal lung fibroblast 1 (HFL-1) cells increased its invasion and migration. Furthermore, Gremlin2 regulates fibrosis functions through mediating TGF-β/BMP signaling, in which Gremlin2 may activate TGF-β signaling and inhibit BMP signaling. Therefore, we provided in vivo and in vitro evidence to demonstrate that Gremlin2 may be a potential therapeutic target for the treatment of IPF.
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Affiliation(s)
- Caijuan Huan
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wangting Xu
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaru Liu
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Kexin Ruan
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yueli Shi
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Hongqiang Cheng
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Zhang
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuehai Ke
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianying Zhou
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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39
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Tanabe N, Kaji S, Sato S, Yokoyama T, Oguma T, Tanizawa K, Handa T, Sakajo T, Hirai T. A homological approach to a mathematical definition of pulmonary fibrosis and emphysema on computed tomography. J Appl Physiol (1985) 2021; 131:601-612. [PMID: 34138650 DOI: 10.1152/japplphysiol.00150.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Three-dimensional imaging is essential to evaluate local abnormalities and understand structure-function relationships in an organ. However, quantifiable and interpretable methods to localize abnormalities remain unestablished. Visual assessments are prone to bias, machine learning methods depend on training images, and the underlying decision principle is usually difficult to interpret. Here, we developed a homological approach to mathematically define emphysema and fibrosis in the lungs on computed tomography (CT). With the use of persistent homology, the density of homological features, including connected components, tunnels, and voids, was extracted from the volumetric CT scans of lung diseases. A pair of CT values at which each homological feature appeared (birth) and disappeared (death) was computed by sweeping the threshold levels from higher to lower CT values. Consequently, fibrosis and emphysema were defined as voxels with dense voids having a longer lifetime (birth-death difference) and voxels with dense connected components having a lower birth, respectively. In an independent dataset including subjects with idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and combined pulmonary fibrosis and emphysema (CPFE), the proposed definition enabled accurate segmentation with comparable quality to deep learning in terms of Dice coefficients. Persistent homology-defined fibrosis was closely associated with physiological abnormalities such as impaired diffusion capacity and long-term mortality in subjects with IPF and CPFE, and persistent homology-defined emphysema was associated with impaired diffusion capacity in subjects with COPD. The present persistent homology-based evaluation of structural abnormalities could help explore the clinical and physiological impacts of structural changes and morphological mechanisms of disease progression.NEW & NOTEWORTHY This study proposes a homological approach to mathematically define a three-dimensional texture feature of emphysema and fibrosis on chest computed tomography using persistent homology. The proposed definition enabled accurate segmentation with comparable quality to deep learning while offering higher interpretability than deep learning-based methods.
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Affiliation(s)
- Naoya Tanabe
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shizuo Kaji
- Institute of Mathematics for Industry, Kyushu University, Fukuoka, Japan
| | - Susumu Sato
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoo Yokoyama
- Department of Mathematics, Kyoto University of Education, Kyoto, Japan
| | - Tsuyoshi Oguma
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kiminobu Tanizawa
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomohiro Handa
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Advanced Medicine for Respiratory Failure, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Sakajo
- Department of Mathematics, Kyoto University, Kyoto, Japan
| | - Toyohiro Hirai
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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40
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Omote N, Matsuda N, Hashimoto N, Nishida K, Sakamoto K, Ando A, Nakahara Y, Nishikimi M, Higashi M, Matsui S, Hasegawa Y. High-flow nasal cannula therapy for acute respiratory failure in patients with interstitial pneumonia: a retrospective observational study. NAGOYA JOURNAL OF MEDICAL SCIENCE 2021; 82:301-313. [PMID: 32581409 PMCID: PMC7276417 DOI: 10.18999/nagjms.82.2.301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
High-flow nasal cannula (HFNC) oxygen is a therapy that has demonstrated survival benefits in acute respiratory failure (ARF). However, the role of HFNC in ARF due to interstitial pneumonia (IP) is unknown. The aim of this study was to compare the effects of HFNC therapy and non-invasive positive pressure ventilation (NPPV) in ARF due to IP. This retrospective observational study included 32 patients with ARF due to IP who were treated with HFNC (n = 13) or NPPV (n = 19). The clinical characteristics, intubation rate and 30-day mortality were analyzed and compared between the HFNC group and the NPPV group. Predictors of 30-day mortality were evaluated using a logistic regression model. HFNC group showed higher mean arterial blood pressure (median 92 mmHg; HFNC group vs 74 mmHg; NPPV group) and lower APACHEII score (median 22; HFNC group vs 27; NPPV group) than NPPV group. There was no significant difference in the intubation rate at day 30 between the HFNC group and the NPPV group (8% vs 37%: p = 0.069); the mortality rate at 30 days was 23% and 63%, respectively. HFNC therapy was a significant determinant of 30-day mortality in univariate analysis, and was confirmed to be an independent significant determinant of 30-day mortality in multivariate analysis (odds ratio, 0.148; 95% confidence interval, 0.025–0.880; p = 0.036). Our findings suggest that HFNC therapy can be a possible option for respiratory management in ARF due to IP. The results observed here warrant further investigation of HFNC therapy in randomized control trials.
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Affiliation(s)
- Norihito Omote
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Pulmonary, Critical Care and Sleep Medicine Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, United States of America
| | - Naoyuki Matsuda
- Department of Emergency and Critical Care, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naozumi Hashimoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuki Nishida
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Koji Sakamoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Ando
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshio Nakahara
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuaki Nishikimi
- Department of Emergency and Critical Care, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michiko Higashi
- Department of Emergency and Critical Care, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shigeyuki Matsui
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Hasegawa
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
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Choi WI. Current and future treatment for idiopathic pulmonary fibrosis. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2021. [DOI: 10.5124/jkma.2021.64.4.256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrosing interstitial lung disease, which is associated with a short survival rate. The decline in forced vital capacity in patients with IPF appears to be almost the same rate regardless of baseline lung function status. This suggests that early treatment would be necessary to prevent further deterioration even lung function is maintained within normal limits. Both pirfenidone and nintedanib significantly slow the decline in lung function, reduce the risk of acute exacerbation, and improve survival rate. However, many individuals with IPF remain untreated. Most IPF patients can tolerate antifibrotic drug therapy, and the dose adjustment has been shown to effectively reduce side effects without modifying efficacy. Although the recent introduction of pirfenidone and nintedanib has led to the slowing of lung function decline, there is no evidence of fibrosis reversal. In the near future, several new drugs are expected to be prescribed to patients with IPF. We are anticipating that some drugs may reverse fibrosis. Fibrosis inhibiting drugs have different pharmacological actions and there are various mechanisms causing fibrosis in the lesion. Therefore, it is imperative to launch efforts to optimize antifibrotic effects through a combination therapy of several drugs. These efforts will hold out hope for patients with IPF.
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Lung gene expression and single cell analyses reveal two subsets of idiopathic pulmonary fibrosis (IPF) patients associated with different pathogenic mechanisms. PLoS One 2021; 16:e0248889. [PMID: 33755690 PMCID: PMC7987152 DOI: 10.1371/journal.pone.0248889] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 03/07/2021] [Indexed: 12/13/2022] Open
Abstract
Idiopathic pulmonary fibrosis is a progressive and debilitating lung disease with large unmet medical need and few treatment options. We describe an analysis connecting single cell gene expression with bulk gene expression-based subsetting of patient cohorts to identify IPF patient subsets with different underlying pathogenesis and cellular changes. We reproduced earlier findings indicating the existence of two major subsets in IPF and showed that these subsets display different alterations in cellular composition of the lung. We developed classifiers based on the cellular changes in disease to distinguish subsets. Specifically, we showed that one subset of IPF patients had significant increases in gene signature scores for myeloid cells versus a second subset that had significantly increased gene signature scores for ciliated epithelial cells, suggesting a differential pathogenesis among IPF subsets. Ligand-receptor analyses suggested there was a monocyte-macrophage chemoattractant axis (including potentially CCL2-CCR2 and CCL17-CCR4) among the myeloid-enriched IPF subset and a ciliated epithelium-derived chemokine axis (e.g. CCL15) among the ciliated epithelium-enriched IPF subset. We also found that these IPF subsets had differential expression of pirfenidone-responsive genes suggesting that our findings may provide an approach to identify patients with differential responses to pirfenidone and other drugs. We believe this work is an important step towards targeted therapies and biomarkers of response.
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Xue C, Wu N, Fan Y, Ma J, Ye Q. Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in China: a case-control study. BMC Pulm Med 2021; 21:91. [PMID: 33731064 PMCID: PMC7971960 DOI: 10.1186/s12890-021-01462-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/09/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Silicosis is a progressive pneumoconiosis characterized by interstitial fibrosis following exposure to silica dust. The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. This study aimed to identify different metabolic features in the plasma of patients with silicosis and dust-exposed workers without silicosis in metabolomics studies. METHODS Patients with silicosis, dust-exposed workers (DEWs) without silicosis and age-matched healthy controls were recruited in a case-control study. The metabolomics analyses by ultra-high performance liquid chromatography-mass spectrometry were conducted. Distinct metabolic features (DMFs) were identified in the pilot study and were validated in the validation study. The enriched signalling pathways of these DMFs were determined. The ability of DMFs to discriminate among the groups was analysed through receiver operating characteristic (ROC) curves. The correlations between DMFs and clinical features were also explored. RESULTS Twenty-nine DMFs and 9 DMFs were detected and had the same trend in the pilot study and the validation study in the plasma of the DEW and silicosis groups, respectively. Sphingolipid metabolism was the major metabolic pathway in the DEWs, and arginine and proline metabolism was associated with silicosis. Twenty DMFs in the DEWs and 3 DMFs in the patients with silicosis showed a discriminatory ability with ROC curve analysis. The abundance of kynurenine was higher in Stage III silicosis than in Stage I or Stage II silicosis. L-arginine and kynurenine were both negatively correlated with the percentage of forced vital capacity predicted in silicosis. CONCLUSIONS Distinct metabolic features in the plasma of DEWs and the patients with silicosis were found to be different. Sphingolipid metabolism and arginine and proline metabolism were identified as the major metabolic pathway in the DEW and silicosis groups, respectively. L-arginine and kynurenine were correlated with the severity of silicosis.
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Affiliation(s)
- Changjiang Xue
- Department of Occupational Medicine and Toxicology, Clinical Centre for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, 100020, China
| | - Na Wu
- Department of Occupational Medicine and Toxicology, Clinical Centre for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, 100020, China
| | - Yali Fan
- Department of Occupational Medicine and Toxicology, Clinical Centre for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, 100020, China
| | - Jing Ma
- Department of Occupational Medicine and Toxicology, Clinical Centre for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, 100020, China
| | - Qiao Ye
- Department of Occupational Medicine and Toxicology, Clinical Centre for Interstitial Lung Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, 100020, China.
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Initial therapeutic dose of corticosteroid for an acute exacerbation of IPF is associated with subsequent early recurrence of another exacerbation. Sci Rep 2021; 11:5782. [PMID: 33707613 PMCID: PMC7952684 DOI: 10.1038/s41598-021-85234-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 02/22/2021] [Indexed: 11/23/2022] Open
Abstract
Some patients with idiopathic pulmonary fibrosis (IPF) undergo recurrent acute exacerbations (AEs). This study aimed to elucidate the risk factors for recurrent AEs of IPF (AE-IPF). Consecutive patients with IPF admitted for their first AE-IPF between January 2008 and December 2018 were retrospectively recruited. Of 63 patients admitted for an AE-IPF and discharged alive, 9 (14.3%) developed a recurrence of AE within 1 year. The mean time to recurrence was 233 ± 103 days. Total doses (mg/month and mg/kg/month) of corticosteroids administered over day 1 to 30 after the AE were significantly higher in patients without recurrences of AE-IPF (5185 ± 2414 mg/month, 93.5 ± 44.0 mg/kg/month) than the doses in patients with recurrences (3133 ± 1990 mg/month, 57.2 ± 37.7 mg/kg/month) (p = 0.02 and p = 0.03, respectively). However, no differences were observed between the total doses of corticosteroids administered over days 31 to 60, 61 to 90, 91 to 120, and 151 to 180 after the AE. Furthermore, differences between the administration rates of immunosuppressive and antifibrotic treatments administered to the 2 patient groups were not significant. An increased total dose of corticosteroid administered over day 1 to 30 after an AE-IPF was associated with a decreased risk of subsequent recurrence of AE-IPF within 1 year after the first AE.
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Comparison of CURB-65, PSI, and qSOFA for predicting pneumonia mortality in patients with idiopathic pulmonary fibrosis. Sci Rep 2021; 11:3880. [PMID: 33594102 PMCID: PMC7887221 DOI: 10.1038/s41598-021-83381-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 02/02/2021] [Indexed: 11/30/2022] Open
Abstract
Some patients with idiopathic pulmonary fibrosis (IPF) require hospitalization due to pneumonia. Although predictive scoring tools have been developed and validated for community-acquired pneumonia (CAP), their usefulness in IPF is unknown. The Confusion, Urea, Respiratory Rate, Blood Pressure and Age (CURB-65) score and the Pneumonia Severity Index (PSI) are validated for CAP. The quick Sequential Organ Failure Assessment (qSOFA) is also reported to be useful. The aim of this study was to investigate the ability of these tools to predict pneumonia mortality among hospitalized patients with IPF. A total of 79 patients with IPF and pneumonia were hospitalized for the first time between January 2008 and December 2017. The hospital mortality rate was 15.1%. A univariate logistic regression analysis revealed that the CURB-65 (odds ratio 4.04, 95% confidence interval 1.60–10.2, p = 0.003), PSI (4.00, 1.48–10.7, 0.006), and qSOFA (5.00, 1.44–1.72, 0.01) scores were significantly associated with hospital mortality. There was no statistically significant difference between the three receiver operating characteristic curves (0.712, 0.736, and 0.692, respectively). The CURB-65, PSI, and qSOFA are useful tools for predicting pneumonia mortality among hospitalized patients with IPF. Because of its simplicity, the qSOFA may be most suitable for early assessment.
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Yamazaki R, Nishiyama O, Yoshikawa K, Saeki S, Sano H, Iwanaga T, Tohda Y. Clinical course and prognosis in survivors of acute exacerbations of idiopathic pulmonary fibrosis. Respir Investig 2021; 59:408-413. [PMID: 33549542 DOI: 10.1016/j.resinv.2020.12.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/06/2020] [Accepted: 12/31/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Patients with idiopathic pulmonary fibrosis (IPF) are at risk of acute exacerbations (AEs) that manifest as respiratory distress. However, the clinical course after AEs of IPF (AE-IPFs) has not been well described. Therefore, we aimed to elucidate the clinical course and prognosis in survivors of AE-IPFs. METHODS Consecutive patients with IPF who presented to our institution with their first AE-IPFs between January 2008 and December 2019 were included in this study. Data were retrospectively collected, and the clinical course, survival, and cause of death were further analyzed. RESULTS Ninety-seven patients were included in this retrospective study. Among them, 67 (69.1%) were discharged alive, with a median survival time after discharge of 1081 days. AE recurrence and pneumonia were the most common causes of death, each accounting for 22.2% of cases among survivors of AE-IPFs. AEs were the most frequent during the first 3 years after discharge, whereas pneumonia was more common thereafter. CONCLUSIONS Survivors of AE-IPFs have a relatively favorable long-term prognosis. Among the survivors of first AE-IPFs, AE recurrence and pneumonia were the most common causes of death after discharge. Therefore, preventing AE recurrence and lung infections is crucial for prolonging survival in survivors of AE-IPFs.
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Affiliation(s)
- Ryo Yamazaki
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan; Department of Respiratory Medicine and Allergology, Kindai University Nara Hospital, Ikoma, Nara 630-0293, Japan
| | - Osamu Nishiyama
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan.
| | - Kazuya Yoshikawa
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Sho Saeki
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Hiroyuki Sano
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Takashi Iwanaga
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Yuji Tohda
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka 589-8511, Japan
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HFpEF without elevated right ventricular systolic pressure is a favorable prognostic indicator in patients with IPF requiring hospitalization for heart failure. PLoS One 2021; 16:e0245778. [PMID: 33481923 PMCID: PMC7822325 DOI: 10.1371/journal.pone.0245778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 01/07/2021] [Indexed: 11/19/2022] Open
Abstract
Background Some patients with idiopathic pulmonary fibrosis (IPF) must be hospitalized because of heart failure (HF), including HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF). The association between IPF and HF has not been clarified. We retrospectively investigated the clinical features and outcomes of patients with IPF who required nonelective hospitalization because of HF. Methods We examined data from IPF patients who required nonelective hospitalization for HF at the Kindai University Hospital from January 2008 to December 2018. We divided the patients into 3 groups: those with HFpEF without elevated right ventricular systolic pressure (RVSP), those with HFpEF and elevated RVSP, and those with HFrEF. The recurrence rates of HF after discharge and the 30- and 90-day mortality rates of the patients were evaluated. Results During the study period, 37 patients with IPF required hospitalization because of HF. Among the 34 patients included in the study, 17 (50.0%) were diagnosed with HFpEF without elevated RVSP, 11 (32.3%) with HFpEF and elevated RVSP, and 6 (17.6%) with HFrEF. Patients with HFrEF had significantly higher values for B-type natriuretic peptide (BNP) and left ventricular (LV) end-systolic and end-diastolic diameters than patients with the 2 types of HFpEF (BNP: P = 0.01 and P = 0.0004, LV end-systolic diameter: P <0.0001 and P <0.0001, and LV end-diastolic diameter: P = 0.01 and P = 0.0004, respectively). Notably, the difference between the LVEFs of the patients with 2 types of HFpEF was not significant. The patients with HFpEF without elevated RVSP had the lowest 30- and 90-day mortality rates (0%, P = 0.02 and 11.7%, P = 0.11, respectively). Conclusions Among patients with IPF, HFpEF without elevated RVSP was the most common type of HF that required hospitalization. Patients with HFpEF without elevated RVSP survived longer than the patients with the other 2 types of HF.
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Yamazaki R, Nishiyama O, Gose K, Saeki S, Sano H, Iwanaga T, Tohda Y. Pneumothorax in patients with idiopathic pulmonary fibrosis: a real-world experience. BMC Pulm Med 2021; 21:5. [PMID: 33407311 PMCID: PMC7789641 DOI: 10.1186/s12890-020-01370-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 12/11/2020] [Indexed: 01/08/2023] Open
Abstract
Background Some patients with idiopathic pulmonary fibrosis (IPF) develop pneumothorax. However, the characteristics of pneumothorax in patients with IPF have not been elucidated. The purpose of this study was to clarify the clinical course, actual management, and treatment outcomes of pneumothorax in patients with IPF. Methods Consecutive patients with IPF who were admitted for pneumothorax between January 2008 and December 2018 were included. The success rates of treatment for pneumothorax, hospital mortality, and recurrence rate after discharge were examined. Results During the study period, 36 patients with IPF were admitted with pneumothorax a total of 58 times. During the first admission, 15 patients (41.7%) did not receive chest tube drainage, but 21 (58.3%) did. Of the 21 patients, 8 (38.1%) received additional therapy after chest drainage. The respective treatment success rates were 86.6% and 66.7% in patients who underwent observation only vs chest tube drainage. The respective hospital mortality rates were 13.3% and 38.0%. The total pneumothorax recurrence rate after hospital discharge was 34.6% (n = 9). Conclusions Pneumothorax in patients with IPF was difficult to treat successfully, had a relatively poor prognosis, and showed a high recurrence rate.
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Affiliation(s)
- Ryo Yamazaki
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Osamu Nishiyama
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
| | - Kyuya Gose
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Sho Saeki
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Hiroyuki Sano
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Takashi Iwanaga
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Yuji Tohda
- Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
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Peng L, Wen L, Shi QF, Gao F, Huang B, Meng J, Hu CP, Wang CM. Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis 2020; 11:978. [PMID: 33188176 PMCID: PMC7666141 DOI: 10.1038/s41419-020-03178-2] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 09/19/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is featured with inflammation and extensive lung remodeling caused by overloaded deposition of extracellular matrix. Scutellarin is the major effective ingredient of breviscapine and its anti-inflammation efficacy has been reported before. Nevertheless, the impact of scutellarin on IPF and the downstream molecular mechanism remain unclear. In this study, scutellarin suppressed BLM-induced inflammation via NF-κB/NLRP3 pathway both in vivo and in vitro. BLM significantly elevated p-p65/p65 ratio, IκBα degradation, and levels of NLRP3, caspase-1, caspase-11, ASC, GSDMDNterm, IL-1β, and IL-18, while scutellarin reversed the above alterations except for that of caspase-11. Scutellarin inhibited BLM-induced epithelial-mesenchymal transition (EMT) process in vivo and in vitro. The expression levels of EMT-related markers, including fibronectin, vimentin, N-cadherin, matrix metalloproteinase 2 (MMP-2) and MMP-9, were increased in BLM group, and suppressed by scutellarin. The expression level of E-cadherin showed the opposite changes. However, overexpression of NLRP3 eliminated the anti-inflammation and anti-EMT functions of scutellarin in vitro. In conclusion, scutellarin suppressed inflammation and EMT in BLM-induced pulmonary fibrosis through NF-κB/NLRP3 signaling.
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Affiliation(s)
- Ling Peng
- Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Key Site of the National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China
| | - Li Wen
- Department of Respiratory Medicine, The Fifth Affiliated Hospital of Guilin Medical University, Guilin People's Hospital, Guilin, 541002, P.R. China
| | - Qing-Feng Shi
- Department of Respiratory Medicine, The Fifth Affiliated Hospital of Guilin Medical University, Guilin People's Hospital, Guilin, 541002, P.R. China
| | - Feng Gao
- Department of Respiratory Medicine, The Fifth Affiliated Hospital of Guilin Medical University, Guilin People's Hospital, Guilin, 541002, P.R. China
| | - Bin Huang
- Department of Respiratory Medicine, The Fifth Affiliated Hospital of Guilin Medical University, Guilin People's Hospital, Guilin, 541002, P.R. China
| | - Jie Meng
- Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Key Site of the National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China
| | - Cheng-Ping Hu
- Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Key Site of the National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China.
| | - Chang-Ming Wang
- Department of Respiratory Medicine, The Fifth Affiliated Hospital of Guilin Medical University, Guilin People's Hospital, Guilin, 541002, P.R. China.
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Koralewski R, Dymek B, Mazur M, Sklepkiewicz P, Olejniczak S, Czestkowski W, Matyszewski K, Andryianau G, Niedziejko P, Kowalski M, Gruza M, Borek B, Jedrzejczak K, Bartoszewicz A, Pluta E, Rymaszewska A, Kania M, Rejczak T, Piasecka S, Mlacki M, Mazurkiewicz M, Piotrowicz M, Salamon M, Zagozdzon A, Napiorkowska-Gromadzka A, Bartlomiejczak A, Mozga W, Dobrzański P, Dzwonek K, Golab J, Nowotny M, Olczak J, Golebiowski A. Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis. J Med Chem 2020; 63:15527-15540. [PMID: 33078933 DOI: 10.1021/acs.jmedchem.0c01179] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.
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Affiliation(s)
- Robert Koralewski
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Barbara Dymek
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Marzena Mazur
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | | | - Sylwia Olejniczak
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | | | | | - Gleb Andryianau
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Piotr Niedziejko
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Michal Kowalski
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Mariusz Gruza
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Bartłomiej Borek
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Karol Jedrzejczak
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | | | - Elżbieta Pluta
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | | | - Magdalena Kania
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Tomasz Rejczak
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Sylwia Piasecka
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Michal Mlacki
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | | | - Michał Piotrowicz
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Magdalena Salamon
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | | | | | - Aneta Bartlomiejczak
- Structural Biology Center, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland
| | - Witold Mozga
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Paweł Dobrzański
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Karolina Dzwonek
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Jakub Golab
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland.,Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland
| | - Marcin Nowotny
- Structural Biology Center, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland
| | - Jacek Olczak
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Adam Golebiowski
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland
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