|
1
|
Kette S, Reccardini N, Salton F, Confalonieri P, Andrisano A, Chianese M, De Nes A, Maggisano M, Galantino A, Nicolosi S, Mari M, Salotti A, Angoni D, Chernovsky M, Hughes M, Confalonieri M, Mondini L, Ruaro B. The Impact of Comorbidities on the Discontinuation of Antifibrotic Therapy in Patients with Idiopathic Pulmonary Fibrosis. Pharmaceuticals (Basel) 2025; 18:411. [PMID: 40143187 PMCID: PMC11944575 DOI: 10.3390/ph18030411] [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: 01/22/2025] [Revised: 03/02/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory comorbidities, which can worsen symptoms and impact overall survival. Background/Objectives: The study aimed to investigate the effect of these comorbidities on the early and permanent discontinuation of pirfenidone or nintedanib in IPF patients. Methods: In this single-centre retrospective study, 101 patients diagnosed with IPF according to ATS/ERS/JRS/ALAT guidelines were treated with AFT. Clinical data were collected at 12 months prior to and up to 24 months following treatment initiation, including age, gender, smoking history, and the presence of respiratory and non-respiratory comorbidities. Results: The data showed that 21 patients (20.8%) discontinued treatment within the first 12 months. Additionally, pre-treatment comorbidities were not statistically correlated with the suspension of antifibrotic treatment. Among the overall cohort, 77 patients (76.2%) had at least one comorbidity and 27 (26.7%) had three or more comorbidities. Notably, 24 (23.8%) had respiratory comorbidities, while 75 (74.3%) had non-respiratory comorbidities. Conclusions: This real-life study emphasises the complexities involved in managing IPF, particularly regarding adherence to treatment when significant comorbidities are present. The evidence suggests that in patients with IPF, pre-treatment respiratory or non-respiratory conditions do not affect AFT discontinuation.
Collapse
Affiliation(s)
- Stefano Kette
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Nicolò Reccardini
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Francesco Salton
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Paola Confalonieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Alessia Andrisano
- Pulmonology Unit, Department of Cardio-Thoracic Surgery, Health Integrated Agency of Friuli Venezia Giulia, 33100 Udine, Italy
| | - Maria Chianese
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Anna De Nes
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Marta Maggisano
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Alessandra Galantino
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Salvatore Nicolosi
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Marco Mari
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Andrea Salotti
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Darina Angoni
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Maria Chernovsky
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Michael Hughes
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester & Salford Royal NHS Foundation Trust, Manchester M6 8HD, UK
| | - Marco Confalonieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Lucrezia Mondini
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Barbara Ruaro
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| |
Collapse
|
|
2
|
Liu H, Cui H, Liu G. The Intersection between Immune System and Idiopathic Pulmonary Fibrosis-A Concise Review. FIBROSIS (HONG KONG, CHINA) 2025; 3:10004. [PMID: 40124525 PMCID: PMC11928166 DOI: 10.70322/fibrosis.2025.10004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
Idiopathic pulmonary fibrosis (IPF) is marked by progressive alveolar destruction, impaired tissue regeneration, and relentless fibrogenesis, culminating in respiratory failure and death. A diverse array of resident and non-resident cells within the lung contribute to disease pathogenesis. Notably, immune cells, both resident and recruited, respond to cues from sites of lung injury by undergoing phenotypic transitions and producing a wide range of mediators that influence, initiate, or dictate the function, or dysfunction, of key effector cells in IPF pathology, such as alveolar epithelial cells, lung fibroblasts, and capillary endothelial cells. The role of the immune system in IPF has undergone an interesting evolution, oscillating from initial enthusiasm to skepticism, and now to a renewed focus. This shift reflects both the past failures of immune-targeting therapies for IPF and the unprecedented insights into immune cell heterogeneity provided by emerging technologies. In this article, we review the historical evolution of perspectives on the immune system's role in IPF pathogenesis and examine the lessons learned from previous therapeutic failures targeting immune responses. We discuss the major immune cell types implicated in IPF progression, highlighting their phenotypic transitions and mechanisms of action. Finally, we identify key knowledge gaps and propose future directions for research on the immune system in IPF.
Collapse
Affiliation(s)
- Hongli Liu
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Huachun Cui
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Gang Liu
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| |
Collapse
|
|
3
|
Tan Y, Qian B, Ma Q, Xiang K, Wang S. Identification and Analysis of Key Immune- and Inflammation-Related Genes in Idiopathic Pulmonary Fibrosis. J Inflamm Res 2025; 18:1993-2009. [PMID: 39959639 PMCID: PMC11829586 DOI: 10.2147/jir.s489210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 12/21/2024] [Indexed: 02/18/2025] Open
Abstract
Background Studies suggest that immune and inflammation processes may be involved in the development of idiopathic pulmonary fibrosis (IPF); however, their roles remain unclear. This study aims to identify key genes associated with immune response and inflammation in IPF using bioinformatics. Methods We identified differentially expressed genes (DEGs) in the GSE93606 dataset and GSE28042 dataset, then obtained differentially expressed immune- and inflammation-related genes (DE-IFRGs) by overlapping DEGs. Two machine learning algorithms were used to further screen key genes. Genes with an area under curve (AUC) of > 0.7 in receiver operating characteristic (ROC) curves, significant expression and consistent trends across datasets were considered key genes. Based on these key genes, we carried out nomogram construction, enrichment and immune analyses, regulatory network mapping, drug prediction, and expression verification. Results 27 DE-IFRGs were identified by intersecting 256 DEGs, 1793 immune-related genes, and 1019 inflammation-related genes. Three genes (RNASE3, S100A12, S100A8) were obtained by crossing two machine algorithms (Boruta and LASSO),which had good diagnostic performance with AUC values. These key genes were all enriched in the same pathways, such as GOCC_azurophil_granule, IL-12 signalling and production in macrophages is the pathway with the strongest role for key genes. Six distinct immune cells, including naive CD4 T cells, T cells CD4 memory resting, T cells regulatory (Tregs), Monocytes, Macrophages M2, Neutrophils were identified. Real-time quantitative polymerase chain reaction (RT-qPCR) results were consistent with the training and validation sets, and the expression of these key genes was significantly upregulated in the IPF samples. Conclusion This study identified three key genes (RNASE3, S100A12 and S100A8) associated with immune response and inflammation in IPF, providing valuable insights into the diagnosis and treatment of IPF.
Collapse
Affiliation(s)
- Yan Tan
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| | - Baojiang Qian
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| | - Qiurui Ma
- Medical School of Kunming University of Science and Technolog, Kunming, People’s Republic of China
| | - Kun Xiang
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| | - Shenglan Wang
- Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China
| |
Collapse
|
|
4
|
Magdaleno C, Tschumperlin DJ, Rajasekaran N, Varadaraj A. SOCS domain targets ECM assembly in lung fibroblasts and experimental lung fibrosis. Sci Rep 2024; 14:31855. [PMID: 39738247 PMCID: PMC11686354 DOI: 10.1038/s41598-024-83187-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 12/12/2024] [Indexed: 01/01/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease defined by a progressive decline in lung function due to scarring and accumulation of extracellular matrix (ECM) proteins. The SOCS (Suppressor Of Cytokine Signaling) domain is a 40 amino acid conserved domain known to form a functional ubiquitin ligase complex targeting the Von Hippel Lindau (VHL) protein for proteasomal degradation. Here we show that the SOCS conserved domain operates as a molecular tool, to disrupt collagen and fibronectin fibrils in the ECM associated with fibrotic lung myofibroblasts. Our results demonstrate that fibroblasts differentiated using TGFβ, followed by transduction with the SOCS domain, exhibit significantly reduced levels of the contractile myofibroblast-marker, α-SMA. Furthermore, in support of its role to retard differentiation, we find that lung fibroblasts expressing the SOCS domain present with significantly reduced levels of α-SMA and fibrillar fibronectin after differentiation with TGFβ. We show that adenoviral delivery of the SOCS domain in the fibrotic phase of experimental lung fibrosis in mice, significantly reduces collagen accumulation in disease lungs. These data underscore a novel function for the SOCS domain and its potential in ameliorating pathologic matrix deposition in lung fibroblasts and experimental lung fibrosis.
Collapse
Affiliation(s)
- Carina Magdaleno
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA
- Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Daniel J Tschumperlin
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Narendiran Rajasekaran
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA.
| | - Archana Varadaraj
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA.
| |
Collapse
|
|
5
|
Moua T, Baqir M, Ryu JH. What Is on the Horizon for Treatments in Idiopathic Pulmonary Fibrosis? J Clin Med 2024; 13:6304. [PMID: 39518443 PMCID: PMC11546700 DOI: 10.3390/jcm13216304] [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: 09/26/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence.
Collapse
Affiliation(s)
- Teng Moua
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA; (M.B.); (J.H.R.)
| | | | | |
Collapse
|
|
6
|
Chang SH, Jung S, Chae JJ, Kim JY, Kim SU, Choi JY, Han HJ, Kim HT, Kim HJ, Kim HJ, Park WY, Sparks JA, Lee EY, Lee JS. Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation. EBioMedicine 2024; 108:105339. [PMID: 39303666 PMCID: PMC11437874 DOI: 10.1016/j.ebiom.2024.105339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/21/2024] [Accepted: 08/30/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial. METHODS Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD. FINDINGS Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment. INTERPRETATION These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor. FUNDING This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.
Collapse
Affiliation(s)
- Sung Hae Chang
- Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, 31151, South Korea
| | - Seyoung Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Jeong Jun Chae
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Jeong Yeon Kim
- Inocras, Inc., San Diego, CA, 92121, USA; Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Seon Uk Kim
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Ji Yong Choi
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Hye-Jeong Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hyun Taek Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hak-Jae Kim
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hyun Je Kim
- Department of Biomedical Science, Seoul National University, Seoul, 03080, Republic of Korea
| | - Woong Yang Park
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Jeffrey A Sparks
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Eun Young Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
| | - Jeong Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea; Inocras, Inc., San Diego, CA, 92121, USA.
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Enzel D, Kriventsov M, Sataieva T, Malygina V. Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review. Int J Mol Sci 2024; 25:8946. [PMID: 39201632 PMCID: PMC11355055 DOI: 10.3390/ijms25168946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Idiopathic pulmonary fibrosis remains a relevant problem of the healthcare system with an unfavorable prognosis for patients due to progressive fibrous remodeling of the pulmonary parenchyma. Starting with the damage of the epithelial lining of alveoli, pulmonary fibrosis is implemented through a cascade of complex mechanisms, the crucial of which is the TGF-β/SMAD-mediated pathway, involving various cell populations. Considering that a number of the available drugs (pirfenidone and nintedanib) have only limited effectiveness in slowing the progression of fibrosis, the search and justification of new approaches aimed at regulating the immune response, cellular aging processes, programmed cell death, and transdifferentiation of cell populations remains relevant. This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.
Collapse
Affiliation(s)
| | | | - Tatiana Sataieva
- Medical Institute Named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Lenina Boulevard 5/7, 295051 Simferopol, Russia; (D.E.); (M.K.); (V.M.)
| | | |
Collapse
|
|
9
|
Colarusso C, Falanga A, Di Caprio S, Terlizzi M, D'Andria E, Antonio M, Maiolino P, Sorrentino R. ATP-induced fibrogenic pathway in circulating cells obtained by idiopathic pulmonary fibrotic (IPF) patients is not blocked by nintedanib and pirfenidone. Biomed Pharmacother 2024; 176:116896. [PMID: 38876049 DOI: 10.1016/j.biopha.2024.116896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/31/2024] [Accepted: 06/06/2024] [Indexed: 06/16/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFβ. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFβ. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFβ induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.
Collapse
Affiliation(s)
- Chiara Colarusso
- Department of Pharmacy, University of Salerno, Fisciano 804084, Italy
| | - Anna Falanga
- Department of Pharmacy, University of Salerno, Fisciano 804084, Italy; Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Simone Di Caprio
- Department of Pharmacy, University of Salerno, Fisciano 804084, Italy; Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Michela Terlizzi
- Department of Pharmacy, University of Salerno, Fisciano 804084, Italy
| | - Emmanuel D'Andria
- Department of Pharmacy, University of Salerno, Fisciano 804084, Italy
| | | | - Piera Maiolino
- Istituto Nazionale Tumori IRCCS, "Fondazione Pascale", National Institute of Cancer, Naples 80131, Italy
| | | |
Collapse
|
|
10
|
Ozaltin B, Chapman R, Arfeen MQU, Fitzpatick N, Hemingway H, Direk K, Jacob J. Delineating excess comorbidities in idiopathic pulmonary fibrosis: an observational study. Respir Res 2024; 25:249. [PMID: 38898447 PMCID: PMC11186192 DOI: 10.1186/s12931-024-02875-2] [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: 02/24/2024] [Accepted: 06/10/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Our study examined whether prevalent and incident comorbidities are increased in idiopathic pulmonary fibrosis (IPF) patients when compared to matched chronic obstructive pulmonary disease (COPD) patients and control subjects without IPF or COPD. METHODS IPF and age, gender and smoking matched COPD patients, diagnosed between 01/01/1997 and 01/01/2019 were identified from the Clinical Practice Research Datalink GOLD database multiple registrations cohort at the first date an ICD-10 or read code mentioned IPF/COPD. A control cohort comprised age, gender and pack-year smoking matched subjects without IPF or COPD. Prevalent (prior to IPF/COPD diagnosis) and incident (after IPF/COPD diagnosis) comorbidities were examined. Group differences were estimated using a t-test. Mortality relationships were examined using multivariable Cox proportional hazards adjusted for patient age, gender and smoking status. RESULTS Across 3055 IPF patients, 38% had 3 or more prevalent comorbidities versus 32% of COPD patients and 21% of matched control subjects. Survival time reduced as the number of comorbidities in an individual increased (p < 0.0001). In IPF, prevalent heart failure (Hazard ratio [HR] = 1.62, 95% Confidence Interval [CI]: 1.43-1.84, p < 0.001), chronic kidney disease (HR = 1.27, 95%CI: 1.10-1.47, p = 0.001), cerebrovascular disease (HR = 1.18, 95%CI: 1.02-1.35, p = 0.02), abdominal and peripheral vascular disease (HR = 1.29, 95%CI: 1.09-1.50, p = 0.003) independently associated with reduced survival. Key comorbidities showed increased incidence in IPF (versus COPD) 7-10 years prior to IPF diagnosis. INTERPRETATION The mortality impact of excessive prevalent comorbidities in IPF versus COPD and smoking matched controls suggests that multiorgan mechanisms of injury need elucidation in patients that develop IPF.
Collapse
Affiliation(s)
- Burcu Ozaltin
- Satsuma Lab, Centre for Medical Image Computing, UCL, London, UK
| | | | | | | | | | - Kenan Direk
- Imperial Clinical Trials Unit, Imperial College London, London, UK
| | - Joseph Jacob
- Satsuma Lab, Centre for Medical Image Computing, UCL, London, UK.
- UCL Respiratory, UCL, London, UK.
| |
Collapse
|
|
11
|
Magdaleno C, Tschumperlin DJ, Rajasekaran N, Varadaraj A. SOCS domain targets ECM assembly in lung fibroblasts and experimental lung fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.14.580347. [PMID: 38469152 PMCID: PMC10926664 DOI: 10.1101/2024.02.14.580347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease defined by a progressive decline in lung function due to scarring and accumulation of extracellular matrix (ECM) proteins. The SOCS (Suppressor Of Cytokine Signaling) domain is a 40 amino acid conserved domain known to form a functional ubiquitin ligase complex targeting the Von Hippel Lindau (VHL) protein for proteasomal degradation. Here we show that the SOCS conserved domain operates as a molecular tool, to disrupt collagen and fibronectin fibrils in the ECM associated with fibrotic lung myofibroblasts. Our results demonstrate that fibroblasts differentiated using TGFß, followed by transduction with the SOCS domain, exhibit significantly reduced levels of the contractile myofibroblast-marker, α-SMA. Furthermore, in support of its role to retard differentiation, we find that lung fibroblasts expressing the SOCS domain present with significantly reduced levels of α-SMA and fibrillar fibronectin after differentiation with TGFß. We show that adenoviral delivery of the SOCS domain in the fibrotic phase of experimental lung fibrosis in mice, significantly reduces collagen accumulation in disease lungs. These data underscore a novel function for the SOCS domain and its potential in ameliorating pathologic matrix deposition in lung fibroblasts and experimental lung fibrosis.
Collapse
Affiliation(s)
- Carina Magdaleno
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, Arizona, USA
| | - Daniel J. Tschumperlin
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Narendiran Rajasekaran
- Correspondence to: Archana Varadaraj, PO Box 5698, Science and Health Building, Rm430, Flagstaff, AZ, 86011, USA. Tel: (928) 523-6394, Fax: (928) 523-8111, ; Narendiran Rajasekaran, PO Box 5698, Science and Health Building, Rm430, Flagstaff, AZ, 86011, USA. Tel: (928) 523-6394, Fax: (928) 523-8111,
| | - Archana Varadaraj
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, Arizona, USA
| |
Collapse
|
|
12
|
Yan P, Liu J, Li Z, Wang J, Zhu Z, Wang L, Yu G. Glycolysis Reprogramming in Idiopathic Pulmonary Fibrosis: Unveiling the Mystery of Lactate in the Lung. Int J Mol Sci 2023; 25:315. [PMID: 38203486 PMCID: PMC10779333 DOI: 10.3390/ijms25010315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/17/2023] [Accepted: 12/23/2023] [Indexed: 01/12/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by excessive deposition of fibrotic connective tissue in the lungs. Emerging evidence suggests that metabolic alterations, particularly glycolysis reprogramming, play a crucial role in the pathogenesis of IPF. Lactate, once considered a metabolic waste product, is now recognized as a signaling molecule involved in various cellular processes. In the context of IPF, lactate has been shown to promote fibroblast activation, myofibroblast differentiation, and extracellular matrix remodeling. Furthermore, lactate can modulate immune responses and contribute to the pro-inflammatory microenvironment observed in IPF. In addition, lactate has been implicated in the crosstalk between different cell types involved in IPF; it can influence cell-cell communication, cytokine production, and the activation of profibrotic signaling pathways. This review aims to summarize the current research progress on the role of glycolytic reprogramming and lactate in IPF and its potential implications to clarify the role of lactate in IPF and to provide a reference and direction for future research. In conclusion, elucidating the intricate interplay between lactate metabolism and fibrotic processes may lead to the development of innovative therapeutic strategies for IPF.
Collapse
Affiliation(s)
| | | | | | | | | | - Lan Wang
- State Key Laboratory of Cell Differentiation and Regulation, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Pingyuan Laboratory, College of Life Science, Henan Normal University, Xinxiang 453007, China; (P.Y.); (J.L.); (Z.L.); (J.W.); (Z.Z.)
| | - Guoying Yu
- State Key Laboratory of Cell Differentiation and Regulation, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Pingyuan Laboratory, College of Life Science, Henan Normal University, Xinxiang 453007, China; (P.Y.); (J.L.); (Z.L.); (J.W.); (Z.Z.)
| |
Collapse
|
|
13
|
Thiam F, Phogat S, Abokor FA, Osei ET. In vitro co-culture studies and the crucial role of fibroblast-immune cell crosstalk in IPF pathogenesis. Respir Res 2023; 24:298. [PMID: 38012580 PMCID: PMC10680329 DOI: 10.1186/s12931-023-02608-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 11/14/2023] [Indexed: 11/29/2023] Open
Abstract
IPF is a fatal lung disease characterized by intensive remodeling of lung tissue leading to respiratory failure. The remodeling in IPF lungs is largely characterized by uncontrolled fibrosis. Fibroblasts and their contractile phenotype the myofibroblast are the main cell types responsible for typical wound healing responses, however in IPF, these responses are aberrant and result in the overactivation of fibroblasts which contributes to the inelasticity of the lung leading to a decrease in lung function. The specific mechanisms behind IPF pathogenesis have been elusive, but recently the innate and adaptive immunity have been implicated in the fibrotic processes of the disease. In connection with this, several in vitro co-culture models have been used to investigate the specific interactions occurring between fibroblasts and immune cells and how this contributes to the pathobiology of IPF. In this review, we discuss the in vitro models that have been used to examine the abnormal interactions between fibroblasts and cells of the innate and adaptive immune system, and how these contribute to the fibrotic processes in the lungs of IPF patients.
Collapse
Affiliation(s)
- Fama Thiam
- Department of Biology, University of British Columbia, 3187 University Way, ASC366, Kelowna, BC, V1V1V7, Canada
| | - Sakshi Phogat
- Department of Biology, University of British Columbia, 3187 University Way, ASC366, Kelowna, BC, V1V1V7, Canada
| | - Filsan Ahmed Abokor
- Department of Biology, University of British Columbia, 3187 University Way, ASC366, Kelowna, BC, V1V1V7, Canada
| | - Emmanuel Twumasi Osei
- Department of Biology, University of British Columbia, 3187 University Way, ASC366, Kelowna, BC, V1V1V7, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.
| |
Collapse
|
|
14
|
Enomoto Y, Katsura H, Fujimura T, Ogata A, Baba S, Yamaoka A, Kihara M, Abe T, Nishimura O, Kadota M, Hazama D, Tanaka Y, Maniwa Y, Nagano T, Morimoto M. Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis. Nat Commun 2023; 14:4956. [PMID: 37653024 PMCID: PMC10471635 DOI: 10.1038/s41467-023-40617-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 07/31/2023] [Indexed: 09/02/2023] Open
Abstract
The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets.
Collapse
Affiliation(s)
- Yasunori Enomoto
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Hiroaki Katsura
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Takashi Fujimura
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
- Department of Drug Modality Development, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., 5-1-35 Saitoaokita, Minoh, 562-0029, Japan
| | - Akira Ogata
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Saori Baba
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Akira Yamaoka
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Miho Kihara
- Laboratory for Animal Resources and Genetic Engineering (LARGE), RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Takaya Abe
- Laboratory for Animal Resources and Genetic Engineering (LARGE), RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Osamu Nishimura
- Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Mitsutaka Kadota
- Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Daisuke Hazama
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yugo Tanaka
- Division of Thoracic Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoshimasa Maniwa
- Division of Thoracic Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Mitsuru Morimoto
- Laboratory for Lung Development and Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
| |
Collapse
|
|
15
|
Golec M, Kamdar M, Barteit S. Comprehensive Ontology of Fibroproliferative Diseases: Protocol for a Semantic Technology Study. JMIR Res Protoc 2023; 12:e48645. [PMID: 37566458 PMCID: PMC10457705 DOI: 10.2196/48645] [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: 05/02/2023] [Revised: 06/16/2023] [Accepted: 07/04/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Fibroproliferative or fibrotic diseases (FDs), which represent a significant proportion of age-related pathologies and account for over 40% of mortality in developed nations, are often underrepresented in focused research. Typically, these conditions are studied individually, such as chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis (IPF), rather than as a collective entity, thereby limiting the holistic understanding and development of effective treatments. To address this, we propose creating and publicizing a comprehensive fibroproliferative disease ontology (FDO) to unify the understanding of FDs. OBJECTIVE This paper aims to delineate the study protocol for the creation of the FDO, foster transparency and high quality standards during its development, and subsequently promote its use once it becomes publicly available. METHODS We aim to establish an ontology encapsulating the broad spectrum of FDs, constructed in the Web Ontology Language format using the Protégé ontology editor, adhering to ontology development life cycle principles. The modeling process will leverage Protégé in accordance with a methodologically defined process, involving targeted scoping reviews of MEDLINE and PubMed information, expert knowledge, and an ontology development process. A hybrid top-down and bottom-up strategy will guide the identification of core concepts and relations, conducted by a team of domain experts based on systematic iterations of scientific literature reviews. RESULTS The result will be an exhaustive FDO accommodating a wide variety of crucial biomedical concepts, augmented with synonyms, definitions, and references. The FDO aims to encapsulate diverse perspectives on the FD domain, including those of clinicians, health informaticians, medical researchers, and public health experts. CONCLUSIONS The FDO is expected to stimulate broader and more in-depth FD research by enabling reasoning, inference, and the identification of relationships between concepts for application in multiple contexts, such as developing specialized software, fostering research communities, and enhancing domain comprehension. A common vocabulary and understanding of relationships among medical professionals could potentially expedite scientific progress and the discovery of innovative solutions. The publicly available FDO will form the foundation for future research, technological advancements, and public health initiatives. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/48645.
Collapse
Affiliation(s)
- Marcin Golec
- Heidelberg Institute of Global Health, Faculty of Medicine and University Hospital, Heidelberg University, Heidelberg, Germany
| | - Maulik Kamdar
- Center for Advanced Clinical Solutions, Optum Health, Eden Prairie, MN, United States
| | - Sandra Barteit
- Heidelberg Institute of Global Health, Faculty of Medicine and University Hospital, Heidelberg University, Heidelberg, Germany
| |
Collapse
|
|
16
|
Simon KS, Coelho LC, Veloso PHDH, Melo-Silva CA, Morais JAV, Longo JPF, Figueiredo F, Viana L, Silva Pereira I, Amado VM, Mortari MR, Bocca AL. Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis. Int J Mol Sci 2023; 24:11049. [PMID: 37446227 DOI: 10.3390/ijms241311049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. BALB/c mice were intratracheally instilled with bleomycin (BLM) and followed for 30 days. The mice were treated with the immune modulatory peptides ToAP3 and ToAP4 every three days, starting on the 5th day post-BLM instillation. ELISA, qPCR, morphology, and respiratory function analyses were performed. The treatment with both peptides delayed the inflammatory process observed in the non-treated group, which showed a fibrotic process with alterations in the production of collagen I, III, and IV that were associated with significant alterations in their ventilatory mechanics. The ToAP3 and ToAP4 treatments, by lung gene modulation patterns, indicated that distinct mechanisms determine the action of peptides. Both peptides controlled the experimental IPF, maintaining the tissue characteristics and standard function properties and regulating fibrotic-associated cytokine production. Data obtained in this work show that the immune response regulation by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process after BLM instillation, making both peptides potential therapeutic alternatives and/or adjuvants for IPF.
Collapse
Affiliation(s)
- Karina Smidt Simon
- Department of Cellular Biology, Institute of Biological Sciences, University of Brasilia, Brasilia 70910-900, Brazil
| | - Luísa Coutinho Coelho
- Department of Cellular Biology, Institute of Biological Sciences, University of Brasilia, Brasilia 70910-900, Brazil
| | | | - Cesar Augusto Melo-Silva
- Laboratory of Respiratory Physiology, Medical School, University of Brasilia, Brasilia 70910-900, Brazil
- Hospital of the University of Brasilia, University of Brasilia, Brasilia 70910-900, Brazil
| | | | - João Paulo Figueiró Longo
- Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasilia, Brasilia 70910-900, Brazil
| | - Florencio Figueiredo
- Laboratory of Pathology, Medical School, University of Brasilia, Brasilia 70910-900, Brazil
| | - Leonora Viana
- Laboratory of Pathology, Medical School, University of Brasilia, Brasilia 70910-900, Brazil
| | - Ildinete Silva Pereira
- Department of Cellular Biology, Institute of Biological Sciences, University of Brasilia, Brasilia 70910-900, Brazil
| | - Veronica Moreira Amado
- Laboratory of Respiratory Physiology, Medical School, University of Brasilia, Brasilia 70910-900, Brazil
- Hospital of the University of Brasilia, University of Brasilia, Brasilia 70910-900, Brazil
| | - Marcia Renata Mortari
- Department de Physiological Sciences, Institute of Biological Sciences, University of Brasilia, Brasilia 70910-900, Brazil
| | - Anamelia Lorenzetti Bocca
- Department of Cellular Biology, Institute of Biological Sciences, University of Brasilia, Brasilia 70910-900, Brazil
| |
Collapse
|
|
17
|
Andronache IT, Şuţa VC, Şuţa M, Ciocodei SL, Vladareanu L, Nicoara AD, Arghir OC. Better Safe than Sorry: Rheumatoid Arthritis, Interstitial Lung Disease, and Medication-A Narrative Review. Biomedicines 2023; 11:1755. [PMID: 37371850 DOI: 10.3390/biomedicines11061755] [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: 05/15/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
It is well known that rheumatoid arthritis (RA) patients are at an increased risk of developing non-infectious pulmonary complications, especially interstitial lung disease (ILD); however, the clinician must keep in mind that lung disease could not only be a manifestation of the underlying condition, but also a consequence of using disease-modifying therapies. New-onset ILD or ILD worsening has also been reported as a possible consequence of both conventional disease-modifying antirheumatic drugs (DMARDs) and biologic agents. This study is a narrative review of the current literature regarding the potential risk of developing interstitial lung disease along with the administration of specific drugs used in controlling rheumatoid arthritis. Its purpose is to fill knowledge gaps related to this challenging patient cohort by addressing various aspects of the disease, including prevalence, disease features, treatment strategies, and patient outcomes.
Collapse
Affiliation(s)
- Iulia-Tania Andronache
- Doctoral School of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
- Department of Rheumatology, Internal Medicine Clinic, "Dr. Alexandru Gafencu" Military Emergency Hospital Constanta, 900527 Constanta, Romania
| | - Victoria-Cristina Şuţa
- 3rd Department-1st Clinical Medical Disciplines, Faculty of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
| | - Maria Şuţa
- Doctoral School of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
| | - Sabina-Livia Ciocodei
- Doctoral School of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
| | - Liliana Vladareanu
- Doctoral School of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
| | - Alina Doina Nicoara
- 3rd Department-1st Clinical Medical Disciplines, Faculty of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
| | - Oana Cristina Arghir
- Doctoral School of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
- 4th Department-2nd Clinical Medical Disciplines, Faculty of Medicine, "Ovidius" University of Constanta, 900470 Constanta, Romania
| |
Collapse
|
|
18
|
Zhu Q, Barnes CE, Mannes PZ, Latoche JD, Day KE, Nedrow JR, Novelli EM, Anderson CJ, Tavakoli S. Targeted imaging of very late antigen-4 for noninvasive assessment of lung inflammation-fibrosis axis. EJNMMI Res 2023; 13:55. [PMID: 37273103 PMCID: PMC10240482 DOI: 10.1186/s13550-023-01006-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 06/01/2023] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND The lack of noninvasive methods for assessment of dysregulated inflammation as a major driver of fibrosis (i.e., inflammation-fibrosis axis) has been a major challenge to precision management of fibrotic lung diseases. Here, we determined the potential of very late antigen-4 (VLA-4)-targeted positron emission tomography (PET) to detect inflammation in a mouse model of bleomycin-induced fibrotic lung injury. METHOD Single time-point and longitudinal VLA-4-targeted PET was performed using a high-affinity peptidomimetic radiotracer, 64Cu-LLP2A, at weeks 1, 2, and 4 after bleomycin-induced (2.5 units/kg) lung injury in C57BL/6J mice. The severity of fibrosis was determined by measuring the hydroxyproline content of the lungs and expression of markers of extracellular matrix remodeling. Flow cytometry and histology was performed to determine VLA-4 expression across different leukocyte subsets and their spatial distribution. RESULTS Lung uptake of 64Cu-LLP2A was significantly elevated throughout different stages of the progression of bleomycin-induced injury. High lung uptake of 64Cu-LLP2A at week-1 post-bleomycin was a predictor of poor survival over the 4-week follow up, supporting the prognostic potential of 64Cu-LLP2A PET during the early stage of the disease. Additionally, the progressive increase in 64Cu-LLP2A uptake from week-1 to week-4 post-bleomycin correlated with the ultimate extent of lung fibrosis and ECM remodeling. Flow cytometry revealed that LLP2A binding was restricted to leukocytes. A combination of increased expression of VLA-4 by alveolar macrophages and accumulation of VLA-4-expressing interstitial and monocyte-derived macrophages as well as dendritic cells was noted in bleomycin-injured, compared to control, lungs. Histology confirmed the increased expression of VLA-4 in bleomycin-injured lungs, particularly in inflamed and fibrotic regions. CONCLUSIONS VLA-4-targeted PET allows for assessment of the inflammation-fibrosis axis and prediction of disease progression in a murine model. The potential of 64Cu-LLP2A PET for assessment of the inflammation-fibrosis axis in human fibrotic lung diseases needs to be further investigated.
Collapse
Affiliation(s)
- Qin Zhu
- Department of Radiology, University of Pittsburgh, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA
| | - Clayton E Barnes
- Department of Radiology, University of Pittsburgh, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA
| | - Philip Z Mannes
- Department of Radiology, University of Pittsburgh, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA
- Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Joseph D Latoche
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kathryn E Day
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jessie R Nedrow
- Department of Radiology, University of Pittsburgh, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA
| | - Enrico M Novelli
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Carolyn J Anderson
- Department of Chemistry, University of Missouri, Columbia, MO, USA
- Department of Radiology, University of Missouri, Columbia, MO, USA
| | - Sina Tavakoli
- Department of Radiology, University of Pittsburgh, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA.
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| |
Collapse
|
|
19
|
Novak CM, Sethuraman S, Luikart KL, Reader BF, Wheat JS, Whitson B, Ghadiali SN, Ballinger MN. Alveolar macrophages drive lung fibroblast function in cocultures of IPF and normal patient samples. Am J Physiol Lung Cell Mol Physiol 2023; 324:L507-L520. [PMID: 36791050 PMCID: PMC10259863 DOI: 10.1152/ajplung.00263.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/19/2023] [Accepted: 02/13/2023] [Indexed: 02/16/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by increased collagen accumulation that is progressive and nonresolving. Although fibrosis progression may be regulated by fibroblasts and alveolar macrophage (AM) interactions, this cellular interplay has not been fully elucidated. To study AM-fibroblast interactions, cells were isolated from IPF and normal human lung tissue and cultured independently or together in direct 2-D coculture, direct 3-D coculture, indirect transwell, and in 3-D hydrogels. AM influence on fibroblast function was assessed by gene expression, cytokine/chemokine secretion, and hydrogel contractility. Normal AMs cultured in direct contact with fibroblasts downregulated extracellular matrix (ECM) gene expression whereas IPF AMs had little to no effect. Fibroblast contractility was assessed by encapsulating cocultures in 3-D collagen hydrogels and monitoring gel diameter over time. Both normal and IPF AMs reduced baseline contractility of normal fibroblasts but had little to no effect on IPF fibroblasts. When stimulated with Toll-like receptor (TLR) agonists, IPF AMs increased production of pro-inflammatory cytokines TNFα and IL-1β, compared with normal AMs. TLR ligand stimulation did not alter fibroblast contraction, but stimulation with exogenous TNFα and TGFβ did alter contraction. To determine if the observed changes required cell-to-cell contact, AM-conditioned media and transwell systems were utilized. Transwell culture showed decreased ECM gene expression changes compared with direct coculture and conditioned media from AMs did not alter fibroblast contraction regardless of disease state. Taken together, these data indicate that normal fibroblasts are more responsive to AM crosstalk, and that AM influence on fibroblast behavior depends on cell proximity.
Collapse
Affiliation(s)
- Caymen M Novak
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, United States
| | - Shruthi Sethuraman
- Department of Biomedical Engineering, Ohio State University, Columbus, Ohio, United States
| | - Kristina L Luikart
- Department of Biomedical Engineering, Ohio State University, Columbus, Ohio, United States
| | - Brenda F Reader
- Department of Biomedical Engineering, Ohio State University, Columbus, Ohio, United States
| | - Jana S Wheat
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, United States
| | - Bryan Whitson
- Department of Biomedical Engineering, Ohio State University, Columbus, Ohio, United States
| | - Samir N Ghadiali
- Department of Biomedical Engineering, Ohio State University, Columbus, Ohio, United States
| | - Megan N Ballinger
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, United States
| |
Collapse
|
|
20
|
Flaxman HA, Chrysovergi MA, Han H, Kabir F, Lister RT, Chang CF, Black KE, Lagares D, Woo CM. Sanglifehrin A mitigates multi-organ fibrosis in vivo by inducing secretion of the collagen chaperone cyclophilin B. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.09.531890. [PMID: 36945535 PMCID: PMC10028952 DOI: 10.1101/2023.03.09.531890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis by myofibroblasts have clinical potential as anti-fibrotic agents. Lysine hydroxylation by the prolyl-3-hydroxylase complex, comprised of cartilage associated protein, prolyl 3-hydroxylase 1, and cyclophilin B, is essential for collagen type I crosslinking and formation of stable fibers. Here, we identify the collagen chaperone cyclophilin B as a major cellular target of the macrocyclic natural product sanglifehrin A (SfA) using photo-affinity labeling and chemical proteomics. Our studies reveal a unique mechanism of action in which SfA binding to cyclophilin B in the endoplasmic reticulum (ER) induces the secretion of cyclophilin B to the extracellular space, preventing TGF-β1-activated myofibroblasts from synthesizing collagen type I in vitro without inhibiting collagen type I mRNA transcription or inducing ER stress. In addition, SfA prevents collagen type I secretion without affecting myofibroblast contractility or TGF-β1 signaling. In vivo, we provide chemical, molecular, functional, and translational evidence that SfA mitigates the development of lung and skin fibrosis in mouse models by inducing cyclophilin B secretion, thereby inhibiting collagen synthesis from fibrotic fibroblasts in vivo . Consistent with these findings in preclinical models, SfA reduces collagen type I secretion from fibrotic human lung fibroblasts and precision cut lung slices from patients with idiopathic pulmonary fibrosis, a fatal fibrotic lung disease with limited therapeutic options. Our results identify the primary liganded target of SfA in cells, the collagen chaperone cyclophilin B, as a new mechanistic target for the treatment of organ fibrosis.
Collapse
|
|
21
|
Matsuzaki S, Pouly JL, Canis M. IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis: IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression. Hum Reprod 2023; 38:14-29. [PMID: 36413036 DOI: 10.1093/humrep/deac248] [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: 08/01/2022] [Revised: 10/25/2022] [Indexed: 11/23/2022] Open
Abstract
STUDY QUESTION Is interleukin-10 (IL-10) anti-fibrotic in endometriosis? SUMMARY ANSWER IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis, because IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression. WHAT IS KNOWN ALREADY We previously showed that persistent activation of signal transducer and activator of transcription 3 (STAT3) via IL-6 trans-signaling promotes fibrosis of endometriosis. Studies showed marked anti-fibrotic effects of IL-10 via the STAT3 signaling pathway, which is generally considered to be anti-inflammatory, in various organs. STUDY DESIGN, SIZE, DURATION Endometrial and/or endometriotic samples of 54 patients who had histological evidence of deep endometriosis, and endometrial samples from 30 healthy fertile women were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS The effects of IL-10/STAT3 signaling as well as inhibition of STAT3 activation by knockdown of STAT3 gene on the pro-fibrotic phenotype in endometrial and endometriotic stromal cells in vitro were investigated. Then, the effects of various time points of IL-10 treatment in combination with transforming growth factor (TGF)-β1 and/or IL-6/soluble IL-6 receptor (sIL-6R) on the profibrotic phenotype of endometrial and endometriotic stromal cells were investigated. MAIN RESULTS AND THE ROLE OF CHANCE IL-10 induced pro-fibrotic phenotype (cell proliferation, collagen type I synthesis, α-smooth muscle actin positive stress fibers and collagen gel contraction) of endometriotic stromal cells. Knockdown of STAT3 gene decreased the IL-10 induced pro-fibrotic phenotype of endometriotic stromal cells. In contrast, IL-10 had no significant effects on pro-fibrotic phenotype of endometrial stromal cells of healthy women. Sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R induced persistent activation of STAT3 and significantly increased proliferation of myofibroblasts (cells with α-smooth muscle actin positive stress fibers) and protein expression of collagen type I in endometriotic stromal cells. TGF-β1 and/or IL-6/sIL6RIL-6/sIL6R treatment significantly increased tissue inhibitor of metalloproteinase 1 (TIMP1) protein expression, whereas IL-10 had no significant effects. Knockdown of STAT3 gene significantly decreased the TGF-β1 and/or IL-6/sIL6R induced TIMP1 protein expression. In contrast, pre-treatment with IL-10 before TGF-β1 and/or IL-6/sIL-6R treatment and sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R significantly decreased proliferation of fibroblasts (cells without α-smooth muscle actin positive stress fibers) and collagen type I protein expression in endometrial stromal cells of healthy women. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Given the large number of complex interactions and signaling pathways of pro- and anti-inflammatory mediators that are involved in the pathophysiology of endometriosis, the present study investigated only a very small portion of the whole. Further in vivo studies are required to validate the present findings. WIDER IMPLICATIONS OF THE FINDINGS Inflammatory mediators in the pathophysiology of endometriosis have been extensively investigated as potential therapeutic targets. However, the present study showed that anti-inflammatory signals of IL-10 and IL-6 through persistent STAT3 activation may promote endometriosis fibrosis. Therapeutic strategies, such as suppression of 'inflammation', might dysregulate the cross-regulation of 'pro- and anti-inflammatory mediators', leading to detrimental effects in patients with endometriosis, such as fibrosis. To develop new, but not deleterious, therapeutic strategies, studies are required to investigate whether, how and what 'anti-inflammatory mediators' along with pro-inflammatory mediators are involved in individual patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by KARL STORZ SE & Co. KG (Tuttlingen, Germany). The authors have no conflict of interest to disclose.
Collapse
Affiliation(s)
- Sachiko Matsuzaki
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Jean-Luc Pouly
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Michel Canis
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| |
Collapse
|
|
22
|
Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms232314959. [PMID: 36499287 PMCID: PMC9735580 DOI: 10.3390/ijms232314959] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.
Collapse
|
|
23
|
Marzoog BA. Pulmonary Fibrosis; Risk Factors and Molecular Triggers, Insight for Neo
Therapeutic Approach. CURRENT RESPIRATORY MEDICINE REVIEWS 2022; 18:259-266. [DOI: 10.2174/1573398x18666220806124019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/20/2022] [Accepted: 04/26/2022] [Indexed: 11/22/2022]
Abstract
Abstract:
Overactivation of the local pulmonary fibroblast induces hyperproduction of the extracellular matrix. A myriad of pathomorphological changes occur during lung fibrosis, including interalveolar space (interstitial) deposition due to proliferation and differentiation of resident fibroblasts, recruitment of circulating stem cells and epithelial–mesenchymal transition, highly reactive and hyperplastic alveolar epithelium. Currently, many endogenous and exogenous factors are believed to be associated with lung fibrosis development. However, pathogenetic treatment remains in the womb of development. Exploring the underlying pathophysiology is crucial for successful development of pathogenetic treatment. Several molecules termed chemokines and cytokines have been found to induce lung fibrosis, such as IL-6, IL-1β, PDGFRα, TNF-α, GM-CSF, and IL-13. However, many others, such as IL-8, RANTES, IP-10, and MIG or lymphotactin, have an antifibrosis effect. However, the pathogenesis is multifactorial and involves dysregulation of the immune system, impaired cell-cell adhesion regulation mechanisms, and loss of DNA repair. The paper aimed to thoroughly addresses the potential risk factors and molecular triggers of lung fibrosis.
Collapse
|
|
24
|
Goodwin AT, Noble PW, Tatler AL. Plasma cells: a feasible therapeutic target in pulmonary fibrosis? Eur Respir J 2022; 60:60/5/2201748. [PMID: 36423920 DOI: 10.1183/13993003.01748-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/17/2022] [Indexed: 11/26/2022]
Affiliation(s)
- Amanda T Goodwin
- Centre for Respiratory Research, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Paul W Noble
- Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Amanda L Tatler
- Centre for Respiratory Research, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| |
Collapse
|
|
25
|
Hung CT, Tsai YW, Wu YS, Yeh CF, Yang KC. The novel role of ER protein TXNDC5 in the pathogenesis of organ fibrosis: mechanistic insights and therapeutic implications. J Biomed Sci 2022; 29:63. [PMID: 36050716 PMCID: PMC9438287 DOI: 10.1186/s12929-022-00850-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Fibrosis-related disorders account for an enormous burden of disease-associated morbidity and mortality worldwide. Fibrosis is defined by excessive extracellular matrix deposition at fibrotic foci in the organ tissue following injury, resulting in abnormal architecture, impaired function and ultimately, organ failure. To date, there lacks effective pharmacological therapy to target fibrosis per se, highlighting the urgent need to identify novel drug targets against organ fibrosis. Recently, we have discovered the critical role of a fibroblasts-enriched endoplasmic reticulum protein disulfide isomerase (PDI), thioredoxin domain containing 5 (TXNDC5), in cardiac, pulmonary, renal and liver fibrosis, showing TXNDC5 is required for the activation of fibrogenic transforming growth factor-β signaling cascades depending on its catalytic activity as a PDI. Moreover, deletion of TXNDC5 in fibroblasts ameliorates organ fibrosis and preserves organ function by inhibiting myofibroblasts activation, proliferation and extracellular matrix production. In this review, we detailed the molecular and cellular mechanisms by which TXNDC5 promotes fibrogenesis in various tissue types and summarized potential therapeutic strategies targeting TXNDC5 to treat organ fibrosis.
Collapse
Affiliation(s)
- Chen-Ting Hung
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Yi-Wei Tsai
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Yu-Shuo Wu
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Chih-Fan Yeh
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan. .,Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan. .,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan. .,Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
| |
Collapse
|
|
26
|
Cottin V, Bonniaud P, Cadranel J, Crestani B, Jouneau S, Marchand-Adam S, Nunes H, Wémeau-Stervinou L, Bergot E, Blanchard E, Borie R, Bourdin A, Chenivesse C, Clément A, Gomez E, Gondouin A, Hirschi S, Lebargy F, Marquette CH, Montani D, Prévot G, Quetant S, Reynaud-Gaubert M, Salaun M, Sanchez O, Trumbic B, Berkani K, Brillet PY, Campana M, Chalabreysse L, Chatté G, Debieuvre D, Ferretti G, Fourrier JM, Just N, Kambouchner M, Legrand B, Le Guillou F, Lhuillier JP, Mehdaoui A, Naccache JM, Paganon C, Rémy-Jardin M, Si-Mohamed S, Terrioux P. [French practical guidelines for the diagnosis and management of IPF - 2021 update, full version]. Rev Mal Respir 2022; 39:e35-e106. [PMID: 35752506 DOI: 10.1016/j.rmr.2022.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.
Collapse
Affiliation(s)
- V Cottin
- Centre national coordonnateur de référence des maladies pulmonaires rares, service de pneumologie, hôpital Louis-Pradel, Hospices Civils de Lyon (HCL), Lyon, France; UMR 754, IVPC, INRAE, Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France; Membre d'OrphaLung, RespiFil, Radico-ILD2, et ERN-LUNG, Lyon, France.
| | - P Bonniaud
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie et soins intensifs respiratoires, centre hospitalo-universitaire de Bourgogne et faculté de médecine et pharmacie, université de Bourgogne-Franche Comté, Dijon ; Inserm U123-1, Dijon, France
| | - J Cadranel
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie et oncologie thoracique, Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Tenon, Paris ; Sorbonne université GRC 04 Theranoscan, Paris, France
| | - B Crestani
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie A, AP-HP, hôpital Bichat, Paris, France
| | - S Jouneau
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, service de pneumologie, hôpital Pontchaillou, Rennes ; IRSET UMR1085, université de Rennes 1, Rennes, France
| | - S Marchand-Adam
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, hôpital Bretonneau, service de pneumologie, CHRU, Tours, France
| | - H Nunes
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie, AP-HP, hôpital Avicenne, Bobigny ; université Sorbonne Paris Nord, Bobigny, France
| | - L Wémeau-Stervinou
- Centre de référence constitutif des maladies pulmonaires rares, Institut Cœur-Poumon, service de pneumologie et immuno-allergologie, CHRU de Lille, Lille, France
| | - E Bergot
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, service de pneumologie et oncologie thoracique, hôpital Côte de Nacre, CHU de Caen, Caen, France
| | - E Blanchard
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, service de pneumologie, hôpital Haut Levêque, CHU de Bordeaux, Pessac, France
| | - R Borie
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie A, AP-HP, hôpital Bichat, Paris, France
| | - A Bourdin
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, département de pneumologie et addictologie, hôpital Arnaud-de-Villeneuve, CHU de Montpellier, Montpellier ; Inserm U1046, CNRS UMR 921, Montpellier, France
| | - C Chenivesse
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie et d'immuno-allergologie, hôpital Albert Calmette ; CHRU de Lille, Lille ; centre d'infection et d'immunité de Lille U1019 - UMR 9017, Université de Lille, CHU Lille, CNRS, Inserm, Institut Pasteur de Lille, Lille, France
| | - A Clément
- Centre de ressources et de compétence de la mucoviscidose pédiatrique, centre de référence des maladies respiratoires rares (RespiRare), service de pneumologie pédiatrique, hôpital d'enfants Armand-Trousseau, CHU Paris Est, Paris ; Sorbonne université, Paris, France
| | - E Gomez
- Centre de compétence pour les maladies pulmonaires rares, département de pneumologie, hôpitaux de Brabois, CHRU de Nancy, Vandoeuvre-les Nancy, France
| | - A Gondouin
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, CHU Jean-Minjoz, Besançon, France
| | - S Hirschi
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, Nouvel Hôpital civil, Strasbourg, France
| | - F Lebargy
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, CHU Maison Blanche, Reims, France
| | - C-H Marquette
- Centre de compétence pour les maladies pulmonaires rares, FHU OncoAge, département de pneumologie et oncologie thoracique, hôpital Pasteur, CHU de Nice, Nice cedex 1 ; Université Côte d'Azur, CNRS, Inserm, Institute of Research on Cancer and Aging (IRCAN), Nice, France
| | - D Montani
- Centre de compétence pour les maladies pulmonaires rares, centre national coordonnateur de référence de l'hypertension pulmonaire, service de pneumologie et soins intensifs pneumologiques, AP-HP, DMU 5 Thorinno, Inserm UMR S999, CHU Paris-Sud, hôpital de Bicêtre, Le Kremlin-Bicêtre ; Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre, France
| | - G Prévot
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, CHU Larrey, Toulouse, France
| | - S Quetant
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie et physiologie, CHU Grenoble Alpes, Grenoble, France
| | - M Reynaud-Gaubert
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, AP-HM, CHU Nord, Marseille ; Aix Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - M Salaun
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, oncologie thoracique et soins intensifs respiratoires & CIC 1404, hôpital Charles Nicole, CHU de Rouen, Rouen ; IRIB, laboratoire QuantiIF-LITIS, EA 4108, université de Rouen, Rouen, France
| | - O Sanchez
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie et soins intensifs, hôpital européen Georges-Pompidou, AP-HP, Paris, France
| | | | - K Berkani
- Clinique Pierre de Soleil, Vetraz Monthoux, France
| | - P-Y Brillet
- Université Paris 13, UPRES EA 2363, Bobigny ; service de radiologie, AP-HP, hôpital Avicenne, Bobigny, France
| | - M Campana
- Service de pneumologie et oncologie thoracique, CHR Orléans, Orléans, France
| | - L Chalabreysse
- Service d'anatomie-pathologique, groupement hospitalier est, HCL, Bron, France
| | - G Chatté
- Cabinet de pneumologie et infirmerie protestante, Caluire, France
| | - D Debieuvre
- Service de pneumologie, GHRMSA, hôpital Emile-Muller, Mulhouse, France
| | - G Ferretti
- Université Grenoble Alpes, Grenoble ; service de radiologie diagnostique et interventionnelle, CHU Grenoble Alpes, Grenoble, France
| | - J-M Fourrier
- Association Pierre-Enjalran Fibrose Pulmonaire Idiopathique (APEFPI), Meyzieu, France
| | - N Just
- Service de pneumologie, CH Victor-Provo, Roubaix, France
| | - M Kambouchner
- Service de pathologie, AP-HP, hôpital Avicenne, Bobigny, France
| | - B Legrand
- Cabinet médical de la Bourgogne, Tourcoing ; Université de Lille, CHU Lille, ULR 2694 METRICS, CERIM, Lille, France
| | - F Le Guillou
- Cabinet de pneumologie, pôle santé de l'Esquirol, Le Pradet, France
| | - J-P Lhuillier
- Cabinet de pneumologie, La Varenne Saint-Hilaire, France
| | - A Mehdaoui
- Service de pneumologie et oncologie thoracique, CH Eure-Seine, Évreux, France
| | - J-M Naccache
- Service de pneumologie, allergologie et oncologie thoracique, GH Paris Saint-Joseph, Paris, France
| | - C Paganon
- Centre national coordonnateur de référence des maladies pulmonaires rares, service de pneumologie, hôpital Louis-Pradel, Hospices Civils de Lyon (HCL), Lyon, France
| | - M Rémy-Jardin
- Institut Cœur-Poumon, service de radiologie et d'imagerie thoracique, CHRU de Lille, Lille, France
| | - S Si-Mohamed
- Département d'imagerie cardiovasculaire et thoracique, hôpital Louis-Pradel, HCL, Bron ; Université de Lyon, INSA-Lyon, Université Claude-Bernard Lyon 1, UJM-Saint Etienne, CNRS, Inserm, CREATIS UMR 5220, U1206, Villeurbanne, France
| | | |
Collapse
|
|
27
|
Spagnolo P, Tonelli R, Samarelli AV, Castelli G, Cocconcelli E, Petrarulo S, Cerri S, Bernardinello N, Clini E, Saetta M, Balestro E. The role of immune response in the pathogenesis of idiopathic pulmonary fibrosis: far beyond the Th1/Th2 imbalance. Expert Opin Ther Targets 2022; 26:617-631. [PMID: 35983984 DOI: 10.1080/14728222.2022.2114897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION . Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown origin characterized by progressive scarring of the lung leading to irreversible loss of function. Despite the availability of two drugs that are able to slow down disease progression, IPF remains a deadly disease. The pathogenesis of IPF is poorly understood, but a dysregulated wound healing response following recurrent alveolar epithelial injury is thought to be crucial. Areas covered. In the last few years, the role of the immune system in IPF pathobiology has been reconsidered; indeed, recent data suggest that a dysfunctional immune system may promote and unfavorable interplay with pro-fibrotic pathways thus acting as a cofactor in disease development and progression. In this article, we review and critically discuss the role of T cells in the pathogenesis and progression of IPF in the attempt to highlight ways in which further research in this area may enable the development of targeted immunomodulatory therapies for this dreadful disease. EXPERT OPINION A better understanding of T cells interactions has the potential to facilitate the development of immune modulators targeting multiple T cell-mediated pathways thus halting disease initiation and progression.
Collapse
Affiliation(s)
- Paolo Spagnolo
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Roberto Tonelli
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults University Hospital of Modena and Reggio Emilia, Modena, Italy.,University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.,Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Anna Valeria Samarelli
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults University Hospital of Modena and Reggio Emilia, Modena, Italy.,University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Gioele Castelli
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Elisabetta Cocconcelli
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Simone Petrarulo
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Stefania Cerri
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults University Hospital of Modena and Reggio Emilia, Modena, Italy.,University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicol Bernardinello
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Enrico Clini
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults University Hospital of Modena and Reggio Emilia, Modena, Italy.,University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Marina Saetta
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Elisabetta Balestro
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| |
Collapse
|
|
28
|
Eyres M, Bell JA, Davies ER, Fabre A, Alzetani A, Jogai S, Marshall BG, Johnston DA, Xu Z, Fletcher SV, Wang Y, Marshall G, Davies DE, Offer E, Jones MG. Spatially resolved deconvolution of the fibrotic niche in lung fibrosis. Cell Rep 2022; 40:111230. [PMID: 35977489 PMCID: PMC10073410 DOI: 10.1016/j.celrep.2022.111230] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 06/07/2022] [Accepted: 07/26/2022] [Indexed: 11/03/2022] Open
Abstract
A defining pathological feature of human lung fibrosis is localized tissue heterogeneity, which challenges the interpretation of transcriptomic studies that typically lose spatial information. Here we investigate spatial gene expression in diagnostic tissue using digital profiling technology. We identify distinct, region-specific gene expression signatures as well as shared gene signatures. By integration with single-cell data, we spatially map the cellular composition within and distant from the fibrotic niche, demonstrating discrete changes in homeostatic and pathologic cell populations even in morphologically preserved lung, while through ligand-receptor analysis, we investigate cellular cross-talk within the fibrotic niche. We confirm findings through bioinformatic, tissue, and in vitro analyses, identifying that loss of NFKB inhibitor zeta in alveolar epithelial cells dysregulates the TGFβ/IL-6 signaling axis, which may impair homeostatic responses to environmental stress. Thus, spatially resolved deconvolution advances understanding of cell composition and microenvironment in human lung fibrogenesis.
Collapse
Affiliation(s)
- Michael Eyres
- Medicines Discovery Catapult, Alderley Park, Cheshire, UK
| | - Joseph A Bell
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Elizabeth R Davies
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
| | - Aurelie Fabre
- Department of Histopathology, St. Vincent's University Hospital & UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Aiman Alzetani
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK
| | - Sanjay Jogai
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK
| | - Ben G Marshall
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK
| | - David A Johnston
- Biomedical Imaging Unit, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Zijian Xu
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Sophie V Fletcher
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK
| | - Yihua Wang
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Gayle Marshall
- Medicines Discovery Catapult, Alderley Park, Cheshire, UK
| | - Donna E Davies
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Emily Offer
- Medicines Discovery Catapult, Alderley Park, Cheshire, UK
| | - Mark G Jones
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK.
| |
Collapse
|
|
29
|
French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2021 update. Full-length version. Respir Med Res 2022; 83:100948. [PMID: 36630775 DOI: 10.1016/j.resmer.2022.100948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably. METHODS Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale. RESULTS After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.
Collapse
|
|
30
|
Mesenchymal Stem Cell-Derived Extracellular Vesicles as Idiopathic Pulmonary Fibrosis Microenvironment Targeted Delivery. Cells 2022; 11:cells11152322. [PMID: 35954166 PMCID: PMC9367455 DOI: 10.3390/cells11152322] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) affects an increasing number of people globally, yet treatment options remain limited. At present, conventional treatments depending on drug therapy do not show an ideal effect in reversing the lung damage or extending the lives of IPF patients. In recent years, more and more attention has focused on extracellular vesicles (EVs) which show extraordinary therapeutic effects in inflammation, fibrosis disease, and tissue damage repair in many kinds of disease therapy. More importantly, EVs can be modified or used as a drug or cytokine delivery tool, targeting injury sites to enhance treatment efficiency. In light of this, the treatment strategy of mesenchymal stem cell-extracellular vesicles (MSC-EVs) targeting the pulmonary microenvironment for IPF provides a new idea for the treatment of IPF. In this review, we summarized the inflammation, immune dysregulation, and extracellular matrix microenvironment (ECM) disorders in the IPF microenvironment in order to reveal the treatment strategy of MSC-EVs targeting the pulmonary microenvironment for IPF.
Collapse
|
|
31
|
Ma H, Wu X, Li Y, Xia Y. Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis. Front Pharmacol 2022; 13:963054. [PMID: 35935869 PMCID: PMC9349351 DOI: 10.3389/fphar.2022.963054] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/24/2022] [Indexed: 12/12/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Recent studies have identified the key role of crosstalk between dysregulated epithelial cells, mesenchymal, immune, and endothelial cells in IPF. In addition, genetic mutations and environmental factors (e.g., smoking) have also been associated with the development of IPF. With the recent development of sequencing technology, epigenetics, as an intermediate link between gene expression and environmental impacts, has also been reported to be implicated in pulmonary fibrosis. Although the etiology of IPF is unknown, many novel therapeutic targets and agents have emerged from clinical trials for IPF treatment in the past years, and the successful launch of pirfenidone and nintedanib has demonstrated the promising future of anti-IPF therapy. Therefore, we aimed to gain an in-depth understanding of the underlying molecular mechanisms and pathogenic factors of IPF, which would be helpful for the diagnosis of IPF, the development of anti-fibrotic drugs, and improving the prognosis of patients with IPF. In this study, we summarized the pathogenic mechanism, therapeutic targets and clinical trials from the perspective of multiple cell types, gene mutations, epigenetic and environmental factors.
Collapse
Affiliation(s)
- Hongbo Ma
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Xuyi Wu
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, China
| | - Yi Li
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, China
| | - Yong Xia
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, China
- *Correspondence: Yong Xia,
| |
Collapse
|
|
32
|
Yu S, Long Y, Li D, Shi A, Deng J, Ma Y, Wen J, Li X, Zhang Y, Liu S, Wan J, Li N, Guo J. Natural essential oils efficacious in internal organs fibrosis treatment: mechanisms of action and application perspectives. Pharmacol Res 2022; 182:106339. [DOI: 10.1016/j.phrs.2022.106339] [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: 05/10/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 02/07/2023]
|
|
33
|
Teague TT, Payne SR, Kelly BT, Dempsey TM, McCoy RG, Sangaralingham LR, Limper AH. Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis. Respir Res 2022; 23:91. [PMID: 35410255 PMCID: PMC9004115 DOI: 10.1186/s12931-022-02001-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high morbidity and limited treatment options. Type 2 diabetes mellitus (T2DM) is a common comorbid illness among patients with IPF and is often treated with metformin, the first-line agent in the management of T2DM. There is growing evidence demonstrating metformin’s anti-fibrotic properties; however, there is little real-world clinical data regarding its potential effectiveness in IPF. This study aims to evaluate the clinical benefit of metformin in patients with IPF and T2DM. Methods This nationwide cohort study used de-identified administrative claims data from OptumLabs® Data Warehouse to identify 3599 adults with IPF and concomitant T2DM between January 1, 2014 and June 30, 2019. Two cohorts were created: a cohort treated with metformin (n = 1377) and a cohort not treated with metformin (n = 2222). A final 1:1 propensity score-matched cohort compared 1100 patients with IPF and T2DM receiving metformin to those with both diagnoses but not receiving metformin; matching accounted for age, sex, race/ethnicity, residence region, year, medications, oxygen use, smoking status, healthcare use, and comorbidities. Outcomes were all-cause mortality (primary) and hospitalizations (secondary). Results Among 2200 patients with IPF and T2DM included in this matched analysis, metformin therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.36–0.58; p < 0.001) and hospitalizations (HR, 0.82; 95% CI, 0.72–0.93; p = 0.003) compared to patients not receiving metformin. Conclusions Among patients with IPF and T2DM, metformin therapy may be associated with improved clinical outcomes. However, further investigation with randomized clinical trials is necessary prior to metformin’s broad implementation in the clinical management of IPF.
Collapse
|
|
34
|
Hufnagel S, Xu H, Sahakijpijarn S, Moon C, Chow LQ, Williams III RO, Cui Z. Dry Powders for Inhalation Containing Monoclonal Antibodies Made by Thin-Film Freeze-Drying. Int J Pharm 2022; 618:121637. [DOI: 10.1016/j.ijpharm.2022.121637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 10/18/2022]
|
|
35
|
Atanasova E, Milosevic D, Bornschlegl S, Krucker KP, Jacob EK, Carmona Porquera EM, Anderson DK, Egan AM, Limper AH, Dietz AB. Normal ex vivo mesenchymal stem cell function combined with abnormal immune profiles sets the stage for informative cell therapy trials in idiopathic pulmonary fibrosis patients. Stem Cell Res Ther 2022; 13:45. [PMID: 35101101 PMCID: PMC8802496 DOI: 10.1186/s13287-021-02692-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 12/21/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung including cellular senescence. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modest effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study characterizes the functionality of autologous MSCs for use as an IPF therapy and presents an attempt to determine whether the disease occurring in the lungs is associated with an alterated immune system. METHODS Comprehensive characterization of autologous adipose-derived MSCs (aMSCs) from 5 IPF patient and 5 age- and gender-matched healthy controls (HC) was done using flow cytometry, PCR (ddPCR), multiplex Luminex xMAP technology, confocal microscopy self-renewal capacity and osteogenic differentiation. Additionally, multi-parameter quantitative flow cytometry of unmanipulated whole blood of 15 IPF patients and 87 (30 age- and gender-matched) HC was used to analyze 110 peripheral phenotypes to determine disease-associated changes in the immune system. RESULTS There are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self-renewal capacity, osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets and increased granulocytes demonstrating disease-associated alterations in the immune system. CONCLUSIONS Our results indicate that there are no differences in aMSC properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy. The altered immune system of IPF patients may be a valuable biomarker for disease burden and monitoring therapeutic response.
Collapse
Affiliation(s)
- Elena Atanasova
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Dragana Milosevic
- Department of Laboratory Medicine and Pathology, Divisions of Clinical Biochemistry and Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Svetlana Bornschlegl
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Karen P Krucker
- Divisions of Transfusion Medicine and Experimental Pathology, Immune Progenitor and Cell Therapeutics (IMPACT) Lab, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Eapen K Jacob
- Division of Transfusion Medicine, Mayo Clinic, Rochester, MN, USA
| | - Eva M Carmona Porquera
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Dagny K Anderson
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Ashley M Egan
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Andrew H Limper
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Allan B Dietz
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
- Divisions of Transfusion Medicine and Experimental Pathology, Immune Progenitor and Cell Therapeutics (IMPACT) Lab, Mayo Clinic College of Medicine, Rochester, MN, USA.
| |
Collapse
|
|
36
|
Morrow LE, Hilleman D, Malesker MA. Management of patients with fibrosing interstitial lung diseases. Am J Health Syst Pharm 2022; 79:129-139. [PMID: 34608488 PMCID: PMC8881211 DOI: 10.1093/ajhp/zxab375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
PURPOSE This article summarizes the appropriate use and pharmacology of treatments for fibrosing interstitial lung diseases, with a specific focus on the antifibrotic agents nintedanib and pirfenidone. SUMMARY The interstitial lung diseases are a heterogenous group of parenchymal lung disorders with a common feature-infiltration of the interstitial space with derangement of the normal capillary-alveolar anatomy. Diseases characterized by fibrosis of the interstitial space are referred to as the fibrosing interstitial lung diseases and often show progression over time: idiopathic pulmonary fibrosis is the most common fibrotic interstitial lung disease. Historically, therapies for fibrosing lung diseases have been limited in number, questionable in efficacy, and associated with potential harms. Food and Drug Administration (FDA) approval of the antifibrotic agents nintedanib and pirfenidone for idiopathic pulmonary fibrosis in 2014 heralded an era of reorganization of therapy for the fibrotic interstitial lung diseases. Subsequent investigations have led to FDA approval of nintedanib for systemic sclerosis-associated interstitial lung disease and interstitial lung diseases with a progressive phenotype. Although supportive care and pulmonary rehabilitation should be provided to all patients, the role(s) of immunomodulators and/or immune suppressing agents vary by the underlying disease state. Several agents previously used to treat fibrotic lung diseases (N-acetylcysteine, anticoagulation, and pulmonary vasodilators) lack efficacy or cause harm. CONCLUSION With the introduction of effective pharmacotherapy for fibrosing interstitial lung disease, pharmacists have an increasingly important role in the interdisciplinary team managing these patients.
Collapse
Affiliation(s)
- Lee E Morrow
- Creighton University School of Medicine, Omaha, NE
- Creighton University School of Pharmacy and Health Professions, Omaha, NE, USA
| | - Daniel Hilleman
- Creighton University School of Pharmacy and Health Professions, Omaha, NE
- Creighton University School of Medicine, Omaha, NE, USA
| | - Mark A Malesker
- Creighton University School of Pharmacy and Health Professions, Omaha, NE
- Creighton University School of Medicine, Omaha, NE, USA
| |
Collapse
|
|
37
|
Dudala SS, Venkateswarulu TC, Kancharla SC, Kodali VP, Babu DJ. A review on importance of bioactive compounds of medicinal plants in treating idiopathic pulmonary fibrosis (special emphasis on isoquinoline alkaloids). FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2021. [DOI: 10.1186/s43094-021-00304-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown cause which disrupts the normal lung architecture and functions by deregulating immune responses and ultimately leads to the death of the individual. A number of factors can lead to its development and currently there is no cure for this disease.
Main text
There are synthetic drugs available to relieve the symptoms and decelerate its development by targeting pathways involved in the development of IPF, but there had also been various side effects detected by their usage. It is known since decades that medicinal plants and their compounds have been used all over the world in natural medicines to cure various diseases. This review article is focused on the effects of various natural bioactive compounds of 26 plant extracts that show prophylactic and therapeutic properties against the disease and so can be used in treating IPF replacing synthetic drugs and reducing the side effects.
Short conclusion
This review includes different mechanisms that cause pulmonary fibrosis along with compounds that can induce fibrosis, drugs used for the treatment of pulmonary fibrosis, diagnosis, the biochemical tests used for the experimental study to determine the pathogenesis of disease with a special note on Isoquinoline alkaloids and their role in reducing various factors leading to IPF thus providing promising therapeutic approach.
Collapse
|
|
38
|
Conte E. Targeting monocytes/macrophages in fibrosis and cancer diseases: Therapeutic approaches. Pharmacol Ther 2021; 234:108031. [PMID: 34774879 DOI: 10.1016/j.pharmthera.2021.108031] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/19/2021] [Accepted: 11/02/2021] [Indexed: 02/08/2023]
Abstract
Over almost 140 years since their identification, the knowledge about macrophages has unbelievably evolved. The 'big eaters' from being thought of as simple phagocytic cells have been recognized as master regulators in immunity, homeostasis, healing/repair and organ development. Long considered to originate exclusively from bone marrow-derived circulating monocytes, macrophages have been also demonstrated to be the first immune cells colonizing tissues in the developing embryo and persisting in adult life by self-renewal, as long-lived tissue resident macrophages. Therefore, heterogeneous populations of macrophages with different ontogeny and functions co-exist in tissues. Macrophages act as sentinels of homeostasis and are intrinsically programmed to lead the wound healing and repair processes that occur after injury. However, in certain pathological circumstances macrophages get dysfunctional, and impaired or aberrant macrophage activities become key features of diseases. For instance, in both fibrosis and cancer, that have been defined 'wounds that do not heal', dysfunctional monocyte-derived macrophages overall play a key detrimental role. On the other hand, due to their plasticity these cells can be 're-educated' and exert anti-fibrotic and anti-cancer functions. Therefore macrophages represent an important therapeutic target in both fibrosis and cancer diseases. The current review will illustrate new insights into the role of monocytes/macrophages in these devastating diseases and summarize new therapeutic strategies and applications of macrophage-targeted drug development in their clinical setting.
Collapse
|
|
39
|
Aronson KI, Suzuki A. Health Related Quality of Life in Interstitial Lung Disease: Can We Use the Same Concepts Around the World? Front Med (Lausanne) 2021; 8:745908. [PMID: 34692737 PMCID: PMC8526733 DOI: 10.3389/fmed.2021.745908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/31/2021] [Indexed: 01/17/2023] Open
Abstract
Health-Related Quality of Life (HRQOL) is increasingly viewed as an important patient-centered outcome by leading health organizations, clinicians, and patients alike. This is especially true in the interstitial lung disease community where patients often struggle with progressive and debilitating disease with few therapeutic options. In order to test the effectiveness of new pharmacologic therapies and non-pharmacologic interventions globally in ILD, this will require expansion of clinical research studies to a multinational level and HRQOL will be an important endpoint to many. In order to successfully expand trials across multiple nations and compare the results of studies between different communities we must recognize that there are differences in the concepts of HRQOL across the world and have strategies to address these differences. In this review, we will describe the different global influences on HRQOL both generally and in the context of ILD, discuss the processes of linguistic translation and cross-cultural adaptation of HRQOL Patient Reported Outcome Measures (PROMs), and highlight the gaps and opportunities for improving HRQOL measurement in ILD across the world.
Collapse
Affiliation(s)
- Kerri I. Aronson
- Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Atsushi Suzuki
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
40
|
Extracellular Heat Shock Proteins as Therapeutic Targets and Biomarkers in Fibrosing Interstitial Lung Diseases. Int J Mol Sci 2021; 22:ijms22179316. [PMID: 34502225 PMCID: PMC8430559 DOI: 10.3390/ijms22179316] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/19/2022] Open
Abstract
Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases.
Collapse
|
|
41
|
Ishikawa G, Liu A, Herzog EL. Evolving Perspectives on Innate Immune Mechanisms of IPF. Front Mol Biosci 2021; 8:676569. [PMID: 34434962 PMCID: PMC8381017 DOI: 10.3389/fmolb.2021.676569] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 07/29/2021] [Indexed: 12/29/2022] Open
Abstract
While epithelial-fibroblast interactions are viewed as the primary drivers of Idiopathic Pulmonary Fibrosis (IPF), evidence gleaned from animal modeling and human studies implicates innate immunity as well. To provide perspective on this topic, this review synthesizes the available data regarding the complex role of innate immunity in IPF. The role of substances present in the fibrotic microenvironment including pathogen associated molecular patterns (PAMPs) derived from invading or commensal microbes, and danger associated molecular patterns (DAMPs) derived from injured cells and tissues will be discussed along with the proposed contribution of innate immune populations such as macrophages, neutrophils, fibrocytes, myeloid suppressor cells, and innate lymphoid cells. Each component will be considered in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area.
Collapse
Affiliation(s)
- Genta Ishikawa
- Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Angela Liu
- Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Erica L. Herzog
- Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States,Department of Pathology, Yale School of Medicine, New Haven, CT, United States,*Correspondence: Erica L. Herzog,
| |
Collapse
|
|
42
|
Duckworth A, Longhurst HJ, Paxton JK, Scotton CJ. The Role of Herpes Viruses in Pulmonary Fibrosis. Front Med (Lausanne) 2021; 8:704222. [PMID: 34368196 PMCID: PMC8339799 DOI: 10.3389/fmed.2021.704222] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 06/24/2021] [Indexed: 12/29/2022] Open
Abstract
Pulmonary fibrosis (PF) is a serious lung disease which can result from known genetic or environmental exposures but is more commonly idiopathic (IPF). In familial PF (FPF), the majority of identified causal genes play key roles in the maintenance of telomeres, the protective end structures of chromosomes. Recent evidence suggests that short telomeres may also be implicated causally in a significant proportion of idiopathic cases. The possible involvement of herpes viruses in PF disease incidence and progression has been examined for many years, with some studies showing strong, statistically significant associations and others reporting no involvement. Evidence is thus polarized and remains inconclusive. Here we review the reported involvement of herpes viruses in PF in both animals and humans and present a summary of the evidence to date. We also present several possible mechanisms of action of the different herpes viruses in PF pathogenesis, including potential contributions to telomere attrition and cellular senescence. Evidence for antiviral treatment in PF is very limited but suggests a potential benefit. Further work is required to definitely answer the question of whether herpes viruses impact PF disease onset and progression and to enable the possible use of targeted antiviral treatments to improve clinical outcomes.
Collapse
Affiliation(s)
- Anna Duckworth
- College of Medicine and Health, University of Exeter, Exeter, United Kingdom
| | - Hilary J. Longhurst
- Department of Medicine, University of Auckland, Auckland, New Zealand
- Dyskeratosis Congenita (DC) Action, London, United Kingdom
| | - Jane K. Paxton
- Dyskeratosis Congenita (DC) Action, London, United Kingdom
| | - Chris J. Scotton
- College of Medicine and Health, University of Exeter, Exeter, United Kingdom
| |
Collapse
|
|
43
|
Oldham JM, Vancheri C. Rethinking Idiopathic Pulmonary Fibrosis. Clin Chest Med 2021; 42:263-273. [PMID: 34024402 DOI: 10.1016/j.ccm.2021.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s, understanding of IPF has evolved considerably. Such evolution has continually challenged prior diagnostic and treatment paradigms, ushering in an era of higher confidence diagnoses with less invasive procedures and more effective treatments. This review details how research and clinical experience over the past half century have led to a rethinking of IPF. Here, the evolution in understanding of IPF pathogenesis, diagnostic evaluation and treatment approach is discussed.
Collapse
Affiliation(s)
- Justin M Oldham
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, 4150 V Street Suite 3400, Sacramento, CA 95817, USA.
| | - Carlo Vancheri
- Department of Clinical and Experimental Medicine, University of Catania, Regional Referral Center for Rare Lung Diseases, University-Hospital "Policlinico -Vittorio Emanuele", Catania, Italy
| |
Collapse
|
|
44
|
The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis. J Mol Med (Berl) 2021; 99:1373-1384. [PMID: 34258628 PMCID: PMC8277227 DOI: 10.1007/s00109-021-02113-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
Pulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1β, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.
Collapse
|
|
45
|
Kadura S, Raghu G. Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management. Eur Respir Rev 2021; 30:30/160/210011. [PMID: 34168062 PMCID: PMC9489133 DOI: 10.1183/16000617.0011-2021] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/13/2021] [Indexed: 12/19/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with the most common extra-articular manifestation of RA being lung involvement. While essentially any of the lung compartments can be affected and manifest as interstitial lung disease (ILD), pleural effusion, cricoarytenoiditis, constrictive or follicular bronchiolitis, bronchiectasis, pulmonary vasculitis, and pulmonary hypertension, RA-ILD is a leading cause of death in patients with RA and is associated with significant morbidity and mortality. In this review, we focus on the common pulmonary manifestations of RA, RA-ILD and airway disease, and discuss evolving concepts in the pathogenesis of RA-associated pulmonary fibrosis, as well as therapeutic strategies, and have revised our previous review on the topic. A rational clinical approach for the diagnosis and management of RA-ILD, as well as an approach to patients with clinical worsening in the setting of treatment with disease-modifying agents, is included. Future directions for research and areas of unmet need in the realm of RA-associated lung disease are raised. Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with the most common extra-articular manifestation of RA being lung involvement. RA-ILD is a leading cause of death in RA patients and is associated with significant morbidity and mortality.https://bit.ly/3w6oY4i
Collapse
Affiliation(s)
- Suha Kadura
- Dept of Medicine, Center for Interstitial Lung Diseases, University of Washington, Seattle, WA, USA
| | - Ganesh Raghu
- Dept of Medicine, Center for Interstitial Lung Diseases, University of Washington, Seattle, WA, USA
| |
Collapse
|
|
46
|
Idiopathic pulmonary fibrosis and systemic sclerosis: pathogenic mechanisms and therapeutic interventions. Cell Mol Life Sci 2021; 78:5527-5542. [PMID: 34145462 PMCID: PMC8212897 DOI: 10.1007/s00018-021-03874-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 05/07/2021] [Accepted: 06/05/2021] [Indexed: 12/19/2022]
Abstract
Fibrotic diseases take a very heavy toll in terms of morbidity and mortality equal to or even greater than that caused by metastatic cancer. In this review, we examine the pathogenesis of fibrotic diseases, mainly addressing triggers for induction, processes that lead to progression, therapies and therapeutic trials. For the most part, we have focused on two fibrotic diseases with lung involvement, idiopathic pulmonary fibrosis, in which the contribution of inflammatory mechanisms may be secondary to non-immune triggers, and systemic sclerosis in which the contribution of adaptive immunity may be predominant.
Collapse
|
|
47
|
Ptasinski V, Stegmayr J, Belvisi MG, Wagner DE, Murray LA. Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis. Am J Respir Cell Mol Biol 2021; 65:347-365. [PMID: 34129811 PMCID: PMC8525210 DOI: 10.1165/rcmb.2020-0476tr] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Idiopathic pulmonary fibrosis is a fatal interstitial lung disease with limited therapeutic options. Current evidence suggests that IPF may be initiated by repeated epithelial injury in the distal lung followed by abnormal wound healing responses which occur due to intrinsic and extrinsic factors. Mechanisms contributing to chronic damage of the alveolar epithelium in IPF include dysregulated cellular processes such as apoptosis, senescence, abnormal activation of developmental pathways, aging, as well as genetic mutations. Therefore, targeting the regenerative capacity of the lung epithelium is an attractive approach in the development of novel therapies for IPF. Endogenous lung regeneration is a complex process involving coordinated cross-talk between multiple cell types and re-establishment of a normal extracellular matrix environment. This review will describe the current knowledge of reparative epithelial progenitor cells in the alveolar region of the lung and discuss potential novel therapeutic approaches for IPF focusing on endogenous alveolar repair. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Collapse
Affiliation(s)
- Victoria Ptasinski
- Lund University Faculty of Medicine, 59568, Lund, Sweden.,AstraZeneca R&D Gothenburg, 128698, Goteborg, Sweden
| | - John Stegmayr
- Lunds University Faculty of Medicine, 59568, Lund, Sweden
| | - Maria G Belvisi
- Imperial College London, 4615, London, United Kingdom of Great Britain and Northern Ireland
| | - Darcy E Wagner
- Lunds Universitet, 5193, Experimental Medical Sciences, Lund, Sweden
| | - Lynne A Murray
- AstraZeneca PLC, 4625, Cambridge, United Kingdom of Great Britain and Northern Ireland;
| |
Collapse
|
|
48
|
Abuserewa ST, Duff R, Becker G. Treatment of Idiopathic Pulmonary Fibrosis. Cureus 2021; 13:e15360. [PMID: 34239792 PMCID: PMC8245298 DOI: 10.7759/cureus.15360] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2021] [Indexed: 12/03/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs. In the past, treatment was aimed at minimizing inflammation and slowing the progression of inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to anti-inflammatory therapies and the prognosis remains poor. In this review of literature, we will be focusing on main lines of treatment including current medications, supportive care, lung transplantation evaluation, and potential future strategies of treatment.
Collapse
Affiliation(s)
- Sherif T Abuserewa
- Internal Medicine, Grand Strand Regional Medical Center, Myrtle Beach, USA
| | - Richard Duff
- Department of Pulmonary and Critical Care Medicine, Grand Strand Medical Center, Myrtle Beach, USA
| | - Gregory Becker
- Department of Pulmonary and Critical Care Medicine, Grand Strand Medical Center, Myrtle Beach, USA
| |
Collapse
|
|
49
|
Kalluri M, Luppi F, Vancheri A, Vancheri C, Balestro E, Varone F, Mogulkoc N, Cacopardo G, Bargagli E, Renzoni E, Torrisi S, Calvello M, Libra A, Pavone M, Bonella F, Cottin V, Valenzuela C, Wijsenbeek M, Bendstrup E. Patient-reported outcomes and patient-reported outcome measures in interstitial lung disease: where to go from here? Eur Respir Rev 2021; 30:30/160/210026. [PMID: 34039675 PMCID: PMC9488962 DOI: 10.1183/16000617.0026-2021] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/02/2021] [Indexed: 12/03/2022] Open
Abstract
Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth. PROMs are essential tools for research and care in ILD and IPF. They report patient perceptions of the impact of disease and its treatments on whole-person wellbeing and can guide research to make care more patient-centred.https://bit.ly/3s7Y0a8
Collapse
Affiliation(s)
- Meena Kalluri
- Division of Pulmonary Medicine, University of Alberta, Edmonton, AB, Canada .,Shared first and last authorship
| | - Fabrizio Luppi
- Respiratory Diseases Unit, University of Milano-Bicocca. "S. Gerardo" Hospital, Monza, Italy.,Shared first and last authorship
| | - Ada Vancheri
- Regional Referral Center for Rare Lung Diseases, University - Hospital "Policlinico G. Rodolico - San Marco", Catania, Italy
| | - Carlo Vancheri
- Dept of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Diseases, University - Hospital "Policlinico G. Rodolico - San Marco", University of Catania, Catania, Italy
| | - Elisabetta Balestro
- Dept of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Francesco Varone
- UOC Pneumologia, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
| | - Nesrin Mogulkoc
- Dept of Pulmonology, Ege University Hospiral, Bornova, Izmir, Turkey
| | - Giulia Cacopardo
- UOSD UTIR, A.R.N.A.S. Ospedali Civico Di Cristina Benfratelli, Palermo, Italy
| | - Elena Bargagli
- Respiratory Diseases Unit, Siena University, Siena, Italy
| | - Elizabeth Renzoni
- Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College, London, UK
| | - Sebastiano Torrisi
- Dept of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Diseases, University - Hospital "Policlinico G. Rodolico - San Marco", University of Catania, Catania, Italy
| | | | - Alessandro Libra
- Regional Referral Center for Rare Lung Diseases, University - Hospital "Policlinico G. Rodolico - San Marco", Catania, Italy
| | - Mauro Pavone
- Dept of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Diseases, University - Hospital "Policlinico G. Rodolico - San Marco", University of Catania, Catania, Italy
| | - Francesco Bonella
- Pneumology Dept, Centre for Interstitial and Rare Lung Disease, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Vincent Cottin
- Dept of Respiratory Medicine, National Reference Coordinating Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France.,University of Lyon, INRAE, IVPC, Lyon, France
| | - Claudia Valenzuela
- Pulmonology Dept, Hospital Universitario de la Princesa, Universidad Autonoma Madrid, Madrid, Spain.,Shared first and last authorship
| | - Marlies Wijsenbeek
- Centre of excellence, Interstitial Lung Diseases and Sarcoidosis, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.,Shared first and last authorship
| | - Elisabeth Bendstrup
- Dept of Respiratory Diseases and Allergy, Centre for Rare Lung Diseases, Aarhus University Hospital, Aarhus N, Denmark.,Shared first and last authorship
| | | |
Collapse
|
|
50
|
Milenkovic U, Boeckx B, Lambrechts D, Janky R, Hatzichristodoulou G, van Renterghem K, Gevaert T, Cellek S, Bivalacqua TJ, De Ridder D, Albersen M. Single-cell Transcriptomics Uncover a Novel Role of Myeloid Cells and T-lymphocytes in the Fibrotic Microenvironment in Peyronie's Disease. Eur Urol Focus 2021; 8:814-828. [PMID: 33962884 DOI: 10.1016/j.euf.2021.04.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 04/04/2021] [Accepted: 04/15/2021] [Indexed: 01/23/2023]
Abstract
BACKGROUND Peyronie's disease (PD) is an acquired fibrotic disease affecting the penile tunica albuginea that can lead to curvature and deformities, shortening, and erectile dysfunction. Although immunological mechanisms have been suggested for the pathophysiology of PD, these have not been investigated using single-cell transcriptomics. OBJECTIVE To investigate the immunological signature of plaques from PD patients using immunohistochemistry (IHC) and single-cell RNA sequencing (scRNA-Seq). DESIGN, SETTING, AND PARTICIPANTS Tunica albuginea biopsy was performed in patients undergoing penile surgery for either PD (n = 12) or plication or penile cancer (control, n = 6). The inclusion criteria for PD patients were stable chronic disease (≥12 mo in duration) and no previous penile surgery or intralesional injection therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS IHC was performed on surgical samples from ten patients with PD and five control subjects. An additional two PD and one control sample were used for scRNA-Seq (droplet-based; 10X Genomics). Cell clusters were visualised using heatmaps and t-distributed stochastic neighbour embedding plots (BioTuring v2.7.5). RESULTS AND LIMITATIONS IHC revealed the presence of myeloid dendritic cells (DCs; CD68+, TLR4+, CD206+), cytotoxic T lymphocytes (CTLs; CD3+, CD8+), and B lymphocytes (CD20+) in PD plaques, which were absent in controls. scRNA-Seq yielded results for 3312 PD and 5658 control cells. Cell clusters contained fibroblasts (COL1A2+), myofibroblasts (COL1A2+, ACTA2+), smooth muscle cells (ACTA2+, DES+), endothelial cells (VWF+), myeloid cells (CD14+), T lymphocytes (CD3D+), and neutrophils (ALPL+). Myeloid cell subclustering showed infiltration of monocyte-derived cells; control tissue contained classical DCs and resident macrophages. Lymphocyte subclustering revealed mucosal-associated invariant T (MAIT) cells and CTLs in PD. Differential gene expression suggests an increase in inflammatory and immune responses in chronic PD. The study is limited by the small scRNA-seq sample size (n = 3) for IHC, mitigated by a larger cohort of historic paraffin-embedded samples (n = 15), which showed largely parallel findings. Owing to tissue stiffness and extracellular matrix adhesion, our single-cell yield was lower for PD than for the control sample. CONCLUSIONS Our data suggest that even in the chronic PD stage (painless and stable curvature) there is a sustained inflammatory reaction. While vascularisation and collagen production are elevated, the inflammation is driven by specialised monocyte-derived CTL and MAIT cells. These findings could uncover new avenues for medical treatment of PD. PATIENT SUMMARY We looked at the role of the immune system in patients suffering from Peyronie's disease, a condition causing shortening and curvature of the penis. We found that even in a stable, chronic stage of the disease, there is activation of the immune system. Our results suggest that there is potential for novel treatments for this condition.
Collapse
Affiliation(s)
- Uros Milenkovic
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium.
| | - Bram Boeckx
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium
| | | | | | | | - Thomas Gevaert
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Selim Cellek
- Medical Technology Centre, Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, Chelmsford, UK
| | - Trinity J Bivalacqua
- James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Dirk De Ridder
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium
| | - Maarten Albersen
- Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|