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Matrix Biology : Journal of the... Sep 2020Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys,... (Review)
Review
Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.
Topics: Amides; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fumarates; Gene Expression Regulation; Humans; Kidney; Liver; Molecular Targeted Therapy; Myocardium; Pyridones; Renin-Angiotensin System; Signal Transduction; Skin; Tetrazoles; Transforming Growth Factor beta
PubMed: 32422329
DOI: 10.1016/j.matbio.2020.04.005 -
Acta Pharmacologica Sinica Apr 2022Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs....
Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.
Topics: Animals; Disease Models, Animal; Fibrosis; Inflammation; Interleukin-17; Janus Kinases; Lung; Mice; Mice, Inbred C57BL; Pneumonia; Pyridones; STAT Transcription Factors; Signal Transduction; Silicon Dioxide
PubMed: 34316030
DOI: 10.1038/s41401-021-00706-4 -
The European Respiratory Journal Oct 2022Systemic sclerosis (SSc) is an autoimmune disease characterised by severe vasculopathy and fibrosis of various organs including the lung. Targeted treatment options for...
BACKGROUND
Systemic sclerosis (SSc) is an autoimmune disease characterised by severe vasculopathy and fibrosis of various organs including the lung. Targeted treatment options for SSc-associated interstitial lung disease (SSc-ILD) are scarce. We assessed the effects of pirfenidone in a mouse model of SSc-ILD.
METHODS
Pulmonary function, inflammation and collagen deposition in response to pirfenidone were assessed in Fra-2-overexpressing transgenic (Fra-2 TG) and bleomycin-treated mice. In Fra-2 TG mice, lung transcriptome was analysed after pirfenidone treatment. , pirfenidone effects on human eosinophil and endothelial cell function were analysed using flow cytometry-based assays and electric cell-substrate impedance measurements, respectively.
RESULTS
Pirfenidone treatment attenuated pulmonary remodelling in the bleomycin model, but aggravated pulmonary inflammation, fibrosis and vascular remodelling in Fra-2 TG mice. Pirfenidone increased interleukin (IL)-4 levels and eosinophil numbers in lung tissue of Fra-2 TG mice without directly affecting eosinophil activation and migration . A pronounced immune response with high levels of cytokines/chemokines and disturbed endothelial integrity with low vascular endothelial (VE)-cadherin levels was observed in pirfenidone-treated Fra-2 TG mice. In contrast, eosinophil and VE-cadherin levels were unchanged in bleomycin-treated mice and not influenced by pirfenidone. , pirfenidone exacerbated the IL-4 induced reduction of endothelial barrier resistance, leading to higher leukocyte transmigration.
CONCLUSION
This study shows that antifibrotic properties of pirfenidone may be overruled by unwanted interactions with pre-injured endothelium in a setting of high T-helper type 2 inflammation in a model of SSc-ILD. Careful ILD patient phenotyping may be required to exploit benefits of pirfenidone while avoiding therapy failure and additional lung damage in some patients.
Topics: Humans; Mice; Animals; Interleukin-4; Scleroderma, Systemic; Bleomycin; Lung Diseases, Interstitial; Lung; Fibrosis; Disease Models, Animal; Inflammation; Collagen; Cytokines; Chemokines; Cadherins
PubMed: 35332068
DOI: 10.1183/13993003.02347-2021 -
Expert Opinion on Investigational Drugs Dec 2021Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and... (Review)
Review
INTRODUCTION
Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients.
AREAS COVERED
The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021).
EXPERT OPINION
Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.
Topics: Animals; Antifibrotic Agents; COVID-19; Critical Illness; Humans; Indoles; Pulmonary Fibrosis; Pyridones
PubMed: 34842488
DOI: 10.1080/13543784.2021.2010188 -
Heart Failure Reviews Mar 2022Myocardial fibrosis is a common feature of several heart diseases. The progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may... (Review)
Review
Myocardial fibrosis is a common feature of several heart diseases. The progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. Some drugs (like renin-angiotensin-aldosterone system inhibitors) have been shown to reduce extracellular matrix deposition, but no primarily anti-fibrotic medications are currently used to treat patients with heart failure (HF). Pirfenidone is an oral antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis. Although its exact mechanism of action is not fully understood, pirfenidone might reduce the expression of profibrotic factors such as transforming growth factor-β (TGF-β), and proinflammatory cytokines, like tumor necrosis factor-α (TNF-α), interleukin (IL)-4, and IL-13, which could modulate the inflammatory response and inhibit collagen synthesis in lung tissue. There is some evidence that pirfenidone has antifibrotic activity in various animal models of cardiac disease. Furthermore, the positive results of the PIROUETTE trial, evaluating pirfenidone in patients with HF with preserved ejection fraction, have been very recently announced. This review summarizes the data about pirfenidone as a potential cardioprotective treatment.
Topics: Animals; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Myocytes, Cardiac; Pyridones
PubMed: 34671871
DOI: 10.1007/s10741-021-10175-w -
The European Respiratory Journal Oct 2023https://bit.ly/3LuzAUJ (Clinical Trial)
Clinical Trial
https://bit.ly/3LuzAUJ
Topics: Humans; Anti-Inflammatory Agents, Non-Steroidal; Diet; Idiopathic Pulmonary Fibrosis; Pyridones; Treatment Outcome; Vital Capacity
PubMed: 37857429
DOI: 10.1183/13993003.00262-2023 -
Cardiac Failure Review Jan 2022Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional... (Review)
Review
Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug.
PubMed: 35516794
DOI: 10.15420/cfr.2021.30 -
BMC Pulmonary Medicine Feb 2023Idiopathic pulmonary fibrosis (IPF) is frequently accompanied by comorbidities, with the management of these comorbidities crucial for clinical outcomes. This study...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is frequently accompanied by comorbidities, with the management of these comorbidities crucial for clinical outcomes. This study investigated the prevalence, incidence, changes over time, and clinical impact of comorbidities in IPF patients, based on nationwide claims data in South Korea.
METHODS
This retrospective cohort study utilised nationwide health claim data in South Korea between 2011 and 2019. Patients with IPF were defined as those with ICD-10 code J84.1 and Rare Intractable Disease code V236 who made at least one claim per year. Patients were classified by sex, age, pirfenidone use and burden of comorbidities, and differences among groups were determined.
RESULTS
The yearly prevalence rate of IPF increased from 7.50 to 23.20 per 100,000 people, and the yearly incidence rate increased from 3.56 to 7.91 per 100,000 person-years over time. The most common respiratory comorbidity was chronic obstructive pulmonary disease (37.34%), followed by lung cancer (3.34%), whereas the most common non-respiratory comorbidities were gastro-oesophageal reflux disease (70.83%), dyslipidaemia (62.93%) and hypertension (59.04%). The proportion of some comorbidities differed by sex, age and use of pirfenidone. The proportion of lung cancer was higher in patients treated with pirfenidone, whereas the proportion of anxiety and depression were lower in patients not treated with pirfenidone. Charlson comorbidity index ≥ 4 was associated with increases in hospitalisations and total medical costs.
CONCLUSIONS
The yearly prevalence and incidence of IPF and comorbidities in Korea increased over time. These comorbidities affected the use of pirfenidone and medical resources.
Topics: Humans; Cohort Studies; Retrospective Studies; Comorbidity; Idiopathic Pulmonary Fibrosis; Lung Neoplasms; Pyridones
PubMed: 36739401
DOI: 10.1186/s12890-023-02340-8 -
International Journal of Dermatology May 2021
Topics: Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Phototoxic; Humans; Pyridones
PubMed: 33615459
DOI: 10.1111/ijd.15361 -
Pulmonary Pharmacology & Therapeutics Dec 2023Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of... (Observational Study)
Observational Study
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2-5 years was reported previously to the advent of antifibrotics. According to clinical trials, nintedanib and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival.
METHODS
A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with immunosuppressive drugs and/or N- acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®.
RESULTS
A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was -40.95 ± 438.26 mL and -0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p < 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656).
CONCLUSIONS
In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.
Topics: Humans; Retrospective Studies; Longitudinal Studies; Idiopathic Pulmonary Fibrosis; Lung; Pyridones; Vital Capacity; Treatment Outcome
PubMed: 37758002
DOI: 10.1016/j.pupt.2023.102261