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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 -
Internal Medicine (Tokyo, Japan) 2017The patient was a 69-year-old man with idiopathic pulmonary fibrosis who was taking pirfenidone. After 7 weeks of treatment, he suffered from left-sided eosinophilic...
The patient was a 69-year-old man with idiopathic pulmonary fibrosis who was taking pirfenidone. After 7 weeks of treatment, he suffered from left-sided eosinophilic pleurisy. Medical thoracoscopy was performed and the histopathological examination of the parietal pleura revealed the massive infiltration of eosinophils and lymphoid follicles. After stopping pirfenidone therapy, the patient's pleural effusion disappeared without additional treatment, and never recurred. This is the first case report of pirfenidone-induced pleurisy.
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Eosinophils; Humans; Male; Pleurisy; Pulmonary Fibrosis; Pyridones; Thoracoscopy
PubMed: 28717083
DOI: 10.2169/internalmedicine.56.7738 -
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 -
Thorax Nov 2023Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients.
METHODS
We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety.
RESULTS
After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events.
CONCLUSIONS
The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP.
TRIAL REGISTRATION MUMBER
NCT02958917.
Topics: Adult; Humans; Idiopathic Pulmonary Fibrosis; Treatment Outcome; Pandemics; COVID-19; Vital Capacity; Pyridones; Double-Blind Method; Disease Progression; Alveolitis, Extrinsic Allergic
PubMed: 37028940
DOI: 10.1136/thorax-2022-219795 -
Annals of Medicine Feb 2015Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of idiopathic interstitial pneumonia. The disease, which occurs primarily in middle-aged and older... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of idiopathic interstitial pneumonia. The disease, which occurs primarily in middle-aged and older adults, is thought to arise following an aberrant reparative response to alveolar epithelial cell injury characterized by secretion of excessive amounts of extracellular matrix components, resulting in scarring of the lung, architectural distortion, and irreversible loss of function. A complex interplay between environmental and host factors is thought to contribute to the development of the disease, although the cause of IPF remains elusive and its pathogenesis incompletely understood. Over the last decade, disease definition and diagnostic criteria have evolved significantly, and this has facilitated the design of a number of high-quality clinical trials evaluating novel therapeutic agents for IPF. This massive effort of the medical and industry community has led to the identification of two compounds (pirfenidone and nintedanib) able to reduce functional decline and disease progression. These promising results notwithstanding, IPF remains a major cause of morbidity and mortality and a largely unmet medical need. A real cure for this devastating disease has yet to emerge and will likely consist of a combination of drugs targeting the plethora of pathways potentially involved in disease pathogenesis.
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Enzyme Inhibitors; Health Services Needs and Demand; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Middle Aged; Pyridones; Risk Factors
PubMed: 25613170
DOI: 10.3109/07853890.2014.982165