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Antifibrotic activities of pirfenidone in animal models.

ABSTRACT: Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-β. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component.

SUBMITTER: Schaefer CJ

PROVIDER: S-EPMC9487788 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Antifibrotic activities of pirfenidone in animal models.

Schaefer C J CJ Ruhrmund D W DW Pan L L Seiwert S D SD Kossen K K

European respiratory review : an official journal of the European Respiratory Society 20110601 120

Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with ...[more]

PMID: 21632796

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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.

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Antifibrotic activities of pirfenidone in animal models.

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Antifibrotic activities of pirfenidone in animal models.

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