Pirfenidone Mitigates TGF-β-induced Inflammation Following Virus Infection.

Abstract

Infection by influenza A virus (IAV) and other viruses causes disease exacerbations in chronic obstructive pulmonary disease (COPD). Immune responses are blunted in COPD, a deficit compounded by current standard-of-care glucocorticosteroids (GCS) to further predispose patients to life-threatening infections. The immunosuppressive effects of elevated transforming growth factor-beta (TGF-β) in COPD may amplify lung inflammation during infections whilst advancing fibrosis. In the current study, we investigated potential repurposing of pirfenidone, currently used as an anti-fibrotic for idiopathic pulmonary fibrosis, as a non-steroidal treatment for viral exacerbations of COPD. Murine models of lung-specific TGF-β overexpression or chronic cigarette smoke exposure with IAV infection were used. Pirfenidone was administered daily by oral gavage commencing pre-or post-infection, while inhaled pirfenidone and GCS treatment pre-infection were also compared. Tissue and bronchoalveolar lavage were assessed for viral replication, inflammation and immune responses. Overexpression of TGF-β enhanced severity of IAV infection contributing to unrestrained airway inflammation. Mechanistically, TGF-β reduced innate immune responses to IAV by blunting interferon regulated gene (IRG) expression and suppressing production of anti-viral proteins. Prophylactic pirfenidone administration opposed these actions of TGF-β, curbing IAV infection and airway inflammation associated with TGF-β overexpression and cigarette smoke-induced COPD. Notably, inhaled pirfenidone caused greater inhibition of viral loads and inflammation than inhaled GCS. These proof-of-concept studies demonstrate that repurposing pirfenidone and employing a preventative strategy may yield substantial benefit over anti-inflammatory GCS in COPD. Pirfenidone can mitigate damaging virus exacerbations without attendant immunosuppressive actions and merits further investigation, particularly as an inhaled formulation.