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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-\u03b2 (TGF-\u03b2) in COPD may amplify lung inflammation during infections while advancing fibrosis. In the present study, we investigated potential repurposing of pirfenidone, currently used as an antifibrotic for idiopathic pulmonary fibrosis, as a nonsteroidal treatment for viral exacerbations of COPD. Murine models of lung-specific TGF-\u03b2 overexpression or chronic cigarette smoke exposure with IAV infection were used. Pirfenidone was administered daily by oral gavage commencing pre- or postinfection, and inhaled pirfenidone and GCS treatment preinfection were also compared. Tissue and BAL were assessed for viral replication, inflammation, and immune responses. Overexpression of TGF-\u03b2 enhanced the severity of IAV infection, contributing to unrestrained airway inflammation. Mechanistically, TGF-\u03b2 reduced innate immune responses to IAV by blunting IFN-regulated gene expression and suppressing production of antiviral proteins. Prophylactic pirfenidone administration opposed these actions of TGF-\u03b2, curbing IAV infection and airway inflammation associated with TGF-\u03b2 overexpression and cigarette smoke\u2013induced 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 antiinflammatory GCS in COPD. Pirfenidone can mitigate damaging viral exacerbations without attendant immunosuppressive actions and merits further investigation, particularly as an inhaled formulation.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0433oc","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T14:39:56Z","timestamp":1744814396000},"page":"545-558","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":9,"title":["Pirfenidone Mitigates Transforming Growth Factor-\u03b2\u2013induced Inflammation after Viral Infection"],"prefix":"10.1093","volume":"73","author":[{"given":"Belinda J.","family":"Thomas","sequence":"first","affiliation":[{"name":"Monash Lung, Sleep, Allergy and Immunology, Monash University and Monash Medical Centre, Melbourne, Australia"},{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"},{"name":"School of Clinical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Kan-o","sequence":"additional","affiliation":[{"name":"Monash Lung, Sleep, Allergy and Immunology, Monash University and Monash Medical Centre, Melbourne, Australia"},{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"},{"name":"Research Institute for Diseases of the Chest, School of Medical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Gantier","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Simpson","sequence":"additional","affiliation":[{"name":"Pathology, Monash Medical Centre, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia G.","family":"Chitty","sequence":"additional","affiliation":[{"name":"Pharmacology, Biomedicine Discovery Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Lam","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"},{"name":"Pharmacology, Biomedicine Discovery Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lovisa","family":"Dousha","sequence":"additional","affiliation":[{"name":"Monash Lung, Sleep, Allergy and Immunology, Monash University and Monash Medical Centre, Melbourne, Australia"},{"name":"School of Clinical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Gottschalk","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Lawlor","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle D.","family":"Tate","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleela","family":"Ruwanpura","sequence":"additional","affiliation":[{"name":"Monash Lung, Sleep, Allergy and Immunology, Monash University and Monash Medical Centre, Melbourne, Australia"},{"name":"Centre for Innate Immunity and Infectious Diseases and"},{"name":"Molecular and Translational Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-4811","authenticated-orcid":false,"given":"Huei Jiunn","family":"Seow","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Melbourne, Australia; 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