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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 TGF\u03b2-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGF\u03b2-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 TGF\u03b2-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGF\u03b2 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 (\u03b1SMA)-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.<\/jats:p>","DOI":"10.1038\/s41598-022-24985-x","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T14:04:27Z","timestamp":1669817067000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGF\u03b2-induced lung fibrosis"],"prefix":"10.1038","volume":"12","author":[{"given":"Afshin","family":"Ebrahimpour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Ahir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil G.","family":"Jegga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Bonnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. 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MDB is an inventor on the patent owned by Baylor College of Medicine. AGJ serves as a member of Scientific Advisory Board of Gen1E Lifesciences, Palo Alto, CA, United States. SBM is supported by the NIH (K23HL15033). She has received funding through her institution from Merck, Boehringer Ingelheim and Pliant Therapeutics. She has received consulting fees from DevPro Biopharma, Gilead Sciences, and Roche, advisory board fees from APIE Therapeutics, and royalties from Wolters Kluwer. The other authors have no relevant conflict of interests to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20668"}}