Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis.

Autor: Ebrahimpour A; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Ahir M; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Wang M; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Jegga AG; Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA., Bonnen MD; Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA., Eissa NT; Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, 92697, USA., Montesi SB; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA., Raghu G; Division of Pulmonary and Critical Care Medicine, Center for Interstitial Lung Disease, University of Washington, Seattle, WA, 98195, USA., Ghebre YT; Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. yohannes.ghebre@bcm.edu.; Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. yohannes.ghebre@bcm.edu.; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. yohannes.ghebre@bcm.edu.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. yohannes.ghebre@bcm.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Nov 30; Vol. 12 (1), pp. 20668. Date of Electronic Publication: 2022 Nov 30.
DOI: 10.1038/s41598-022-24985-x
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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