Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis
Abstract 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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-11-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-24985-x |
| _version_ | 1811190298868449280 |
|---|---|
| author | Afshin Ebrahimpour Manisha Ahir Min Wang Anil G. Jegga Mark D. Bonnen N. Tony Eissa Sydney B. Montesi Ganesh Raghu Yohannes T. Ghebre |
| author_facet | Afshin Ebrahimpour Manisha Ahir Min Wang Anil G. Jegga Mark D. Bonnen N. Tony Eissa Sydney B. Montesi Ganesh Raghu Yohannes T. Ghebre |
| author_sort | Afshin Ebrahimpour |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T14:49:03Z |
| format | Article |
| id | doaj.art-3ce6a0a83e064759a2ff579276fe6229 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T14:49:03Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3ce6a0a83e064759a2ff579276fe62292022-12-22T04:17:33ZengNature PortfolioScientific Reports2045-23222022-11-0112111210.1038/s41598-022-24985-xCombination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosisAfshin Ebrahimpour0Manisha Ahir1Min Wang2Anil G. Jegga3Mark D. Bonnen4N. Tony Eissa5Sydney B. Montesi6Ganesh Raghu7Yohannes T. Ghebre8Department of Radiation Oncology, Baylor College of MedicineDepartment of Radiation Oncology, Baylor College of MedicineDepartment of Radiation Oncology, Baylor College of MedicineDivision of Biomedical Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineDepartment of Radiation Oncology, The University of Texas Health Science Center at San AntonioDepartment of Medicine, University of California, Irvine School of MedicineDivision of Pulmonary and Critical Care Medicine, Massachusetts General HospitalDivision of Pulmonary and Critical Care Medicine, Center for Interstitial Lung Disease, University of WashingtonDepartment of Radiation Oncology, Baylor College of MedicineAbstract 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.https://doi.org/10.1038/s41598-022-24985-x |
| spellingShingle | Afshin Ebrahimpour Manisha Ahir Min Wang Anil G. Jegga Mark D. Bonnen N. Tony Eissa Sydney B. Montesi Ganesh Raghu Yohannes T. Ghebre Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis Scientific Reports |
| title | Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis |
| title_full | Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis |
| title_fullStr | Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis |
| title_full_unstemmed | Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis |
| title_short | Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis |
| title_sort | combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of tgfβ induced lung fibrosis |
| url | https://doi.org/10.1038/s41598-022-24985-x |
| work_keys_str_mv | AT afshinebrahimpour combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT manishaahir combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT minwang combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT anilgjegga combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT markdbonnen combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT ntonyeissa combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT sydneybmontesi combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT ganeshraghu combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis AT yohannestghebre combinationofesomeprazoleandpirfenidoneenhancesantifibroticefficacyinvitroandinamousemodeloftgfbinducedlungfibrosis |