title: Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis.
abstract: BACKGROUND
  The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated.
  
  
  METHODS
  Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival.
  
  
  RESULTS
  The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years).
  
  
  CONCLUSIONS
  Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave, R10-111, Houston, TX, 77030, USA. ytghebremariam@tmhs.org.|Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA. ytghebremariam@tmhs.org.
authors.forename: Yohannes T
authors.initials: YT
authors.lastname: Ghebremariam
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave, R10-211, Houston, TX, 77030, USA. jpcooke@tmhs.org.
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
authors.affiliation: Altitude Pharmaceuticals, Inc, San Diego, CA, USA. wgerhart@altitudepharma.com.
authors.forename: William
authors.initials: W
authors.lastname: Gerhart
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM, USA. cgriego@lrri.org.
authors.forename: Carol
authors.initials: C
authors.lastname: Griego
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM, USA. jbrower@lrri.org.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Brower
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM, USA. mdoyle@lrri.org.
authors.forename: Melanie
authors.initials: M
authors.lastname: Doyle-Eisele
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM, USA. bmoeller@lrri.org.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Moeller
authors.affiliation: Department of Respiratory Medicine, Peking University Third Hospital, Beijing, China. zhouqingtaobysy@sina.com.
authors.forename: Qingtao
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Division of Pulmonary Medicine, School of Medicine, Stanford University, Stanford, CA, USA. laho@uw.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Ho
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. joao@uab.edu.
authors.forename: Joao
authors.initials: J
authors.lastname: de Andrade
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Center for Interstitial Lung Disease (ILD), University of Washington, Seattle, WA, USA. graghu@uw.edu.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raghu
authors.affiliation: Center for Biostatistics, Houston Methodist Research Institute, Houston, TX, USA. LEPeterson@tmhs.org.
authors.forename: Leif
authors.initials: L
authors.lastname: Peterson
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA. alrivera@tmhs.org.
authors.forename: Andreana
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Division of Pulmonary Medicine, School of Medicine, Stanford University, Stanford, CA, USA. gdrosen2@gmail.com.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Rosen
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015415:Biomarkers / Q000097:blood; D001761:Bleomycin; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002469:Cell Separation; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D064098:Esomeprazole / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D058685:Genetic Pleiotropy; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011839:Radiation, Ionizing; D011916:Rats, Inbred F344; D012995:Solubility; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D054328:Proton Pump Inhibitors; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen; D064098:Esomeprazole