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Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis
Ghebremariam, Yohannes T.1,2; Cooke, John P.1; Gerhart, William3; Griego, Carol4; Brower, Jeremy B.4; Doyle-Eisele, Melanie4; Moeller, Benjamin C.4; Zhou, Qingtao5; Ho, Lawrence6; de Andrade, Joao7; Raghu, Ganesh8; Peterson, Leif9; Rivera, Andreana10; Rosen, Glenn D.6
关键词Proton Pump Inhibitors Inflammation Oxidative Stress Fibrosis
刊名JOURNAL OF TRANSLATIONAL MEDICINE
2015-08-01
DOI10.1186/s12967-015-0614-x
13
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Medicine, Research & Experimental
资助者Stanford School of Medicine ; Tobacco-Related Disease Research Program of the University of California ; National Institutes of Health National Heart, Lung, and Blood Institute ; Houston Methodist Research Institute ; Stanford SPARK Translational Research Program ; Stanford School of Medicine ; Tobacco-Related Disease Research Program of the University of California ; National Institutes of Health National Heart, Lung, and Blood Institute ; Houston Methodist Research Institute ; Stanford SPARK Translational Research Program
研究领域[WOS]Research & Experimental Medicine
关键词[WOS]IDIOPATHIC PULMONARY-FIBROSIS ; DIMETHYLARGININE DIMETHYLAMINOHYDROLASE DDAH ; GASTROESOPHAGEAL-REFLUX THERAPY ; ALVEOLAR EPITHELIAL-CELLS ; FREE-RADICAL PRODUCTION ; PROTEIN-KINASE PATHWAY ; NITRIC-OXIDE ; HEME OXYGENASE-1 ; CARBON-MONOXIDE ; ASYMMETRIC DIMETHYLARGININE
英文摘要

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-alpha) and interleukins (IL-1 beta 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 beta (TGF beta), 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.

语种英语
所属项目编号1049528-149- KAVFB ; 20FT-0090 ; 5K01HL118683 ; P01HL114470 ; 25150001
资助者Stanford School of Medicine ; Tobacco-Related Disease Research Program of the University of California ; National Institutes of Health National Heart, Lung, and Blood Institute ; Houston Methodist Research Institute ; Stanford SPARK Translational Research Program ; Stanford School of Medicine ; Tobacco-Related Disease Research Program of the University of California ; National Institutes of Health National Heart, Lung, and Blood Institute ; Houston Methodist Research Institute ; Stanford SPARK Translational Research Program
WOS记录号WOS:000358774500001
引用统计
被引频次:17[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/53396
专题北京大学第三临床医学院_呼吸科
作者单位1.Stanford Univ, Sch Med, Div Pulm Med, Stanford, CA 94305 USA
2.Houston Methodist Res Inst, Ctr Biostat, Houston, TX 77030 USA
3.Houston Methodist Res Inst, Dept Pathol & Genom Med, Houston, TX USA
4.Houston Methodist Res Inst, Dept Cardiovasc Sci, Houston, TX 77030 USA
5.Altitude Pharmaceut Inc, San Diego, CA USA
6.Lovelace Resp Res Inst, Albuquerque, NM USA
7.Cornell Univ, Weill Cornell Med Coll, Dept Cardiothorac Surg, New York, NY 10021 USA
8.Peking Univ, Hosp 3, Dept Resp Med, Beijing 100871, Peoples R China
9.Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL USA
10.Univ Washington, Ctr Interstitial Lung Dis ILD, Div Pulm & Crit Care Med, Seattle, WA 98195 USA
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Ghebremariam, Yohannes T.,Cooke, John P.,Gerhart, William,et al. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis[J]. JOURNAL OF TRANSLATIONAL MEDICINE,2015,13.
APA Ghebremariam, Yohannes T..,Cooke, John P..,Gerhart, William.,Griego, Carol.,Brower, Jeremy B..,...&Rosen, Glenn D..(2015).Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis.JOURNAL OF TRANSLATIONAL MEDICINE,13.
MLA Ghebremariam, Yohannes T.,et al."Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis".JOURNAL OF TRANSLATIONAL MEDICINE 13(2015).
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