Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis.
Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis.
复制标题
DOI：
10.1186/s12967-015-0614-x
复制
发表时间：
2015-08-01
影响因子：
7.4
通讯作者：
Rosen GD
中科院分区：
文献类型：
--
作者：
Ghebremariam YT;Cooke JP;Gerhart W;Griego C;Brower JB;Doyle-Eisele M;Moeller BC;Zhou Q;Ho L;de Andrade J;Raghu G;Peterson L;Rivera A;Rosen GD
在回顾性研究中报告了使用质子泵抑制剂（PPI）治疗特发性肺纤维化（IPF）的有益结局。迄今为止，尚未进行前瞻性研究来证实这些结果。此外，PPI改善IPF患者肺功能和/或无移植生存率指标的潜在机制尚未阐明。在这里，我们使用生物化学，细胞生物学和临床前研究来评估与炎症和纤维化相关的标志物的调节。在我们的体外研究中，我们将原代肺成纤维细胞、上皮细胞和内皮细胞暴露于电离辐射或博来霉素;刺激通常用于诱导炎症和纤维化。此外，我们培养了IPF患者的肺成纤维细胞，并研究了埃索美拉唑对胶原释放的影响。我们的临床前研究测试了埃索美拉唑在博莱霉素诱导的肺损伤大鼠模型中的疗效。此外，我们对间质性肺病（ILD）数据库进行了回顾性分析，以检查PPI对无移植生存率的影响。细胞培养研究表明，埃索美拉唑通过抑制促炎分子（包括血管细胞粘附分子-1、诱导型一氧化氮合酶、肿瘤坏死因子-α（TNF-α）和白细胞介素（IL-1β和IL-6））的表达来控制炎症。抗氧化作用与强烈诱导应激诱导细胞保护蛋白血红素加氧酶-1（HO 1）相关，抗纤维化作用与有效抑制成纤维细胞增殖以及下调促纤维化蛋白（包括转化生长因子β（TGFβ）受体、纤连蛋白和基质金属蛋白酶（MMP））相关。此外，埃索美拉唑在减轻急性肺损伤小鼠模型中的炎症和纤维化反应方面显示出稳健的效果。最后，对两个ILD数据库进行了回顾性分析，以评估PPI对IPF患者无移植生存期的影响。有趣的是，该数据表明，接受PPI治疗的IPF患者的生存期较对照组延长（中位生存期为3.4 vs 2年）。总体而言，这些数据表明PPI可能通过直接调节疾病进程对IPF具有保护作用，并表明其在治疗以炎症和/或纤维化阶段为特征的肠外疾病中可能具有其他临床效用。本文的在线版本（doi：10.1186/s12967-015-0614-x）包含补充材料，可供授权用户使用。
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. 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. 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). 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. The online version of this article (doi:10.1186/s12967-015-0614-x) contains supplementary material, which is available to authorized users.