Idiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3–4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process. We stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes. Our study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets. Taken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.

中文翻译：

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埃索美拉唑通过MAPK / Nrf2 / HO1途径减弱肺细胞的炎症和纤维化反应

特发性肺纤维化（IPF）是一种孤儿疾病，其特征是肺功能逐渐丧失，导致呼吸急促，并在诊断后3-4年内死亡。据信易感个体中的重复性肺损伤可促进慢性氧化应激，炎症和胶原沉积不受控制。IPF的一些临床前和回顾性临床研究报告了与使用质子泵抑制剂（PPI）（例如埃索美拉唑）相关的有益结果。因此，我们试图研究PPIs有利地调节疾病过程的分子机制。我们刺激了氧化应激，经博来霉素或转化生长因子β（TGFβ）处理后，原代人肺上皮细胞和成纤维细胞的促炎和纤维化前表型，并评估了原型PPI埃索美拉唑在调节这些过程中的作用。我们的研究表明，埃索美拉唑通过转录因子核因子样2（Nrf2）的核易位和细胞保护分子血红素加氧酶1（HO1）的诱导来控制促炎和纤维化分子。Nrf2的基因缺失或HO1的药理抑制会损害埃索美拉唑介导的促炎和纤维化分子调节。其他研究表明，该过程涉及丝裂原活化蛋白激酶（MAPK）途径的激活。我们的实验数据得到了NIH化学文库的生物信息学研究的证实，该化学文库具有IPE肺成纤维细胞的基因表达谱，其中所述IPF肺成纤维细胞经过20,000种化合物（包括艾美拉唑）处理。有趣的是，我们发现45个基因在IPF中被上调，但被埃索美拉唑下调。途径分析表明，这些基因在纤维化过程中富集。无偏高通量RNA-seq研究支持埃索美拉唑的抗纤维化作用，并揭示了几个新的靶标。两者合计，PPI可能通过直接调节MAPK / Nrf2 / HO1途径在IPF中发挥抗纤维化作用，从而有利地影响IPF的疾病进程。我们发现45个基因在IPF中被上调，但被埃索美拉唑下调。途径分析表明，这些基因在纤维化过程中富集。无偏高通量RNA-seq研究支持埃索美拉唑的抗纤维化作用，并揭示了几个新的靶标。两者合计，PPI可能通过直接调节MAPK / Nrf2 / HO1途径在IPF中发挥抗纤维化作用，从而有利地影响IPF的疾病进程。我们发现45个基因在IPF中被上调，但被埃索美拉唑下调。途径分析表明，这些基因在纤维化过程中富集。无偏高通量RNA-seq研究支持埃索美拉唑的抗纤维化作用，并揭示了几个新的靶标。两者合计，PPI可能通过直接调节MAPK / Nrf2 / HO1途径在IPF中发挥抗纤维化作用，从而有利地影响IPF的疾病进程。