Combination of PPI and pirfenidone to enhance antifibrotic efficacy

项目总结 特发性肺纤维化(IPF)是一种病因不明的进展性、致死性肺部疾病。当前 据估计，疾病发病率为每10万人中有93.7人患病，其中包括美国超过12.5万人。 最近FDA批准了两种药物，吡非尼酮和9tedanib。然而，这些疗法只会延缓 疾病进展，但无法逆转已建立的纤维化和治愈IPF。因此，这是一个机会 开发一种联合疗法，以提高现有抗纤维化药物治疗IPF的疗效。 根据我们的新研究，质子泵抑制剂(PPI)可能是一种可以联合使用的药物 用于IPF的吡非尼酮。这一信念源于我们对高通量筛选(HTS)的深入研究 130,000种化合物将发现和验证PPI作为涉及肺的过程的重要调节器 使用分子、细胞生物学和临床前模型的炎症和纤维化。此外，生物信息学 我们对130名IPF患者的间质性肺疾病(ILD)数据库的分析表明， 与对照组相比，接受PPI治疗的患者有显著的肺移植无移植生存期(1241天比730天， P&lt；0.005)。最近，IPF的循证治疗指南有条件地建议使用 IPF中的PPI。最近，参与吡非尼酮临床试验的623名IPF患者的数据显示 接受吡非尼酮和PPI联合治疗的患者有更有利的结果，包括 与单独服用吡非尼酮的IPF患者相比，无进展生存期。然而，无论是 PPI对IPF的条件推荐或有前景的轶事证据都是基于分子的 了解PPI如何调节IPF的疾病过程以及它们如何与抗纤维化药物相互作用 我们的机制研究表明，PPI独立地抑制诱导型一氧化氮合酶(INOS)，而 上调肺成纤维细胞中血红素加氧酶(HO1)的表达以影响肺参与的过程 改建。我们关于吡非尼酮和埃索美拉唑联合治疗的初步数据显示 抑制成纤维细胞增殖和胶原沉积，增强抗纤维化效果。因此，我们 计划测试我们的中心假说：埃索美拉唑抑制iNOS，激活HO1，以及 吡非尼酮的抗纤维化作用，能够延缓或阻止由 调节失调的亚硝化/氧化应激与纤维增殖“。为了测试这一点，我们提出了以下目标：i) 了解诱导型一氧化氮合酶-HO1异常促进纤维化形成的机制(S)。在这里，我们计划 评价iNOS抑制和HO1激活调节成纤维细胞增殖和增殖的机制 胶原产生II)破译PPI和iNOS/HO1之间的相互作用(S)以影响疾病过程 IPF。Iii)评价埃索美拉唑联合吡非尼酮治疗两种肺损伤模型的体内疗效。 这是一个创新的项目，计划将一种有前途的仿制药与FDA批准的抗纤维化药物相结合。 有效延缓或阻止已形成的肺纤维化的药物。

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Current estimates of disease incidence are 93.7 per 100,000 and include over 125,000 cases in the United States. Recently the FDA approved two drugs, pirfenidone and nintedanib. However, these therapies only slow the disease progression but are unable to reverse established fibrosis and cure IPF. Thus, there is an opportunity to develop a combination therapy that enhances the efficacy of the current antifibrotic drugs to treat IPF. According to our new study, proton pump inhibitors (PPIs) might be a choice of drug to combine with pirfenidone for IPF. This conviction stems from our extended studies of high throughput screening (HTS) 130,000 compounds to discover and validate PPIs as significant regulators of processes involved in lung inflammation and fibrosis using molecular, cell biological and preclinical models. In addition, bioinformatics analysis of our interstitial lung disease (ILD) database of 130 IPF patients indicated that patients who happen to be on PPIs had significant lung transplant-free survival compared to controls (1241 days Vs 730 days, p<0.005). Recently, the evidence-based guideline for treatment of IPF conditionally recommended the use of PPIs in IPF. More recently, data from 623 IPF patients who participated in pirfenidone clinical trials indicated that the patients who were on a combined pirfenidone plus PPI therapy had more favorable outcomes including progression-free survival compared to IPF patients who were on pirfenidone alone. However, neither the conditional recommendation of PPIs for IPF nor the promising anecdotal evidence is based on molecular understanding of how PPIs regulate the disease process in IPF and how they interact with the antifibrotic drugs Our mechanistic studies indicate that PPIs independently inhibit inducible nitric oxide synthase (iNOS) while upregulating heme oxygenase (HO1) expression in IPF lung fibroblasts to influence processes involved in lung remodeling. Our preliminary data of combined pirfenidone and esomeprazole therapy demonstrates profound inhibition of fibroblast proliferation and collagen deposition to enhance antifibrotic efficacy. Accordingly, we plan to test our central hypothesis “suppression of iNOS, and activation of HO1 by esomeprazole, together with the antifibrotic action of pirfenidone, is able to slow or halt established lung fibrosis orchestrated by dysregulated nitrosative/oxidative stress and fibroproliferation”. To test this, we propose the following aims: i) understand the mechanism(s) by which dysregulated iNOS-HO1 promotes fibrogenesis. Here, we plan to evaluate the mechanism by which iNOS suppression and HO1 activation regulates fibroblast proliferation and collagen production ii) decipher interaction(s) between PPI and iNOS/HO1 to influence the disease process in IPF. iii) evaluate the in vivo efficacy of esomeprazole and pirfenidone combination in two models of lung injury. This is an innovative project proposing to combine a promising generic drug with an FDA-approved antifibrotic drug to effectively slow or halt established lung fibrosis.