Combination of PPI and pirfenidone to enhance antifibrotic efficacy

PPI 与吡非尼酮联用增强抗纤维化功效

• 批准号: 9361253
• 负责人: Yohannes T Ghebre
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9361253
• 关键词: Acidity; Affect; Animals; Attenuated; Bilirubin; Binding Sites; Bioinformatics; Biological Models; Bleomycin; Carbon Monoxide; Cell Nucleus; Cells; Clinical Trials; Collagen; Combined Modality Therapy; Conduct Clinical Trials; Data; Databases; Dependency; Deposition; Development; Disease; Disease Progression; Enzymes; Esomeprazole; Etiology; FDA approved; Ferritin; Fibroblasts; Fibrosis; Generic Drugs; Hamman-Rich syndrome; Heme; Human; In Vitro; Incidence; Inflammation; Interstitial Lung Diseases; Lung; Lung Inflammation; Lung Transplantation; Lung diseases; Modeling; Molecular; Molecular Models; N,N-dimethylarginine; NOS2A gene; Nuclear Translocation; Outcome; Oxidative Stress; Oxygenases; Patients; Pharmaceutical Preparations; Pirfenidone; Pre-Clinical Model; Process; Production; Progression-Free Survivals; Promoter Regions; Proton Pump Inhibitors; Pulmonary Fibrosis; Radiation; Rare Diseases; Recommendation; Reducing Agents; Regulation; Research; Roentgen Rays; Stomach; Testing; Tissues; Toxic effect; Transforming Growth Factor beta; United States; base; clinically relevant; convict; dimethylargininase; evidence based guidelines; fibrogenesis; heme oxygenase-1; heme synthase; high throughput screening; in vivo; innovation; lung injury; molecular modeling; mouse model; nitrosative stress; response; small molecule; stem; synergism; trafficking; transcription factor

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.

项目摘要 特发性肺纤维化（IPF）是一种病因不明的进行性和致死性肺部疾病。电流 疾病发病率估计为每100，000人93.7例，包括美国的125，000例。 最近，FDA批准了两种药物，吡非尼酮和尼达尼布。然而，这些疗法只能减缓 疾病进展，但不能逆转已建立的纤维化和治愈IPF。因此，有一个机会 开发一种联合疗法，增强目前抗纤维化药物治疗IPF的疗效。 根据我们的新研究，质子泵抑制剂（PPI）可能是一种选择药物，联合收割机 吡非尼酮治疗IPF。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，以发现和验证PPI作为肺相关过程的重要调节剂 使用分子、细胞生物学和临床前模型研究炎症和纤维化。此外，生物信息学 我们对130例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，服用PPI的患者无肺移植生存率显着（1241天Vs 730天， p<0.005）。最近，IPF治疗的循证指南有条件地推荐使用 IPF中的PPI。最近，来自参加吡非尼酮临床试验的623例IPF患者的数据表明， 接受吡非尼酮+PPI联合治疗的患者结局更有利，包括 与接受吡非尼酮单药治疗的IPF患者相比，无进展生存期。然而，无论是 有条件推荐PPI治疗IPF，也没有有希望的轶事证据是基于分子 了解PPI如何调节IPF的疾病进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）， 在IPF肺成纤维细胞中上调血红素加氧酶（HO 1）表达以影响肺成纤维细胞中涉及的过程。 重塑我们对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以增强抗纤维化功效。因此我们 计划检验我们的中心假设“埃索美拉唑抑制iNOS和激活HO 1，以及 吡非尼酮的抗纤维化作用能够减缓或停止已建立的肺纤维化， 亚硝化/氧化应激失调和纤维增生”。为了验证这一点，我们提出了以下目标： 了解失调的iNOS-HO 1促进纤维形成的机制。在这里，我们计划 评估iNOS抑制和HO 1激活调节成纤维细胞增殖的机制， 胶原蛋白的产生ii）解释PPI和iNOS/HO 1之间的相互作用以影响疾病过程， IPF。iii）评估埃索美拉唑和吡非尼酮组合在两种肺损伤模型中的体内功效。 这是一个创新的项目，提出将一种有前途的仿制药与FDA批准的抗纤维化药物联合收割机相结合。 有效减缓或停止已形成的肺纤维化的药物。