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: 10165794
• 负责人: Yohannes T Ghebre
• 金额: --
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165794
• 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; Dependence; Deposition; Development; Disease; Disease Progression; Enzymes; Esomeprazole; Etiology; FDA approved; Ferritin; Fibroblasts; Fibrosis; Generic Drugs; Heme; Human; In Vitro; Incidence; Inflammation; Interstitial Lung Diseases; Lung; Lung Inflammation; Lung Transplantation; Lung diseases; Modeling; Molecular; N,N-dimethylarginine; NOS2A gene; Nitric Oxide Synthase Type I; 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; 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; efficacy evaluation; evidence based guidelines; fibrogenesis; heme oxygenase-1; heme synthase; high throughput screening; idiopathic pulmonary fibrosis; in vivo; innovation; lung injury; molecular modeling; mouse model; nitrosative stress; radiation-induced lung injury; response; small molecule; stem; synergism; trafficking; transcription factor; treatment guidelines

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.

项目概要 特发性肺纤维化（IPF）是一种目前病因不明的进行性致命性肺部疾病。 疾病发病率估计为每 100,000 人中有 93.7 例，其中美国有超过 125,000 例病例。 最近，FDA 批准了两种药物：吡非尼酮和尼达尼布，但这些疗法只能减缓病情。 疾病进展，但无法逆转已形成的纤维化并治愈 IPF，因此，还有机会。 开发一种联合疗法，增强当前抗纤维化药物治疗 IPF 的功效。 根据我们的新研究，质子泵抑制剂（PPI）可能是与 这一信念源于我们对高通量筛选 (HTS) 的深入研究。 130,000 种化合物用于发现和验证 PPI 作为肺部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。 对 130 名 IPF 患者的间质性肺疾病 (ILD) 数据库的分析表明，发生以下情况的患者 与对照组相比，使用 PPI 的患者具有显着的无肺移植生存期（1241 天 vs 730 天， 最近，IPF 治疗循证指南有条件地推荐使用 最近，参加吡非尼酮临床试验的 623 名 IPF 患者的数据表明。 接受吡非尼酮加 PPI 联合治疗的患者具有更有利的结果，包括 与单独使用吡非尼酮的 IPF 患者相比，无生存期。 有条件地推荐 PPI 治疗 IPF 或有希望的轶事证据均基于分子水平 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 独立抑制诱导型一氧化氮合酶 (iNOS)，同时 上调 IPF 肺成纤维细胞中血红素加氧酶 (HO1) 的表达，影响肺相关过程 我们的吡非尼酮和埃索美拉唑联合治疗的初步数据表明了深远的影响。 抑制成纤维细胞增殖和胶原沉积以增强抗纤维化功效。 计划检验我们的中心假设“埃索美拉唑抑制 iNOS 和激活 HO1，以及 吡非尼酮的抗纤维化作用，能够减缓或阻止已形成的肺纤维化 亚硝化/氧化应激失调和纤维增殖”为了测试这一点，我们提出以下目标：i) 了解失调的 iNOS-HO1 促进纤维形成的机制。 评估 iNOS 抑制和 HO1 激活调节成纤维细胞增殖的机制 胶原蛋白的产生 ii) 破译 PPI 和 iNOS/HO1 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。 这是一个创新项目，提议将一种有前途的仿制药与 FDA 批准的抗纤维化药物相结合 有效减缓或阻止已形成的肺纤维化的药物。