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.

项目摘要 特发性肺纤维化（IPF）是一种病因的进行性肺部疾病。当前的 疾病事件的估计值为每10万人93.7，在美国包括125,000例。 最近，FDA批准了两种药物，即Pirfenidone和Nintedanib。但是，这些疗法只会放慢 疾病进展，但无法逆转确定的纤维化和治愈IPF。那有机会 为了开发一种组合疗法，以提高当前抗纤维化药物治疗IPF的效率。 根据我们的新研究，质子泵抑制剂（PPI）可能是与 pirfenidone用于IPF。从我们对高吞吐量筛查（HTS）的扩展研究中的这种信念阶段 130,000种发现和验证PPI作为肺部涉及过程的重要调节剂 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 对130名IPF患者的间质肺疾病（ILD）数据库的分析表明，发生的患者 与对照组相比，在PPI上具有明显的无肺移植生存期（1241天，730天， p <0.005）。最近，基于证据的IPF治疗指南有条件地建议使用 IPF中的PPI。最近，参与Pirfenidone临床试验的623名IPF患者的数据表明 在合并的吡非酮和PPI疗法中的患者的结果更有利，包括 与单独使用Pirfenidone的IPF患者相比，无进展生存期。但是，都不是 PPI对IPF的有条件建议或承诺的轶事证据基于分子 了解PPI如何调节IPF中的疾病过程以及它们如何与抗纤维化药物相互作用 我们的机械研究表明，PPI独立抑制了诱导型一氧化氮合酶（Inos），而 IPF肺成纤维细胞中上调血红素加氧酶（HO1）表达以影响参与肺的过程 重塑。我们的吡非酮和埃索美瑞唑疗法的初步数据证明了深刻的 抑制成纤维细胞增殖和胶原蛋白沉积以提高抗纤维化效率。根据我们的说法 计划测试我们的中心假设“抑制iNOS和埃索美拉唑激活HO1，以及 Pirfenidone的抗纤维化作用能够缓慢或停止建立的肺纤维化。 硝酸/氧化应激和纤维增生的失调”。为了测试这一点，我们提出了以下目的：i） 了解iNOS-HO1失调的机制促进纤维发生。在这里，我们计划 评估iNOS抑制和HO1激活调节成纤维细胞增殖的机制和 胶原蛋白产生ii）PPI和iNOS/HO1之间的解密相互作用，以影响疾病过程 IPF。 iii）在两种模型的肺损伤模型中评估埃索美丙唑和吡啶酮组合的体内效率。 这是一个创新的项目，建议将有希望的仿制药与FDA批准的抗纤维化相结合 药物有效缓慢或停止建立的肺纤维化。