Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease

项目概要 许多患者都不同程度地出现累及气道、脉管系统、肺泡和胸膜的纤维化。 临床综合征，包括哮喘、慢性阻塞性肺疾病的亚表型、肺 高血压和特发性肺纤维化（IPF）。 IPF是最神秘和致命的纤维化肺 失调。尽管最近批准了两种药物，但生存率并未显着改善。肺部 纤维化代表了对肺损伤的复杂组织反应，涉及多种细胞类型、介质、 和信号通路。在过去的几年里，一些疾病发病机制的新概念被提出。 出现了；这些包括代谢重编程、表观遗传学、免疫调节、巨噬细胞生物学和 肌成纤维细胞 (myoFbs) 的侵袭/抗凋亡表型。这些概念/范式中的每一个都是 在此 tPPG 的更新申请中进行了解决。该 tPPG 周期 I 期间开展的工作已得到验证 活性氧 (ROS) 再生酶、NADPH 氧化酶 4 (NOX4) 的促纤维化作用， 并鉴定了 IPF 人类受试者氧化应激的循环血浆生物标志物。在项目1中，我们 将使用多种药物进行 NOX1/4 抑制剂治疗 IPF 的安全性和有效性的 IIb 期临床试验 生物标志物和生理测量作为主要和次要终点。项目2将检验假设 myoFb 的氧化还原代谢重编程解释了观察到的 NOX4 的促纤维化作用。基于 根据纤维化中巨噬细胞-myoFb 相互作用的新数据，项目 3 将检验 NOX4 的假设 调节巨噬细胞线粒体 ROS 和代谢，使肺泡巨噬细胞极化为促纤维化 表型。项目 4 将测试 B 细胞衍生的自身抗体进行表观遗传重编程的新假设 Fbs 具有抗凋亡表型。该 tPPG 将共同阐明细胞氧化还原之间的关键联系 控制和代谢重编程，揭示巨噬细胞极化的新调节机制，以及 阐明先天/适应性免疫、表观遗传学和肺之间以前未被认识的联系 纤维化。重要的是，这种 tPPG 将推进一种新型抗纤维化药物疗法，该疗法更具体地针对 IPF 中的氧化还原生物学，这将使未来的 III 期临床试验成为可能。

PROJECT SUMMARY Fibrosis involving the airways, vasculature, alveoli, and pleura is seen, to varying degrees, in a number of clinical syndromes, including asthma, subphenotypes of chronic obstructive pulmonary disease, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF). IPF is the most enigmatic and fatal of the fibrotic lung disorders. Despite the recent approval of two drugs, survival has not significantly improved. Pulmonary fibrosis represents a complex tissue response to lung injury that involves a number of cell types, mediators, and signaling pathways. In just over the last few years, several new concepts in disease pathogenesis have emerged; these include metabolic reprogramming, epigenetics, immune modulation, macrophage biology and the invasive/apoptosis-resistant phenotype of myofibroblasts (myoFbs). Each of these concepts/paradigms is addressed in this renewal application of this tPPG. Work conducted during Cycle I of this tPPG has validated the pro-fibrotic effects of the reactive oxygen species (ROS)-regenerating enzyme, NADPH oxidase 4 (NOX4), and identified circulating plasma biomarkers of oxidative stress in human subjects with IPF. In Project 1, we will conduct a Phase IIb clinical trial of the safety and efficacy of a NOX1/4 inhibitor in IPF using multiple biomarkers and physiologic measures as primary and secondary end-points. Project 2 will test the hypothesis that redox-metabolic reprogramming of myoFbs accounts for the observed pro-fibrotic effects of NOX4. Based on emerging data on macrophage-myoFb interactions in fibrosis, Project 3 will test the hypothesis that NOX4 modulates macrophage mitochondrial ROS and metabolism to polarize alveolar macrophages to a pro-fibrotic phenotype. Project 4 will test the novel hypothesis that B-cell derived autoantibodies epigenetically reprogram Fbs to an anti-apoptotic phenotype. Together, this tPPG will elucidate critical links between cellular redox control and metabolic reprogramming, uncover novel regulatory mechanisms of macrophage polarization, and illuminate previously unrecognized connections between innate/adaptive immunity, epigenetics and lung fibrosis. Importantly, this tPPG will advance a novel anti-fibrotic drug therapy that more specifically targets redox biology in IPF, which will enable future Phase III clinical trials.