Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease

项目摘要 纤维化涉及气道，脉管系统，肺泡和胸膜，在不同程度上， 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是纤维化肺中最神秘和致命的 紊乱尽管最近批准了两种药物，但生存率并没有显著提高。肺 纤维化代表了对肺损伤的复杂组织反应，其涉及许多细胞类型，介质， 和信号通路。在过去的几年里，疾病发病机制中的几个新概念已经 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）的侵袭性/抗肿瘤表型。这些概念/范例中的每一个都是 在本tPPG的续期申请中解决。本tPPG周期I期间开展的工作已得到确认 活性氧（ROS）-再生酶，NADPH氧化酶4（NOX 4）， 并鉴定了患有IPF的人类受试者中氧化应激的循环血浆生物标志物。在项目1中，我们 将进行一项关于NOX 1/4抑制剂在IPF中的安全性和疗效的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 myoFbs的氧化还原代谢重编程解释了观察到的NOX 4的促纤维化作用。基于 关于纤维化中巨噬细胞-myoFb相互作用的新数据，项目3将检验NOX 4 调节巨噬细胞线粒体活性氧和代谢，使肺泡巨噬细胞极化为促纤维化细胞 表型。项目4将测试新的假设，B细胞衍生的自身抗体表观遗传重编程 抗凋亡表型。总之，这tPPG将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控机制， 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将推动一种新的抗纤维化药物治疗， IPF中的氧化还原生物学，这将使未来的III期临床试验。

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.