Aging, Fibroblast Senescence, and Apoptosis in Lung Fibrosis

描述(由申请人提供)： 特发性肺纤维化(IPF)是一种最终致命的疾病，其特征是进行性瘢痕组织形成导致呼吸衰竭。衰老与IPF之间有很强的相关性，然而很少有研究调查衰老对持续性肺纤维化易感性的影响。我们的初步研究表明，老年小鼠对肺损伤的反应表现出持续性的纤维化。我们先前报道了NOX4/H_2O_2在介导肌成纤维细胞功能和肺纤维化中的关键作用。然而，NOX4表达的年龄相关性变化以及NOX4/H_2O_2在介导促纤维化的肺肌成纤维细胞表型(衰老、抗凋亡)中的作用尚未见报道。在拟议的研究中，我们将探索这样的假设，即在衰老的背景下，NOX4通过积累衰老的肌成纤维细胞促进持续性纤维化，从而可能诱导上皮细胞凋亡。我们建议开发一种新的老年小鼠持续性纤维化的动物模型，更准确地模拟IPF患者的持续性/进行性纤维化。这些研究将提供：(1)用于IPF研究和临床前评估的更相关的体外和体内实验模型；(2)对衰老和IPF发病机制的新见解；(3)NOX4/H2O2在衰老中的扩大作用，以及进一步验证以NOX4为靶点治疗纤维化疾病的概念。 公共卫生相关性： 即使在没有疾病的情况下，衰老也会伴随着肺部生理的变化。这些与年龄相关的变化可能会增加肺部疾病的易感性。特发性肺纤维化(IPF)是以进行性瘢痕组织形成导致呼吸衰竭为特征的疾病，常见于老年人。了解肺损伤-修复 在老龄化的背景下，可能为旨在治疗纤维化疾病的治疗干预措施的开发提供新的见解，例如IPF。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an ultimately fatal disease, characterized by progressive scar tissue formation leading to respiratory failure. There is a strong association between aging and IPF, however few studies have investigated the effects of aging on susceptibility to persistent lung fibrosis. Our preliminary studies indicate that aged mice exhibit persistent fibrosis in response to lung injury. We previously reported a critical role for NOX4/H2O2 in mediating myofibroblast functions and lung fibrosis. However, age-associated alterations in NOX4 expression as well as the role of NOX4/H2O2 in mediating pro-fibrotic lung myofibroblast phenotypes (senescence, apoptosis-resistance) have not previously been reported. The proposed studies, we will explore the hypothesis that, in the context of aging, NOX4 contributes to persistent fibrosis by the accumulation of senescent myofibroblasts, which may then induce apoptosis of epithelial cells. We propose to develop a novel animal model of persistent fibrosis in aged mice, which more accurately mimics the persistent/progressive fibrosis seen in IPF patients. These studies will provide: (1) more relevant ex vivo and in vivo experimental models for investigation of IPF and pre-clinical evaluation; (2) novel insights into the role of aging andin the pathogenesis of IPF; and, (3) expanded roles of NOX4/H2O2 in aging and further proof-of-concept for therapeutic targeting NOX4 in fibrotic diseases. PUBLIC HEALTH RELEVANCE: Even in the absence of disease, aging is accompanied by changes in pulmonary physiology. These age-related changes may increase susceptibility to pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scar tissue formation leading to respiratory failure, which is prevalent in the elderly population. Understanding lung injury-repair in the context of aging may offer novel insights for the development of therapeutic interventions aimed to treat fibrotic diseases, such as IPF.