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之间存在很强的相关性，但很少有研究研究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，老年小鼠表现出持续的纤维化，对肺损伤的反应。我们先前报道了NOX 4/H2 O2在介导肌成纤维细胞功能和肺纤维化中的关键作用。然而，与年龄相关的NOX 4表达的改变以及NOX 4/H2 O2在介导促纤维化肺肌成纤维细胞表型（衰老、肺纤维化抗性）中的作用以前尚未报道。在拟议的研究中，我们将探讨这样的假设，即在衰老的背景下，NOX 4通过衰老的肌成纤维细胞的积累而导致持续的纤维化，然后可能诱导上皮细胞的凋亡。我们建议在老年小鼠中开发一种新的持续性纤维化动物模型，其更准确地模拟IPF患者中观察到的持续性/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离体和体内实验模型;（2）对衰老和IPF发病机制的作用的新见解;（3）扩大了NOX 4/H2 O2在衰老中的作用，并进一步验证了NOX 4在纤维化疾病中的治疗靶向概念。 公共卫生相关性： 即使在没有疾病的情况下，衰老也伴随着肺生理学的变化。这些与年龄相关的变化可能会增加对肺部疾病的易感性。特发性肺纤维化（IPF）的特征是进行性瘢痕组织形成，导致呼吸衰竭，这在老年人群中很常见。了解肺损伤-修复 在老龄化背景下的研究可能为开发旨在治疗纤维化疾病（如IPF）的治疗干预提供新的见解。

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.