Aging, Fibroblast Senescence, and Apoptosis in Lung Fibrosis

肺纤维化中的衰老、成纤维细胞衰老和细胞凋亡

• 批准号: 8803286
• 负责人: LOUISE HECKER
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803286
• 关键词: Age; Aging; Alveolar; Animal Model; Antibodies; Apoptosis; Biochemical; Biological Assay; Bleomycin; Cell Communication; Cells; Cicatrix; Coculture Techniques; Development; Diagnosis; Disease; Elderly; Environmental Exposure; Epithelial; Epithelial Cells; Epithelium; Exhibits; Experimental Models; Extracellular Matrix; Fibroblasts; Fibrosis; Generations; Genetic; Hamman-Rich syndrome; Hydrogen Peroxide; Immunofluorescence Immunologic; Immunohistochemistry; Incidence; Induction of Apoptosis; Injury; Investigation; Link; Lung; Lung diseases; Measurement; Mediating; Mediator of activation protein; Mesenchymal; Methods; Morphology; Mus; Muscle; Myofibroblast; NADPH Oxidase; Natural regeneration; Nature; Oxidative Stress; Pathogenesis; Pathologic; Patients; Phenotype; Physiological; Physiology; Population; Predisposition; Prevalence; Process; Pulmonary Fibrosis; Reporting; Resistance; Resolution; Respiratory Failure; Respiratory physiology; Risk; Risk Factors; Role; Severities; Site; System; Therapeutic Intervention; Time; Tissues; Tumor Necrosis Factor Ligand Superfamily Member 6; Wound Healing; age effect; age related; aged; body system; cigarette smoking; cohort; extracellular; genetic approach; human TGFB1 protein; in vivo; injured; injury and repair; insight; lung injury; male; novel; older patient; paracrine; pre-clinical; preclinical efficacy; progenitor; reconstitution; research clinical testing; response; response to injury; senescence; therapeutic target; tissue repair; wound

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.

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，其特征是进行性疤痕组织形成，导致呼吸衰竭。衰老与 IPF 之间存在密切关联，但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，老年小鼠因肺损伤而表现出持续性纤维化。我们之前报道过 NOX4/H2O2 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 NOX4 表达变化以及 NOX4/H2O2 在介导促纤维化肺肌成纤维细胞表型（衰老、细胞凋亡抵抗）中的作用此前尚未报道。在拟议的研究中，我们将探讨这样的假设：在衰老的背景下，NOX4 通过衰老肌成纤维细胞的积累导致持续纤维化，然后可能诱导上皮细胞凋亡。我们建议在老年小鼠中开发一种新型持续性纤维化动物模型，该模型更准确地模拟 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) 对衰老的作用和 IPF 发病机制的新见解； (3)扩大 NOX4/H2O2 在衰老中的作用，并进一步验证针对纤维化疾病的 NOX4 治疗的概念。