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: 8332589
• 负责人: LOUISE HECKER
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 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/8332589
• 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; 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. 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.

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种最终致命疾病，其特征是进行性疤痕组织形成导致呼吸衰竭。衰老和IPF之间存在很强的关联，但是很少有研究研究了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，老年小鼠对肺损伤表现出持续的纤维化。我们此前曾报道过NOX4/H2O2在介导肌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表达的改变以及NOX4/H2O2在介导促纤维化肺肌纤维细胞表型（衰老，凋亡抗性）中的作用。提出的研究将探讨以下假设：在衰老的背景下，NOX4通过衰老肌纤维细胞的积累有助于持续的纤维化，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型的持续纤维化动物模型，该模型更准确地模仿IPF患者中看到的持续/进行性纤维化。这些研究将提供：（1）对IPF和临床前评估进行研究的更相关的离体和体内实验模型； （2）对衰老和IPF发病机理的作用的新颖见解； （3）扩展了NOX4/H2O2在衰老中的作用，并进一步概念验证靶向NOX4在纤维化疾病中的作用。 公共卫生相关性： 即使在没有疾病的情况下，衰老也伴随着肺部生理的变化。这些与年龄有关的变化可能会增加对肺部疾病的敏感性。特发性肺纤维化（IPF）的特征是进行性疤痕组织形成导致呼吸衰竭，这在老年人群中很普遍。了解肺损伤修复 在衰老的背景下，可以为开发旨在治疗纤维化疾病（例如IPF）的治疗干预措施提供新的见解。