Myofibroblast Senescence in Pulmonary Fibrosis

肺纤维化中的肌成纤维细胞衰老

• 批准号: 8786336
• 负责人: Victor J. Thannickal
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786336
• 关键词: Accounting; Affect; Age; Aging; Animal Model; Antioxidants; Apoptosis; Applications Grants; Attenuated; Bioenergetics; Biological; Blood Vessels; Cell Aging; Cicatrix; Clinical; Data; Development; Diagnosis; Disease; Enzymes; Equilibrium; Exhibits; FDA approved; Fibroblasts; Fibrosis; Gases; Gene Expression; Genes; Genetic; Hamman-Rich syndrome; Heart; Homeostasis; Human; Human Characteristics; Incidence; Kidney; Laboratories; Lead; Link; Liver; Lung; Lung diseases; Mediating; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; NADPH Oxidase; Nuclear; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Prevalence; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Research; Resistance; Resolution; Respiratory Failure; Role; Small Interfering RNA; Structure of parenchyma of lung; Survival Rate; Testing; Time; Tissues; age related; aged; body system; burden of illness; effective therapy; fibrogenesis; human subject; impaired capacity; in vivo; inhibitor/antagonist; insight; lung injury; mitochondrial dysfunction; mortality; novel; novel therapeutic intervention; nuclear factor-erythroid 2; older patient; public health relevance; response; senescence; transcription factor

DESCRIPTION (provided by applicant): Human fibrotic disorders affect many organ systems including heart, blood vessels, kidney, liver and lung. The most common fibrotic lung disease, idiopathic pulmonary fibrosis (IPF) is a disease of aging carries a high morbidity and mortality, with a median survival rate of less than three years. There are currently no U.S. FDA-approved anti-fibrotic drugs. The incidence and prevalence of IPF increase drastically with age; however, despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Recent studies from our laboratory indicate that the biological effects of the ROS-generating enzyme, NADPH oxidase-4 (Nox4) is determined by the capacity of myofibroblasts (MFbs) to maintain redox homeostasis via the induction of the antioxidant response transcription factor, nuclear factor-like 2 (Nrf2), a respons that is deficient with aging. Loss of this cellular homeostatic mechanism results in the emergence of a senescent and apoptosis-resistant phenotype of MFbs, at least in part related to mitochondrial dysfunction. Human subjects with IPF exhibit elevated expression of Nox4 and decreased Nrf2 expression in myofibroblastic foci, supporting this cellular redox imbalance in a human fibrotic disease. In contrast to self-limited, resolving fibrosis in young mice, aged mice manifest an impaired capacity for resolution of fibrosis. This represents, to our knowledge, the first aging model of fibrosis that recapitulates the non-resolving nature of human IPF. The central hypothesis to be tested in this project is that an imbalance of Nox4-Nrf2 induces sustained oxidative stress that induces MFb senescence and apoptosis resistance, leading to persistent fibrosis associated with aging. Our specific aims are to: (1) Determine mechanisms for the (dys)regulation of Nrf2 expression/induction by oxidative stress with cellular senescence; (2) Determine the role of Nox4-Nrf2 imbalance and mitochondrial bioenergetics in promoting Fb senescence; and (3) Determine whether conditional genetic deletion of Nrf2 in Fbs mediates persistent fibrosis in young mice; and whether Nrf2 induction or Nox4 inhibition (by pharmacologic approaches) promotes fibrosis resolution in aged mice. This grant application is responsive to PA-10-014: Development and Characterization of Animal Models for Aging Research. The completion of the aims in this project will: (a) establish a disease-relevant animal model of non-resolving fibrosis; (b) define mechanisms for the loss of redox homeostatic control in MFbs; (c) establish mechanistic links between mitochondrial dysfunction and senescence; and (d) provide proof-of-concept that correction of cellular redox balance will promote fibrosis resolution and lead to the development of novel therapeutic approaches to non-resolving fibrotic disorders such as IPF.

描述（由申请人提供）：人类纤维化疾病影响许多器官系统，包括心脏、血管、肾脏、肝脏和肺。特发性肺纤维化（IPF）是最常见的纤维化性肺疾病，是一种发病率和死亡率较高的老年性疾病，中位生存期不到3年。目前没有美国FDA批准的抗纤维化药物。IPF的发病率和患病率随着年龄的增长而急剧增加;然而，尽管存在这种强烈的相关性，但尚未阐明导致纤维化疾病的衰老易感性的细胞/分子机制。 我们实验室最近的研究表明，ROS生成酶NADPH氧化酶-4（Nox 4）的生物学效应是由肌成纤维细胞（MFbs）通过诱导抗氧化反应转录因子核因子样2（Nrf 2）维持氧化还原稳态的能力决定的，Nrf 2是一种衰老缺乏的反应。这种细胞内稳态机制的丧失导致MFbs的衰老和凋亡抗性表型的出现，至少部分与线粒体功能障碍有关。患有IPF的人类受试者在肌纤维母细胞灶中表现出Nox 4表达升高和Nrf 2表达降低，支持人类纤维化疾病中的这种细胞氧化还原失衡。与年轻小鼠中的自限性、消退性纤维化相反，老年小鼠表现出纤维化消退能力受损。据我们所知，这代表了第一个纤维化老化模型，其重现了人IPF的非消退性质。 在该项目中要测试的中心假设是Nox 4-Nrf 2的不平衡诱导持续的氧化应激，其诱导MFb衰老和凋亡抗性，导致与衰老相关的持续纤维化。我们的具体目标是：（1）确定通过氧化应激和细胞衰老对Nrf 2表达/诱导的（dys）调节机制;（2）确定Nox 4-Nrf 2失衡和线粒体生物能量学在促进Fb衰老中的作用;和（3）确定Fbs中Nrf 2的条件性遗传缺失是否介导年轻小鼠中的持续纤维化;以及Nrf 2诱导或Nox 4抑制（通过药理学方法）是否促进老年小鼠的纤维化消退。 此拨款申请是响应PA-10-014：衰老研究动物模型的开发和表征。完成本项目的目标将：（a）建立一个与疾病相关的非消退性纤维化动物模型;（B）确定MFbs中氧化还原稳态控制丧失的机制;（c）建立线粒体功能障碍和衰老之间的机制联系;及（d）提供以下事项的证明─细胞氧化还原平衡的纠正将促进纤维化的解决，并导致新的治疗方法的发展，解决纤维化疾病如IPF。