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）是最常见的纤维化肺病，是一种发病率和死亡率较高的衰老疾病，中位生存率不到三年。目前还没有美国 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，尽管存在这种密切的关联，但导致衰老易患纤维化疾病的细胞/分子机制尚未阐明。 我们实验室的最新研究表明，ROS 生成酶 NADPH 氧化酶 4 (Nox4) 的生物效应取决于肌成纤维细胞 (MFb) 通过诱导抗氧化反应转录因子核因子样 2 (Nrf2) 维持氧化还原稳态的能力，而这种反应随着衰老而缺乏。这种细胞稳态机制的丧失会导致 MFb 出现衰老和抗凋亡表型，至少部分与线粒体功能障碍有关。患有 IPF 的人类受试者在肌成纤维细胞病灶中表现出 Nox4 表达升高和 Nrf2 表达降低，支持人类纤维化疾病中的细胞氧化还原失衡。与年轻小鼠的自限性纤维化消退相反，老年小鼠的纤维化消退能力受损。据我们所知，这是第一个纤维化衰老模型，它概括了人类 IPF 的非解决性质。 该项目要测试的中心假设是，Nox4-Nrf2 的不平衡会诱导持续的氧化应激，从而诱导 MFb 衰老和细胞凋亡抵抗，从而导致与衰老相关的持续纤维化。我们的具体目标是：（1）确定氧化应激和细胞衰老对 Nrf2 表达/诱导的（失调）调节机制； (2)确定Nox4-Nrf2失衡和线粒体生物能学在促进Fb衰老中的作用； (3)确定Fb中Nrf2的条件性基因缺失是否介导幼鼠的持续纤维化；以及 Nrf2 诱导或 Nox4 抑制（通过药理学方法）是否能促进老年小鼠纤维化的消退。 该拨款申请响应 PA-10-014：衰老研究动物模型的开发和表征。完成该项目的目标将： (a) 建立与疾病相关的非消退性纤维化动物模型； (b) 定义 MFb 失去氧化还原稳态控制的机制； (c) 建立线粒体功能障碍和衰老之间的机制联系； (d) 提供概念验证，证明细胞氧化还原平衡的纠正将促进纤维化消退，并导致开发针对非消退性纤维化疾病（如 IPF）的新治疗方法。