The role of Nampt in age-associated persistent lung fibrosis

Nampt 在年龄相关的持续性肺纤维化中的作用

• 批准号: 10046286
• 负责人: LOUISE HECKER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046286
• 关键词: Acute; Affect; Age; Aging; Animal Model; Antineoplastic Agents; Apoptosis; Automobile Driving; Cells; Chronic; Cicatrix; Clinical; Data; Development; Disease; Down-Regulation; Enzymes; Exhibits; Failure; Fibroblasts; Fibrosis; Functional disorder; Genetic; Healthcare; Human; Hydrogen Peroxide; Impairment; In Vitro; Injury; Innate Immune Response; Lung; Lung diseases; Mediating; Modeling; Molecular; Mus; Myofibroblast; NADPH Oxidase; Oxidants; Pathogenesis; Pathologic; Patients; Pharmacology; Pharmacotherapy; Phase II Clinical Trials; Phenotype; Play; Predisposition; Process; Proteins; Pulmonary Fibrosis; Quality of life; Resistance; Resolution; Risk Factors; Role; Signal Transduction; Structure of parenchyma of lung; Survival Rate; TLR4 gene; Testing; Therapeutic Agents; Tissues; Transforming Growth Factor beta; Treatment Efficacy; Up-Regulation; Veterans; age related; aged; cancer clinical trial; clinical translation; cohort; conditional knockout; cytokine; drug candidate; efficacy evaluation; extracellular; genetic approach; healing; idiopathic pulmonary fibrosis; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; lung injury; military veteran; mouse model; neutralizing antibody; nicotinamide phosphoribosyltransferase; novel; novel therapeutics; pre-clinical; preclinical efficacy; promoter; receptor; response; senescence; therapeutic target; tissue injury; treatment strategy

The pathophysiology of Idiopathic pulmonary fibrosis (IPF), a rapidly progressive and deadly fibrotic lung disease remains poorly understood. Aging is a well-recognized risk factor for IPF, and IPF disproportionately affects the aging veteran population. Given this shift in demographic, it is critical to understand the contribution of aging to the cellular/molecular mechanism(s) leading to the pathogenesis of age-related diseases, such as IPF. In resolving fibrosis, lung myofibroblasts (the key `scar tissue generating' cell) undergo apoptosis to promote healing. In contrast, myofibroblasts from aged mice with non-resolving fibrosis acquire a senescent and apoptosis-resistant phenotype, mediated in part by persistent expression of NADPH- oxidase-4 (Nox4). Similarly, lung myofibroblasts from IPF patients exhibit senescence and apoptosis- resistance, associated with elevated Nox4 expression. However, the mechanisms that drive persistence of Nox4 and apoptosis-resistance of myofibroblasts in the context of aging/IPF remain unknown. We have identified a critical role for Nampt, a known regulator of innate immune responses and apoptosis, in driving the senescent and apoptosis-resistant myofibroblast phenotype in age-associated pathological lung fibrosis. We demonstrate that Nampt is upregulated in vivo in 2 injury models of age-dependent fibrosis, and in fibrotic regions of the IPF lung. Intracellular Nampt (iNampt) is persistently expressed in senescent and IPF fibroblasts, which fail to undergo apoptosis, and these cells secrete significantly elevated levels of extracellular Nampt (eNampt). We found that eNampt mediates profibrotic effects via TLR4, including myofibroblast differentiation, oxidative signaling, senescence, and apoptosis-resistance. Our data suggest that defective TGF-mediated downregulation of iNampt in senescent/IPF fibroblasts contributes to persistent iNampt expression, subsequent elevated eNampt levels, which promotes profibrotic effects. Reductions in Nampt expression facilitated myofibroblast apoptosis and led to protection from fibrosis in vivo. The mechanisms that drive continued propagation of fibrogenic responses, beyond initial injury, are not well understood. We propose a novel auto-regulatory mechanism (eNampt/iNampt), which temporally reinforces profibrotic responses in age-dependent pathological fibrosis. These studies will prvide insight into novel age-relevant mechanisms/cellular phenotypes in IPF pathogenesis. Further, we will evaluate the pre-clinical efficacy of FK-866 (iNampt inhibitor currently in phase II clinical trials as an anti-cancer agent) in rigorous aging animal models of fibrosis, enhancing the potential fo rapid clinical translation of novel therapeutics for IPF.

特发性肺纤维化（IPF）的病理生理学，一种快速进展和致命的纤维化肺