The role of Nampt in age-associated persistent lung fibrosis

特发性肺纤维化(IPF)的病理生理学研究 人们对这种疾病仍然知之甚少。老龄化是公认的IPF的危险因素，而IPF不成比例 影响到老龄化的退伍军人群体。鉴于人口结构的这种转变，理解其贡献至关重要 衰老对细胞/分子机制的影响(S)，导致衰老相关疾病的发病机制，如 作为IPF。在解决纤维化的过程中，肺肌成纤维细胞(关键的“疤痕组织生成”细胞)经历了凋亡 以促进治愈。相比之下，患有非消退性纤维化的老年小鼠的肌成纤维细胞获得了 衰老和抗凋亡表型，部分由NADPH-1持续表达介导 氧化酶-4(NOX4)。同样，IPF患者的肺肌成纤维细胞也表现出衰老和凋亡- 耐药性，与NOX4表达升高有关。然而，推动持久化的机制 在衰老/IPF的背景下，NOX4和肌成纤维细胞的凋亡抵抗仍不清楚。我们有 发现了NAMPT的关键作用，NAMPT是一种已知的先天免疫反应和细胞凋亡的调节器，在驱动 年龄相关的病理性肺纤维化中衰老和抗凋亡的肌成纤维细胞表型。 我们证明NAMPT在两种年龄依赖性纤维化损伤模型和纤维化模型中表达上调。 IPF肺的区域。细胞内NAMPT(INampt)在衰老和IPF中持续表达 无法发生凋亡的成纤维细胞，这些细胞分泌显著升高的细胞外 名称(ENampt)。我们发现eNampt通过包括肌成纤维细胞在内的TLR4介导促纤维化作用 分化、氧化信号、衰老和抗凋亡。我们的数据显示有缺陷的 转化生长因子介导的iNampt在衰老/IPF成纤维细胞中的下调促进iNampt持续存在 表达，随后eNampt水平升高，这促进了促纤维化作用。NAMPT的减少 在体内，表达促进了肌成纤维细胞的凋亡并导致了对纤维化的保护。这些机制可以 除了最初的损伤外，驱动纤维化反应的持续传播还不是很清楚。我们 提出一种新的自动调节机制(eNampt/iNampt)，它可以暂时加强纤维化 年龄相关性病理性纤维化的反应。这些研究将提供对与年龄相关的小说的洞察 IPF发病机制/细胞表型。此外，我们将评估阿司匹林的临床前疗效 FK-866(作为抗癌剂的iNampt抑制剂目前处于II期临床试验)在严格老化中 纤维化动物模型，增强新型治疗药物快速临床翻译的潜力 IPF。

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.