The role of Nampt in age-associated persistent lung fibrosis

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 疾病仍然知之甚少。老龄化是公认的IPF风险因素， 影响了老年退伍军人的数量考虑到人口结构的这种变化，理解这种贡献至关重要。 衰老的细胞/分子机制导致与年龄有关的疾病的发病机制， 如IPF。在解决纤维化时，肺肌成纤维细胞（关键的“瘢痕组织生成”细胞）经历凋亡 来促进愈合相比之下，来自纤维化未消退的老年小鼠的肌成纤维细胞获得了 衰老和抗衰老表型，部分由NADPH- 氧化酶-4（Nox 4）。类似地，来自IPF患者的肺肌成纤维细胞表现出衰老和凋亡- 耐药，与Nox 4表达升高相关。然而，驱动持久性的机制 Nox 4和肌成纤维细胞在衰老/IPF背景下的抗凋亡性仍然未知。我们有 Nampt是一种已知的先天免疫反应和细胞凋亡的调节因子， 在年龄相关的病理性肺纤维化中的衰老和抗凋亡肌成纤维细胞表型。 我们证明，Nampt在2种年龄依赖性纤维化损伤模型中体内上调，在纤维化模型中上调。 IPF肺的区域。细胞内Nampt（iNampt）在衰老和IPF中持续表达 成纤维细胞，其不能经历凋亡，并且这些细胞分泌显著升高水平的细胞外基质。 Nampt（eNampt）.我们发现eNampt通过TLR 4介导促纤维化作用，包括肌成纤维细胞， 分化、氧化信号传导、衰老和抗衰老。我们的数据显示， TGF介导的衰老/IPF成纤维细胞中iNampt的下调有助于持续的iNampt 表达，随后升高的eNampt水平，其促进促纤维化作用。Nampt的减少 表达促进肌成纤维细胞凋亡并导致体内免于纤维化。的机制 除了最初的损伤外，还没有很好地理解纤维化反应的持续传播。我们 提出了一种新的自动调节机制（eNampt/iNampt），它在时间上加强了促纤维化 年龄依赖性病理性纤维化的反应。这些研究将提供新的年龄相关的洞察力， IPF发病机制/细胞表型。此外，我们将评估以下药物的临床前疗效： FK-866（iNampt抑制剂，目前正作为抗癌药物进行II期临床试验）在严格老化中的应用 纤维化的动物模型，增强了快速临床转化新疗法的潜力， 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.