Mitigating Lung Fibrosis by Targeting Dysfunctional Alveolar Epithelial Cell Lipid Metabolism.
Mitigating Lung Fibrosis by Targeting Dysfunctional Alveolar Epithelial Cell Lipid Metabolism.
复制标题
通过针对功能失调的肺泡上皮细胞脂质代谢来减轻肺纤维化。
DOI：
10.1165/rcmb.2018-0070ed
复制
发表时间：
2018
影响因子：
6.4
通讯作者：
Kamp,DavidW
中科院分区：
文献类型：
--
作者：
Kamp,DavidW
特发性肺纤维化（IPF）是一种慢性、进行性、年龄相关性和致死性肺部疾病，中位生存期为3-5年（1，2）。尽管两种药物（吡非尼酮和尼达尼布）可减缓IPF疾病进展，但均不能治愈或改善肺功能。此外，这些药物在除IPF外的其他衰弱性纤维化肺病中的作用尚不清楚。因此，有一个迫切的，未满足的需要，以确定创新的目标，可以扩大我们非常有限的药理学工具箱。尽管在过去的二十年里，我们对IPF的病理生物学的理解有了相当大的进步，但所涉及的确切机制尚未确定。越来越多的证据表明，暴露于环境毒素（如病毒和烟草）的遗传易感宿主中产生的异常激活的细支气管和肺泡上皮细胞（AEC）在促进肺纤维化（包括IPF）中发挥关键作用（2，3）。异常活化的肺上皮细胞，包括经历凋亡、衰老或不完整的AEC，基本上产生驱动肺成纤维细胞和肌成纤维细胞群体扩增以及IPF特征性细胞外基质重塑所需的所有关键促纤维化信号传导，包括转化生长因子-b（TGF-b）和各种基质金属蛋白酶和趋化因子（2）。虽然促进纤维化肺病中异常肺上皮细胞发展的机制尚不确定，但“夸大”的肺老化途径明显相关（2，4，5）。所有关键的衰老途径在人类和动物纤维化肺的AEC中都是明显的，最值得注意的包括AEC DNA损伤、肺泡2型细胞端粒缩短、AEC α介导的（内在）凋亡和激活内质网（ER）未折叠蛋白反应（UPR）的蛋白质折叠异常（综述见参考文献2-9）。ER使用各种伴侣蛋白（即葡萄糖相关肽78）调节细胞内蛋白质折叠和运输，并在应激时激活协调良好的UPR信号级联，涉及三种途径：激活转录因子6、胰腺ER激酶和肌醇需要酶1a。正常的UPR调节新蛋白质的合成，包括增加蛋白质折叠的伴侣蛋白，以及ER相关的降解系统。然而，异常激活的ER应激反应常见于多种退行性疾病，包括IPF。正如最近综述的（8，9）和本文的简要总结，几条证据有力地支持持续的AEC ER应激在介导肺纤维化中的重要病理生理作用，包括以下发现：1）AEC ER应激是IPF患者和各种肺纤维化动物模型肺中的共同特征; 2）编码仅在肺泡2型细胞中合成的各种表面活性蛋白的基因突变在患有肺纤维化的人中是明显的;和3）表达各种突变表面活性蛋白的鼠转基因模型诱导AEC ER应激，其单独不足以引发肺纤维化，但使小鼠对“第二次打击”（即，低剂量博来霉素）敏感。尽管异常ER应激诱导肺纤维化的详细机制知之甚少，但肺上皮细胞凋亡、炎症信号传导和上皮-间充质细胞分化的诱导都涉及其中（8，9）。225-236）在本期杂志中提供了将ER应激与肺纤维化联系起来的额外信息，并通过显示缺乏AEC脂质合成...
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, age-related, and fatal lung disease with a median survival of 3–5 years (1, 2). Although two drugs (pirfenidone and nintedanib) slow IPF disease progression, neither is curative or improves lung function. Moreover, the role of these agents in other debilitating fibrotic lung disorders besides IPF is unknown. Accordingly, there is an urgent, unmet need to identify innovative targets that can expand our very limited pharmacologic toolbox. Despite considerable advances in our understanding of the pathobiology of IPF over the past two decades, the precise mechanisms involved are not established. Accumulating evidence suggests that aberrantly activated bronchiolar and alveolar epithelial cells (AECs) arising in a genetically predisposed host exposed to environmental toxins (eg, viruses and tobacco) play a key role in promoting lung fibrosis, including IPF (2, 3). Aberrantly activated lung epithelial cells, including AECs undergoing apoptosis, senescence, or disintegrity, produce essentially all of the key profibrotic signaling necessary to drive the expansion of lung fibroblast and myofibroblast populations and extracellular matrix remodeling that are characteristic of IPF, including transforming growth factor-b (TGF-b) and various matrix metalloproteinases and chemokines (2). Although the mechanisms that promote the development of aberrant lung epithelium in fibrotic lung diseases are uncertain,“exaggerated” lung aging pathways are prominently implicated (2, 4, 5). All of the key aging pathways are evident in AECs of human and animal fibrotic lungs, most notably including AEC DNA damage, shortened alveolar type 2 cell telomeres, AEC mitochondria-mediated (intrinsic) apoptosis, and protein folding abnormalities that activate an endoplasmic reticulum (ER) unfolded protein response (UPR)(for reviews, see References 2–9). The ER regulates intracellular protein folding and trafficking using various chaperone proteins (ie, glucose-related peptide 78) and, upon stress, activates a well-coordinated UPR signaling cascade involving three pathways: activating transcription factor 6, pancreatic ER kinase, and inositol-requiring enzyme 1a. A normal UPR regulates new protein synthesis, including chaperone proteins that augment protein folding, as well as the ER-associated degradation system. However, an abnormally activated ER stress response is commonly seen in a wide array of degenerative conditions, including IPF. As recently reviewed (8, 9) and briefly summarized here, several lines of evidence firmly support an important pathophysiologic role of ongoing AEC ER stress in mediating pulmonary fibrosis, including the findings that 1) AEC ER stress is a common feature in the lungs of patients with IPF and various animal models of lung fibrosis; 2) mutations in genes encoding various surfactant proteins, which are only synthesized in alveolar type 2 cells, are evident in humans with pulmonary fibrosis; and 3) murine transgenic models expressing various mutant surfactant proteins induce AEC ER stress, which alone is insufficient to trigger pulmonary fibrosis but sensitizes mice to a “second hit”(ie, low-dose bleomycin). Although the detailed mechanisms by which abnormal ER stress induces lung fibrosis are poorly understood, induction of lung epithelial cell apoptosis, inflammatory signaling, and epithelial–mesenchymal cell differentiation are all implicated (8, 9).In this context, Romero and colleagues (pp. 225–236) in this issue of the Journal provide additional information linking ER stress to lung fibrosis, and elegantly extend our understanding of the field by showing that deficient AEC lipid synthesis …