Survivin IPF: Targeting Cellular Metabolism to Promote Apoptosis in IPF Fibroblasts.
Survivin IPF: Targeting Cellular Metabolism to Promote Apoptosis in IPF Fibroblasts.
复制标题
Survivin IPF：靶向细胞代谢促进 IPF 成纤维细胞凋亡。
DOI：
10.1165/rcmb.2018-0270ed
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发表时间：
2019
影响因子：
6.4
通讯作者：
Ligresti,Giovanni
中科院分区：
文献类型：
--
作者：
Jones,DakotaL;Ligresti,Giovanni
特发性肺纤维化（IPF）是一种多因素疾病，其特征是活化的成纤维细胞（肌成纤维细胞）在肺部进行性积累，导致细胞外基质持续沉积和器官功能丧失(1)。尽管导致IPF肺中肌成纤维细胞异常积聚的原因尚不完全清楚，但获得持续的抗凋亡表型已被认为是这些疾病效应细胞的关键病理特征之一(2)。细胞凋亡受到一系列复杂且相互关联的分子事件的精细调控，这些事件最终导致半胱氨酸蛋白酶（也称为半胱天冬酶）的激活，而半胱天冬酶是这一过程的最终效应器(3)。凋亡激活因子和抑制因子分别在促进细胞死亡或存活中发挥关键作用，这些调节因子的表达改变会导致细胞反应功能失调(3)。例如，通过表观遗传机制改变凋亡抑制基因的表达已被证明可促进肿瘤生长和癌细胞的侵袭(4)。此外，在从IPF患者分离的成纤维细胞中观察到与几个关键凋亡基因相关的表观遗传改变，从而驱动这些细胞的凋亡抵抗（5,6）。因此，在肺纤维化进展过程中，识别促进肌成纤维细胞凋亡抵抗的信号通路可能为改善患者治疗提供一个有希望的策略。在过去的十年中，基因转录的异常表观遗传调控越来越被认为是促进肌成纤维细胞分化和肺纤维化进展的重要机制（6-9）。表观遗传修饰，如DNA和组蛋白的共价修饰，在调节基因转录中起重要作用。表观遗传状态的病理改变可以对基因表达产生深远的影响（10）。组蛋白的翻译后修饰是促进或抑制基因表达的重要表观遗传机制。组蛋白修饰是由特定的染色质相互作用酶介导的，其活性对来自代谢途径的特定底物的可用性敏感，包括三羧酸循环、b氧化和糖酵解（11）。鉴于IPF的特征是异常的细胞代谢（12,13）以及改变的表观遗传程序(9)，人们越来越感兴趣的是了解改变的细胞代谢如何直接影响肌成纤维细胞的表观遗传状态，从而促进和维持其致病表型。
Idiopathic pulmonary fibrosis (IPF) is a multifactorial disease characterized by progressive accumulation of activated fibroblasts (myofibroblasts) in the lungs, which leads to sustained deposition of extracellular matrix and loss of organ function (1). Although the causes that contribute to the abnormal accumulation of myofibroblasts in the IPF lungs are not fully understood, the acquisition of a sustained apoptosis-resistant phenotype has been recognized as one of the key pathological features of these diseaseeffector cells (2). Apoptosis is finely regulated by a cascade of complex and interconnected molecular events that culminate in the activation of cysteine proteases (also known as caspases), which are the final effectors of this process (3). Both apoptosis activators and suppressors play a critical role in promoting cell death or survival, respectively, and altered expression of these regulators leads to dysfunctional cell responses (3). For example, altered expression of apoptosis suppressor genes by epigenetic mechanisms has been shown to facilitate tumor growth and invasion of cancer cells (4). Additionally, epigenetic alterations associated with several key apoptotic genes have been observed in fibroblasts isolated from patients with IPF, thereby driving apoptosis resistance in these cells (5, 6). Thus, identification of signaling pathways that promote apoptosis resistance in myofibroblasts during lung fibrosis progression may provide a promising strategy to improve patient therapy.During the last decade, aberrant epigenetic regulation of gene transcription has been increasingly recognized as an important mechanism promoting myofibroblast differentiation and lung fibrosis progression (6-9). Epigenetic modifications, such as covalent modifications to DNA and histones, play important roles in regulating gene transcription. Pathological modification of epigenetic states can have profound effects on gene expression (10). Post-translational modification of histones is an important epigenetic mechanism involved in promoting or repressing gene expression. Histone modifications are mediated by specific chromatin-interacting enzymes whose activities are sensitive to the availability of specific substrates derived from metabolic pathways, including the tricarboxylic acid cycle, b oxidation, and glycolysis (11). Given that IPF is characterized by aberrant cellular metabolism (12, 13) as well as altered epigenetic programs (9), there is growing interest in understanding how altered cell metabolism directly influences the epigenetic state of myofibroblasts to promote and maintain their disease-contributing phenotype.