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首页> 外文期刊>Journal of Agricultural and Food Chemistry >Gallic Acid Induces Apoptosis of Lung Fibroblasts via a Reactive Oxygen Species-Dependent Ataxia Telangiectasia Mutated-p53 Activation Pathway
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Gallic Acid Induces Apoptosis of Lung Fibroblasts via a Reactive Oxygen Species-Dependent Ataxia Telangiectasia Mutated-p53 Activation Pathway

机译：没食子酸通过依赖于活性氧的共济失调毛细血管扩张-p53激活途径诱导肺成纤维细胞凋亡。

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摘要

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by the activation of fibroblasts and the overproduction of extracellular matrix. Fibroblast resistance to apoptosis leads to increased fibrosis. Targeting fibroblasts with apoptotic agents represents a major therapeutic intervention for debilitating IPF. Gallic acid (3,4,5-trihydroxybenzoic acid), a naturally occurring plant phenol, has been reported to induce apoptosis in tumor cell lines and renal fibroblasts. However, the effects of gallic acid on lung fibroblasts have not been investigated. The aim of the present study is to determine the effects of gallic acid on primary cultured mouse fibroblasts. Our results showed that gallic acid induces the apoptotic death of fibroblasts via both intrinsic and extrinsic apoptotic pathways by the elevation of PUMA, Fas, and FasL protein levels. Moreover, intracellular reactive oxygen species (ROS) generation and 8-hydroxy-2'-deoxyguanosine production were observed in gallic acid-stimulated fibroblasts. Mechanistic studies showed that gallic acid induces early phosphorylation of p53~(Ser18) and histone 2AX~(Ser139) (H2AX) via ataxia telangiectasia mutated (ATM) activation in response to ROS-provoked DNA damage. When mouse lung fibroblasts were treated with caffeine, an ATM kinase inhibitor, the levels of p53, phosphorylated p53~(Ser18), and cell death induced by gallic acid were significantly attenuated. Additionally, pretreatment with antioxidants drastically inhibited the gallic acid-induced 8-hydroxy-2'-deoxyguanosine (8-OH-dG) formation and phosphorylation of p53~(Ser18) and ATM~(Ser1981), as well as apoptosis. Our results provide the first evidence of the activation of ROS-dependent ATM/p53 signaling as a critical mechanism of gallic acid-induced cell death in primary cultured mouse lung fibroblasts.
机译：特发性肺纤维化（IPF）是一种进行性慢性疾病，其特征在于成纤维细胞的活化和细胞外基质的过度生产。成纤维细胞对凋亡的抗性导致纤维化增加。用凋亡因子靶向成纤维细胞代表了使IPF衰弱的主要治疗手段。没食子酸（3,4,5-三羟基苯甲酸），一种天然存在的植物酚，据报道可诱导肿瘤细胞系和肾成纤维细胞凋亡。但是，没食子酸对肺成纤维细胞的作用尚未研究。本研究的目的是确定没食子酸对原代培养的小鼠成纤维细胞的影响。我们的结果表明，没食子酸通过PUMA，Fas和FasL蛋白水平的升高，通过内在和外在的凋亡途径诱导成纤维细胞的凋亡死亡。此外，在没食子酸刺激的成纤维细胞中观察到细胞内活性氧（ROS）的产生和8-羟基-2'-脱氧鸟苷的产生。机理研究表明，没食子酸通过共济失调性毛细血管扩张突变（ATM）激活，诱导ROS引起的DNA损伤，从而诱导p53〜（Ser18）和组蛋白2AX〜（Ser139）（H2AX）早期磷酸化。当用咖啡因（一种ATM激酶抑制剂）处理小鼠肺成纤维细胞时，没食子酸诱导的p53，磷酸化p53〜（Ser18）水平和细胞死亡显着减弱。此外，用抗氧化剂预处理可大大抑制没食子酸诱导的p53〜（Ser18）和ATM〜（Ser1981）的8-羟基-2'-脱氧鸟苷（8-OH-dG）形成和磷酸化以及细胞凋亡。我们的结果提供了ROS依赖性ATM / p53信号转导的激活的初步证据，该信号转导是在原代培养的小鼠肺成纤维细胞中没食子酸诱导细胞死亡的关键机制。

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