PM2.5 induces liver fibrosis via triggering ROS-mediated mitophagy
PM2.5 induces liver fibrosis via triggering ROS-mediated mitophagy
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DOI：
10.1016/j.ecoenv.2018.08.050
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发表时间：
2019-01-15
影响因子：
6.8
通讯作者：
Zhang, Ke-Zhong
中科院分区：
文献类型：
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作者：
Qiu, Yi-Ning;Wang, Guo-Hui;Zhang, Ke-Zhong
研究背景：细颗粒物（PM2.5）的流行日益严重，对人类健康构成严重威胁。它诱导肝纤维化的发生，但其分子机制尚不清楚。方法：采用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四氮唑溴化物（MTD）法检测LX-2细胞和原代肝星状细胞（HSC）的细胞活力。采用体外酶联免疫吸附试验（ELISA）检测抗氧化酶和活性氧（ROS）的浓度。用JC-1染料测定线粒体跨膜电位（MTP）。通过Parkin特异性siRNA转染进行Parkin的敲低。结果：PM2. 5可激活LX-2细胞和原代HSC，诱导肝纤维化，沿着明胶酶MMP-2表达下调，肌成纤维细胞标志物Ⅰ型胶原和α-SMA表达上调。PM2.5处理的LX-2细胞和原代HSC中ROS和活性氮（RNS）水平以及脂质过氧化标记物丙二醛（MDA）水平显著上调。此外，酶抗氧化剂水平受到PM2.5的干扰。此外，PM2.5降低了MTP，将细胞色素c从线粒体释放到细胞质中。PM2.5通过促进线粒体分裂来调节线粒体的动力学。结论：PM2. 5可能通过增加ROS激活PINK 1/Parking信号通路诱导线粒体自噬，进而激活HSC，导致肝纤维化。
Background: The increasing epidemic of fine particulate matter (PM2.5) is a serious threat to human health. It induces the occurrence of liver fibrosis, but its molecular mechanism is not yet clear. The molecular mechanisms of PM2.5 inducing liver fibrosis were investigated in this study.Methods: The cell viability of LX-2 cells and primary hepatic stellate cells (HSCs) was detected using 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTD assay. In vitro enzyme-linked immune sorbent assay (ELISA) kits were used to detect the concentrations of antioxidant enzymes and reactive oxygen species (ROS). The mitochondria] transmembrane potential (MTP) was determined by JC-1 dye. Knockdown of Parkin was carried out by Parkin-specific siRNA transfection. Relative mRNA and protein expressions were evaluated by qRT-PCR, Western blotting, and immunofluorescence analysis.Results: PM2.5 activated LX-2 cells and primary HSCs, inducing the liver fibrosis along with down-regulation of the gelatinases MMP-2, and up-regulation of myofibroblast markers collagen type I and alpha-SMA. The levels of ROS and reactive nitrogen species (RNS), as well as the lipid peroxidation marker malondialdehyde (MDA) were significantly up-regulated in LX-2 cells and primary HSCs treated with PM2.5. Also, the enzymatic antioxidants levels were disturbed by PM2.5. Furthermore, PM2.5 decreased the MTP, releasing cytochrome c from the mitochondria to the cytosol. The dynamics of mitochondria were regulated by PM2.5 via facilitating mitochondrial fission. The excess ROS induced by PM2.5 triggered the mitophagy by activating PINK1/Parkin pathway, and inhibition of mitophagy induced by PM2.5 diminished the liver fibrosis.Conclusion: PM2.5 may induce mitophagy via activating PINK1/Parking signal pathway by increasing ROS, thereby activating HSCs and causing liver fibrosis.