Hydrogen Sulfide Protects against Paraquat-Induced Acute Liver Injury in Rats by Regulating Oxidative Stress, Mitochondrial Function, and Inflammation
Hydrogen Sulfide Protects against Paraquat-Induced Acute Liver Injury in Rats by Regulating Oxidative Stress, Mitochondrial Function, and Inflammation
复制标题
硫化氢通过调节氧化应激、线粒体功能和炎症来防止百草枯引起的大鼠急性肝损伤
DOI：
10.1155/2020/6325378
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发表时间：
2020-01-23
影响因子：
--
通讯作者：
Zhao, Min
中科院分区：
文献类型：
--
作者：
Liu, Zhenning;Wang, Xiaofeng;Zhao, Min
除了肺，肝脏被认为是百草枯(PQ)中毒的另一个主要目标。硫化氢(H_2S)已被证明能有效地抑制氧化应激和炎症。本研究旨在探讨外源性H_2S对PQ所致急性肝损伤的保护作用。通过一次腹腔注射PQ建立小鼠急性肝损伤模型，观察组织学改变和血清转氨酶水平升高。在暴露于PQ前1小时，给予不同剂量的NaHS。数据分析表明，外源性硫化氢以剂量依赖的方式减轻PQ诱导的肝损伤和氧化应激。H_2S显著抑制了活性氧(ROS)的产生和丙二醛含量的升高，提高了GSH/GSSG比值和抗氧化酶包括SOD、GSH-Px、HO-1和NQO-1的水平。当肝细胞受到PQ诱导的氧化应激时，H_2S通过KEAP1的S水合作用显著增加NRF2的核转位，并通过调节SIRT3的S水合作用导致IDH2活性增加。此外，在PQ诱导的急性肝损伤中，H_2S显著抑制NLRP3炎性小体的激活和随后的IL-1β的分泌。此外，在Nrf2基因敲除的肝细胞中，H_2S不能逆转PQ引起的SIRT3的降低和NLRP3炎性小体的激活。综上所述，硫化氢通过增强抗氧化能力、调节线粒体功能、抑制ROS诱导的NLRP3炎性小体激活来减轻PQ诱导的急性肝损伤。在PQ诱导的肝损伤中，H_2S的抗氧化作用至少部分可以归因于通过Keap1 S水合促进Nrf2驱动的抗氧化酶，以及通过Nrf2依赖的SIRT3基因转录和SIRT3 S-水合调节SIRT3/IDH2信号转导通路。因此，补充硫化氢可以形成一种有前景的治疗PQ所致急性肝损伤的新策略的基础。
In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase levels. Different doses of NaHS were administered intraperitoneally one hour before exposure to PQ. Analysis of the data shows that exogenous H2S attenuated the PQ-induced liver injury and oxidative stress in a dose-dependent manner. H2S significantly suppressed reactive oxygen species (ROS) generation and the elevation of malondialdehyde content while it increased the ratio of GSH/GSSG and levels of antioxidant enzymes including SOD, GSH-Px, HO-1, and NQO-1. When hepatocytes were subjected to PQ-induced oxidative stress, H2S markedly enhanced nuclear translocation of Nrf2 via S-sulfhydration of Keap1 and resulted in the increase in IDH2 activity by regulating S-sulfhydration of SIRT3. In addition, H2S significantly suppressed NLRP3 inflammasome activation and subsequent IL-1β excretion in PQ-induced acute liver injury. Moreover, H2S cannot reverse the decrease in SIRT3 and activation of the NLRP3 inflammasome caused by PQ in Nrf2-knockdown hepatocytes. In summary, H2S attenuated the PQ-induced acute liver injury by enhancing antioxidative capability, regulating mitochondrial function, and suppressing ROS-induced NLRP3 inflammasome activation. The antioxidative effect of H2S in PQ-induced liver injury can at least partly be attributed to the promotion of Nrf2-driven antioxidant enzymes via Keap1 S-sulfhydration and regulation of SIRT3/IDH2 signaling via Nrf2-dependent SIRT3 gene transcription as well as SIRT3 S-sulfhydration. Thus, H2S supplementation can form the basis for a promising novel therapeutic strategy for PQ-induced acute liver injury.