Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Institute of Anesthesiology, Tianjin, China.
Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, China.
Int Immunopharmacol. 2019 Jun;71:61-67. doi: 10.1016/j.intimp.2019.03.021. Epub 2019 Mar 14.
Sepsis-induced hepatic dysfunction is considered as an independent risk factor of multiple organ dysfunction syndrome (MODS) and death. Mitophagy, a selective form of autophagy, plays a major role in sepsis-induced organ damage. We have demonstrated that hydrogen gas (H), a selective antioxidant, exerts protective effects in septic mice. Here, we hypothesize that the therapeutic effects of H on septic animals with liver damages may be exerted through regulation of the Fun14 domain-containing protein 1 (FUDNC1)-induced mitophagy pathway. Male C57BL/6J mice were subjected to sham or cecal ligation and puncture (CLP) operation and treated with 2% H gas inhalation for 3 h starting at 1 h after sham or CLP surgery. To verify the role of FUNDC1, the cell-penetrating peptide P (NH2-GRKKRRQRRRPQDYESDDESYEVLDLTEY-COOH) (1 mg/kg) that functions as a FUNDC1 inhibitor was intraperitoneally injected into mice 24 h before the sham or CLP operation. To evaluate the severity of septic liver injury, the 7-day survival rate, liver histopathologic score, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respiration control ratio (RCR), and FUDNC1, P-18-FUDNC1, P62, LC3B-II, Tim23, and caspase-1 levels were evaluated after the sham or CLP operation. The results demonstrated that 2% H gas inhalation resulted in an increase in the 7-day survival rate, ALT and AST levels, RCR, and P62 and LC3B-II expression but decreased the histological score and FUDNC1, P-18-FUDNC1, Tim23, and caspase-1 levels after sepsis. However, no significant differences were reported between the CLP + peptide P and CLP + H + peptide P groups. These observations indicate that 2% H gas inhalation for 3 h may serve as an effective therapeutic strategy for sepsis-induced liver injury through the regulation of FUNDC1-dependent mitophagy.
脓毒症诱导的肝功能障碍被认为是多器官功能障碍综合征（MODS）和死亡的独立危险因素。自噬是一种选择性的自噬形式，在脓毒症引起的器官损伤中起着重要作用。我们已经证明，氢气（H）作为一种选择性抗氧化剂，在脓毒症小鼠中发挥保护作用。在这里，我们假设 H 对有肝损伤的脓毒症动物的治疗效果可能是通过调节 Fun14 结构域包含蛋白 1（FUDNC1）诱导的线粒体自噬途径来实现的。雄性 C57BL/6J 小鼠接受假手术或盲肠结扎和穿孔（CLP）手术，并在假手术或 CLP 手术后 1 小时开始用 2% H 气体吸入 3 小时。为了验证 FUNDC1 的作用，在假手术或 CLP 手术前 24 小时，将穿透细胞的肽 P（NH2-GRKKRRQRRRPQDYESDDESYEVLDLTEY-COOH）（1mg/kg）作为 FUNDC1 抑制剂腹膜内注射到小鼠体内。为了评估脓毒症性肝损伤的严重程度，在假手术或 CLP 手术后，评估 7 天存活率、肝组织病理学评分、丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平、呼吸控制比（RCR）以及 FUDNC1、P-18-FUDNC1、P62、LC3B-II、Tim23 和 caspase-1 水平。结果表明，2%H 气体吸入可增加 7 天存活率、ALT 和 AST 水平、RCR 以及 P62 和 LC3B-II 表达，但降低组织学评分和 FUDNC1、P-18-FUDNC1、Tim23 和 caspase-1 水平在脓毒症后。然而，CLP+肽 P 和 CLP+H+肽 P 组之间没有报道显著差异。这些观察结果表明，3 小时 2%H 气体吸入可能通过调节 FUNDC1 依赖性线粒体自噬，成为脓毒症性肝损伤的有效治疗策略。
