OBJECTIVE Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. METHODS SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1β and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1β and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. CONCLUSION SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway.

中文翻译：

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氢通过 NRF2 介导的 NLRP3 通路失活减轻败血症相关脑病。

目的 脓毒症相关脑病 (SAE) 是全世界死亡的主要原因。氧化应激、炎症反应和细胞凋亡参与了 SAE 的发病机制。核因子类红细胞 2 相关因子 2 (Nrf2) 和核苷酸结合寡聚化域样受体包含 pyrin 域 3 (NLRP3) 通路参与氧化应激和炎症反应。我们报告说氢气可以保护野生型 (WT) 而非 Nrf2 基因敲除 (KO) 小鼠的败血症。因此，确定氢气治疗脓毒症相关脑病的根本原因至关重要。方法 通过盲肠结扎和穿刺 (CLP) 在 WT 和 Nrf2 KO 小鼠中诱导 SAE。作为 NLRP3 炎症小体抑制剂，MCC950 (50 mg/kg) 在手术前通过腹腔 (ip) 注射给药。在假手术和 CLP 手术后 1 小时和 6 小时，通过腹腔注射注射富含氢气 (H2) 的盐水溶液 (5 mL/kg)。收集脑组织以通过蛋白质印迹、逆转录聚合酶链反应 (RT-PCR) 和免疫荧光评估 NLRP3 和 Nrf2 通路。结果 SAE 增加了小胶质细胞中 NLRP3 和 Nrf2 的表达。MCC950 抑制 SAE 诱导的 NLRP3 表达、白细胞介素 (IL)-1β 和 IL-18 细胞因子释放、神经元凋亡和线粒体功能障碍。与 Nrf2 KO 小鼠相比，SAE 增加了 WT 小鼠的 NLRP3 和 caspase-1 表达。氢增加了 Nrf2 的表达，并抑制了 SAE 诱导的 NLRP3、caspase-1、细胞因子 IL-1β 和 IL-18 的表达、神经元凋亡和 WT 小鼠但不是 Nrf2 KO 小鼠的线粒体功能障碍。结论 SAE 增加了小胶质细胞中 NLRP3 和 Nrf2 的表达。