Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Nutrients. 2020 Apr 14;12(4):1086. doi: 10.3390/nu12041086.
The liver is the main organ responsible for bacterial and endotoxin clearance. Pyroptosis is a form of proinflammatory programmed cell death activated by caspase-1/11 and gasdermin D (GadD). Pyroptosis protects the host against bacterial infection; however, overactive pyroptosis can lead to organ injury. Glutamine (GLN) is a specific amino acid with anti-inflammatory and immunomodulatory properties. This study investigated the effects of GLN pretreatment on liver pyroptosis in a mouse model of polymicrobial sepsis. Mice were assigned to sham, sepsis control (Sepsis-C), and sepsis GLN (Sepsis-G) groups. The sham and Sepsis-C groups were fed the AIN-93G diet. The Sepsis-G group was provided with identical diet components except that part of the casein was replaced by GLN. After feeding the respective diets for 2 weeks, a cecal ligation and puncture (CLP) procedure was performed in the sepsis groups. An antibiotic was administered after CLP. Mice were sacrificed at either 24 or 72 h after CLP. The results showed that sepsis resulted in upregulated liver caspase-1/11 expression. Compared to the Sepsis-C group, the Sepsis-G group had higher liver caspase-11 and NLRP3 gene expressions at 24 h and lower active caspase-1/11 and cleaved GadD protein levels at 72 h after sepsis. Additionally, liver inflammatory cytokine gene expressions had decreased by 72 h post-CLP. The findings suggest that prophylactic administration of GLN initially upregulated liver pyroptosis to eradicate pathogens, yet the process of pyroptosis was suppressed in the late phase of sepsis. This may have beneficially attenuated liver inflammation and injury in an antibiotic-treated septic condition.
肝脏是负责清除细菌和内毒素的主要器官。细胞焦亡是一种被半胱天冬酶-1/11 和 Gasdermin D（GadD）激活的促炎程序性细胞死亡形式。细胞焦亡可保护宿主免受细菌感染；然而，过度活跃的细胞焦亡可导致器官损伤。谷氨酰胺（GLN）是一种具有抗炎和免疫调节特性的特定氨基酸。本研究探讨了 GLN 预处理对多微生物脓毒症小鼠模型肝脏细胞焦亡的影响。将小鼠分为假手术组、脓毒症对照组（Sepsis-C）和脓毒症 GLN 组（Sepsis-G）。假手术组和 Sepsis-C 组喂饲 AIN-93G 饮食。Sepsis-G 组给予相同的饮食成分，只是部分乳清蛋白被 GLN 替代。在分别喂饲相应饮食 2 周后，对脓毒症组进行盲肠结扎穿刺（CLP）手术。CLP 后给予抗生素。在 CLP 后 24 或 72 小时处死小鼠。结果表明，脓毒症导致肝脏半胱天冬酶-1/11 表达上调。与 Sepsis-C 组相比，Sepsis-G 组在脓毒症 24 小时时肝脏 caspase-11 和 NLRP3 基因表达较高，而在 72 小时时活性 caspase-1/11 和 cleaved GadD 蛋白水平较低。此外，肝炎性细胞因子基因表达在 CLP 后 72 小时下降。这些发现表明，预防性给予 GLN 最初可上调肝脏细胞焦亡以清除病原体，但在脓毒症后期细胞焦亡过程受到抑制。这可能有益地减轻了抗生素治疗的脓毒症条件下的肝炎症和损伤。
