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Title: [Effect of lipoxin A4 on the expression of Toll-like receptor 4 and TNF receptor-associated factor 6 in the liver of obese rats with sepsis].
Author: Jiang WW, Gao LL, Wu M, Zhao T, Shen DL.
Journal: Zhongguo Dang Dai Er Ke Za Zhi; 2018 Jul; 20(7):578-584. PubMed ID: 30022762.
Abstract:
OBJECTIVE: To study the protective effect of lipoxin A4 (LXA4) against sepsis induced by lipopolysaccharide (LPS) in rats with obesity and its effect on the expression of Toll-like receptor 4 (TLR4) and TNF receptor-associated factor 6 (TRAF6) in the liver. METHODS: A total of 60 male Sprague-Dawley rats aged three weeks were randomly divided into a normal group and an obesity group, with 30 rats in each group. A rat model of obesity was established by high-fat diet. Each of the two groups was further randomly divided into control group, sepsis group, and LXA4 group, and 8 rats were selected from each group. The rats in the control, sepsis, and LXA4 groups were treated with intraperitoneal injection of normal saline, LPS, and LXA4+LPS respectively. Twelve hours later, blood samples were collected from the heart and liver tissue samples were also collected. ELISA was used to measure the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Western blot was used to measure the protein expression of TLR4 and TRAF6 in liver tissue. Quantitative real-time PCR was used to measure the mRNA expression of TLR4 and TRAF6. RESULTS: After being fed with high-fat diet for 6 weeks, the obesity group had significantly higher average weight and Lee's index than the normal group (P<0.05). Compared with the normal group, the obesity group had significant increases in the serum levels of IL-6 and TNF-α (P<0.05). In the normal group or the obesity group, the sepsis subgroup had significant increases in the serum levels of IL-6 and TNF-α compared with the control subgroup (P<0.05), while the LXA4 subgroup had significant reductions in the two indices compared with the sepsis subgroup (P<0.05). Compared with the normal group, the obesity group had significant increases in the protein and mRNA expression of TLR4 and TRAF6 (P<0.05). In the normal group or the obesity group, the sepsis subgroup had significant increases in the protein and mRNA expression of TLR4 and TRAF6 compared with the control subgroup (P<0.05). Compared with the sepsis subgroup, the LXA4 subgroup had significant reductions in the protein and mRNA expression of TLR4 and TRAF6 (P<0.05). CONCLUSIONS: LXA4 can reduce the serum levels of IL-6 and TNF-α and alleviate inflammatory response. LXA4 can inhibit the expression of TLR4 and TRAF6 in the liver of septic rats, possibly by inhibiting the TLR4 signaling pathway. 目的: 探讨脂氧素A4（LXA4）对脂多糖诱导肥胖大鼠感染脓毒症的保护作用及其对肝脏Toll样受体4（TLR4）、肿瘤坏死因子受体相关因子6（TRAF6）表达的影响。方法: 选取3周龄雄性SpragueDawley大鼠60只随机分为普通组和肥胖组（n=30），建立高脂饮食诱导的肥胖大鼠模型，将两组大鼠再随机分成对照组、脓毒症组、脂氧素组，每组各取8只大鼠。对照组、脓毒症组、脂氧素组分别予生理盐水、脂多糖、脂氧素A4+脂多糖腹腔注射，观察12 h后心脏采血并采集肝脏组织。ELISA法检测血清白细胞介素6（IL-6）及肿瘤坏死因子-α（TNF-α）水平；蛋白免疫印迹法检测肝脏组织TLR4、TRAF6蛋白水平；实时荧光定量PCR法检测TLR4 mRNA、TRAF6 mRNA的表达水平。结果: 高脂饮食喂养6周后，肥胖组大鼠的平均体重、Lee's指数明显高于普通组（P < 0.05）。与普通组比较，肥胖组血清IL-6、TNF-α水平明显增高（P < 0.05）；同一饮食组内，脓毒症组较对照组血清IL-6、TNF-α水平明显增高（P < 0.05），脂氧素组较脓毒症组血清IL-6、TNF-α水平显著降低（P < 0.05）。与普通组比较，肥胖组大鼠肝脏组织中TLR4、TRAF6蛋白及TLR4 mRNA、TRAF6mRNA表达水平上调（P < 0.05）；同一饮食组内，脓毒症组较对照组TLR4、TRAF6蛋白及TLR4 mRNA、TRAF6 mRNA表达量明显增高（P < 0.05），而与脓毒症组比较，脂氧素组TLR4、TRAF6蛋白及TLR4 mRNA、TRAF6 mRNA表达量显著降低（P < 0.05）。结论: LXA4能降低血清IL-6、TNF-α水平，减轻炎症反应。LXA4能抑制TLR4、TRAF6在脓毒症大鼠肝脏中的表达，可能是通过抑制TLR4的信号传导途径来实现的。

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