GSK-3β inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat
GSK-3β inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat
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DOI：
10.1097/01.ccm.0000178350.21839.44
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发表时间：
2005-09-01
影响因子：
8.8
通讯作者：
Thiemermann, Christoph
中科院分区：
文献类型：
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作者：
Dugo, Laura;Collin, Marika;Thiemermann, Christoph
目的：丝氨酸-苏氨酸蛋白激酶糖原合成酶激酶(GSK)-3参与许多细胞功能的调节，但其在炎症反应中的调节作用尚不清楚。本研究探讨GSK-3 β抑制对脂多糖或脂多糖与肽聚糖共给药引起的大鼠器官损伤/功能障碍的影响。设计：前瞻性、随机研究。设置：校本研究实验室。实验对象：麻醉雄性Wistar大鼠99只。干预措施：研究1：大鼠静脉注射大肠杆菌脂多糖（6mg /kg）或载体（1ml /kg；生理盐水）。研究2：大鼠静脉注射大肠杆菌脂多糖（1 mg/kg）和金黄色葡萄球菌肽聚糖（0.3 mg/kg）或载药。强效和选择性GSK-3 β抑制剂TDZD-8 （1 mg/kg静脉注射）、SB216763 （0.6 mg/kg静脉注射）和SB415286 （1 mg/kg静脉注射）或对照物（10%二甲亚砜）在脂多糖或脂多糖和肽聚糖前30分钟给药。测量结果和主要结果：内毒素血症导致血清肌酐（肾功能障碍指标）、天冬氨酸转氨酶、丙氨酸转氨酶（肝细胞损伤指标）、脂肪酶（胰腺损伤指标）和肌酸激酶（神经肌肉损伤指标）水平升高。脂多糖和肽聚糖共同给药可导致肝细胞损伤和肾功能障碍。所有GSK-3 β抑制剂均能减轻脂多糖或脂多糖和肽聚糖引起的器官损伤/功能障碍。GSK-3 β抑制可降低核因子-kappa B亚基p65的Ser536磷酸化和核因子-kappa B依赖性促炎介质的信使RNA表达，但对肺组织核因子-kappa B/DNA结合活性无影响。GSK-3 β抑制可降低体外人胚胎肾细胞中白细胞介素-1引起的核因子- κ B p65活性升高。结论：强效、选择性的GSK-3 β抑制剂TDZD-8、SB216763和SB415286可减轻脂多糖或脂多糖与肽聚糖引起的大鼠器官损伤/功能障碍。我们建议GSK-3 β抑制可能有助于治疗败血症、休克和其他与局部或全身性炎症相关的疾病相关的器官损伤/功能障碍。
Objective: Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3 beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.Design: Prospective, randomized study.Setting: University-based research laboratory.Subjects: Ninety-nine anesthetized male Wistar rats.Interventions: Study 1: Rats received either intravenous Escherichia coli lipopolysaccharide (6 mg/kg) or vehicle (1 mL/kg; saline). Study 2: Rats received either intravenous E coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle. The potent and selective GSK-3 beta inhibitors TDZD-8 (1 mg/kg intravenously), SB216763 (0.6 mg/kg intravenously), and SB415286 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 mins before lipopolysaccharide or lipopolysaccharide and peptidoglycan.Measurements and Main Results: Endotoxemia resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), aspartate aminotransferase, alanine aminotransferase (markers for hepatocellular injury), lipase (indicator of pancreatic injury), and creatine kinase (indicator of neuromuscular injury). Coadministration of lipopolysaccharide and peptidoglycan resulted in hepatocellular injury and renal dysfunction. All GSK-3 beta inhibitors attenuated the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3 beta inhibition reduced the Ser536 phosphorylation of nuclear factor-kappa B subunit p65 and the messenger RNA expression of nuclear factor-kappa B-dependent proinflammatory mediators but had no effect on the nuclear factor-kappa B/DNA binding activity in the lung. GSK-3 beta inhibition reduced the increase in nuclear factor-kappa B p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro.Conclusions: The potent and selective GSK-3 beta inhibitors TDZD-8, SB216763, and SB415286 reduced the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan in the rat. We propose that GSK-3 beta inhibition may be useful in the therapy of the organ injury/dysfunction associated with sepsis, shock, and other diseases associated with local or systemic inflammation.