Dugo Laura, Collin Marika, Allen David A, Patel Nimesh S A, Bauer Inge, Mervaala Eero M A, Louhelainen Marjut, Foster Simon J, Yaqoob Muhammad M, Thiemermann Christoph
Centre for Experimental Medicine, Nephrology and Critical Care Medicine, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, UK.
Crit Care Med. 2005 Sep;33(9):1903-12. doi: 10.1097/01.ccm.0000178350.21839.44.
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-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.
Prospective, randomized study.
University-based research laboratory.
Ninety-nine anesthetized male Wistar rats.
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-3beta 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.
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-3beta inhibitors attenuated the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor-kappaB subunit p65 and the messenger RNA expression of nuclear factor-kappaB-dependent proinflammatory mediators but had no effect on the nuclear factor-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in nuclear factor-kappaB p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro.
The potent and selective GSK-3beta 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-3beta 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.
丝氨酸 - 苏氨酸蛋白激酶糖原合酶激酶（GSK）-3参与多种细胞功能的调节，但其在炎症反应调节中的作用尚不清楚。在此，我们研究GSK-3β抑制对脂多糖或脂多糖与肽聚糖联合给药所致大鼠器官损伤/功能障碍的影响。
前瞻性、随机研究。
大学研究实验室。
99只麻醉的雄性Wistar大鼠。
研究1：大鼠静脉注射大肠杆菌脂多糖（6mg/kg）或赋形剂（1mL/kg；生理盐水）。研究2：大鼠静脉注射大肠杆菌脂多糖（1mg/kg）和金黄色葡萄球菌肽聚糖（0.3mg/kg）或赋形剂。在注射脂多糖或脂多糖与肽聚糖前30分钟，静脉注射强效选择性GSK-3β抑制剂TDZD-8（1mg/kg）、SB216763（0.6mg/kg）和SB415286（1mg/kg）或赋形剂（10%二甲亚砜）。
内毒素血症导致血清肌酐水平（肾功能障碍指标）、天冬氨酸转氨酶、丙氨酸转氨酶（肝细胞损伤标志物）、脂肪酶（胰腺损伤指标）和肌酸激酶（神经肌肉损伤指标）升高。脂多糖与肽聚糖联合给药导致肝细胞损伤和肾功能障碍。所有GSK-3β抑制剂均减轻了脂多糖或脂多糖与肽聚糖所致的器官损伤/功能障碍。GSK-3β抑制降低了核因子-κB亚基p65的Ser536磷酸化以及核因子-κB依赖性促炎介质的信使核糖核酸表达，但对肺组织中核因子-κB/DNA结合活性无影响。GSK-3β抑制降低了体外人胚肾细胞中白细胞介素-1引起的核因子-κB p65活性增加。
强效选择性GSK-3β抑制剂TDZD-8、SB216763和SB415286减轻了脂多糖或脂多糖与肽聚糖所致大鼠的器官损伤/功能障碍。我们认为，GSK-3β抑制可能对治疗与脓毒症、休克及其他局部或全身炎症相关疾病的器官损伤/功能障碍有用。
