Treatment strategy of septic shock by inhibition of transcription factor, NF-kB

目的：研究核因子-kB激活抑制剂吡咯烷酮衍生物(N2733)是否能改善内毒素休克引起的代谢和器官功能改变。23只麻醉雄性Beagle犬接受机械通气，并使用肺动脉导管和胃压计进行监测。在整个研究期间，将中心静脉导管插入股静脉，并给予乳酸林格液(10ml/kg/hr)。实验分为三组：(A)脂多糖组(n=8)，注射脂多糖(250 ng/kg/min，持续2小时)；(B)脂多糖+N2733组(n=8)，在开始注射后给予N2733(30 mg/kg静脉注射，10 mg/kg/hr持续6小时)；(C)N2733组(n=7)，给予N2733(30 mg/kg静脉注射，10 mg/kg/hr持续6小时)。观察6小时后血流动力学、血气、胃壁pH值、肝肾功能的变化。联合应用N2733可增加氧输送指数，预防内毒素引起的低血压、代谢性酸中毒和胃粘膜酸中毒，但不影响肾或肝功能。在麻醉犬内毒素休克模型中，给予N2733可增加氧输送指数，预防内毒素引起的低血压、代谢和胃粘膜酸中毒，提示N2733对局部血流量有保护作用。这些发现表明，阻断核因子-kB的激活可以预防内毒素休克时的低动力性休克和胃低灌流。

To investigate whether pyrrolidinone derivative (N2733), an inhibitor of nuclear factor (NF)-kB activation, improves altered metabolic and organ dysfunctions caused by endotoxic shock. Twenty-three anesthetized male beagle dogs were mechanically ventilated and monitored with a pulmonary arterial catheter and a gastric tonometer. A central venous catheter was inserted into the femoral vein, and lactated Ringer's solution (10ml/kg/hr) was administered throughout the study period. Three groups of animals were studied : (a) the lipopolysaccharide (LPS) group (n=8), which received LPS (250ng/kg/min for 2hr) ; (b) the LPS plus N2733 group (n=8), which received N2733 (30mg/kg intravenously and 10mg/kg/hr for 6hr) after the start of LPS ; and (C) the N2733 group (n=7), which received N2733 (30mg/kg intravenously and 10mg/kg/hr for 6hr). Changes in hemodynamic, blood gas, gastric intramural pH, and renal and hepatic function were measured for 6hr. Coadministration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension, metabolic acidosis, and gastric mucosal acidosis but did not affect renal or hepatic function. Administration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension and metabolic and gastric mucosal acidosis in an anesthetized canine endotoxic shock model, suggesting its beneficial effect on local blood flow against tissue hypoxia. These findings suggest that blockade of NF-kB activation prevents hypodynamic shock and gastric hypoperfusion in endotoxic shock.