Chen Chin-Ming, Hou Ching-Cheng, Cheng Kuo-Chen, Tian Ru-Ling, Chang Ching-Ping, Lin Mao-Tsun
Department of Critical Care Medicine, Mei Medical Center, Tainan, Taiwan.
Crit Care Med. 2006 Jul;34(7):1960-6. doi: 10.1097/01.CCM.0000224231.01533.B1.
To evaluate the therapeutic effects of activated protein C in an animal model of heat stroke.
Laboratory investigation.
Chi-Mei Medical Center research laboratory.
Male Sprague-Dawley rats weighing 252-304 g.
Anesthetized animals were subjected to heat stress (40 degrees C) to induce heat stroke. A bolus injection of normal saline or recombinant human activated protein C (drotrecogin alfa, activated) was conducted via femoral catheters immediately after the onset of heat stroke. Blood sampling was done before initiation of heat stress and 0 and 40 mins after the onset of heat stroke.
When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 56-64 mins (n = 16). Resuscitation with activated protein C significantly and dose-dependently improved survival during heat stroke (108-246 mins for doses of 0.5-20 mg of activated protein C per kilogram of body weight) (n = 32). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor-alpha, prothrombin time, activated partial thromboplastin time, and D-dimer and decreased platelet count and protein C. Biochemical markers evidenced by cellular ischemia and injury/dysfunction included increased plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase; increased striatal levels of glutamate, glycerol, and lactate/pyruvate ratio; and decreased striatal levels of partial pressure of oxygen and local cerebral blood flow, which were all observed during heat stroke. These heat stroke reactions were all significantly suppressed by resuscitation with activated protein C but not vehicle solution.
The results indicate that systemic delivery of human recombinant activated protein C at the time point of onset of heat stroke may improve survival by ameliorating systemic inflammation, hypercoagulable state, and tissue ischemia and injury in multiple organs.
评估活化蛋白C在热射病动物模型中的治疗效果。
实验室研究。
奇美医学中心研究实验室。
体重252 - 304克的雄性Sprague-Dawley大鼠。
对麻醉后的动物施加热应激（40摄氏度）以诱导热射病。热射病发作后立即通过股动脉导管进行一次推注生理盐水或重组人活化蛋白C（活化的重组人活化蛋白C）。在热应激开始前以及热射病发作后0分钟和40分钟进行采血。
接受载体处理的大鼠受热暴露时，其存活时间为56 - 64分钟（n = 16）。用活化蛋白C进行复苏可显著且剂量依赖性地提高热射病期间的存活率（每千克体重给予0.5 - 20毫克活化蛋白C时，存活时间为108 - 246分钟）（n = 32）。所有受热应激的动物均表现出全身炎症和凝血激活，表现为肿瘤坏死因子-α、凝血酶原时间、活化部分凝血活酶时间和D - 二聚体升高，血小板计数和蛋白C降低。细胞缺血及损伤/功能障碍的生化标志物包括血浆中血尿素氮、肌酐、谷草转氨酶、谷丙转氨酶和碱性磷酸酶水平升高；纹状体中谷氨酸、甘油和乳酸/丙酮酸比值升高；纹状体中氧分压和局部脑血流量降低，这些均在热射病期间观察到。用活化蛋白C而非载体溶液进行复苏可显著抑制这些热射病反应。
结果表明，在热射病发作时间点全身给予人重组活化蛋白C可通过改善全身炎症、高凝状态以及多器官组织缺血和损伤来提高存活率。
