Activated protein C therapy in a rat heat. stroke model
Activated protein C therapy in a rat heat. stroke model
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DOI：
10.1097/01.ccm.0000224231.01533.b1
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发表时间：
2006-07-01
影响因子：
8.8
通讯作者：
Lin, Mao-Tsun
中科院分区：
文献类型：
--
作者：
Chen, Chin-Ming;Hou, Ching-Cheng;Lin, Mao-Tsun
目的：探讨活化蛋白C对中暑动物模型的治疗作用。奇美医学中心研究室。体重252-304 g的雄性Sprague-Dawley大鼠。使麻醉的动物经受热应激（40摄氏度）以诱导中暑。在中暑发作后立即通过股动脉导管推注生理盐水或重组人活化蛋白C（α-屈洛酮，活化）。在热应激开始前和中暑发作后0分钟和40分钟采集血样。测量和主要结果。当溶剂处理的大鼠经历热暴露时，发现它们的存活时间值为56-64分钟（n = 16）。用活化蛋白C进行复苏显著且剂量依赖性地改善了中暑期间的存活率（对于每千克体重0.5-20 mg活化蛋白C的剂量，108-246分钟）（n = 32）。所有热应激动物均表现出全身炎症和活化凝血，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-二聚体增加以及血小板计数和蛋白C减少。由细胞缺血和损伤/功能障碍证明的生化标志物包括血尿素氮、肌酐、谷草转氨酶、谷丙转氨酶和碱性磷酸酶的血浆水平升高;谷氨酸、甘油和乳酸/丙酮酸比率的纹状体水平升高;以及氧分压和局部脑血流量的纹状体水平降低，这些均在中暑期间观察到。这些中暑反应都显着抑制复苏与活化蛋白C，而不是车辆解决方案。结果表明，在中暑发作的时间点全身递送人重组活化蛋白C可以通过改善全身炎症、高凝状态、组织缺血和多器官损伤来改善存活率。
Objective: To evaluate the therapeutic effects of activated protein C in an animal model of heat stroke.Design: Laboratory investigation.Setting. Chi-Mei Medical Center research laboratory.Subjects. Male Sprague-Dawley rats weighing 252-304 g.Interventions. 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.Measurements and Main Results. 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.Conclusions. 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.