ROLE OF COMPLEMENT IN ENDOTOXIC SHOCK

对正常人给予亚致死剂量内毒素的研究表明， 心肺反应类似于人类脓毒症 冲击. 这种正常的人体模型已被用于对照研究 阐明败血性休克的病理生理学（N Engl J Med 1989;321：280）。 感染性休克是一种高致死性疾病（50-50%的死亡率），尽管最佳的治疗方案是 抗生素和心血管支持治疗。 败血症死亡率 休克是由心血管崩溃或多器官系统引起的 失败 脓毒症是最常见的死亡原因的病人， 密集的汽车单位。 内毒素，一种细胞外壁的成分， 革兰氏阴性细菌，被释放到患者的循环中， 败血性休克，被认为是主要的致病毒素。 在脓毒症期间，宿主细胞响应细菌毒素释放介质 （内毒素）。 这些介质产生特征性的心肺 脓毒症和脓毒性休克的反应。 补体系统是一个级联反应， 在脓毒症期间激活的宿主介质， 对宿主有害。 如果补体产生了，总的来说， 在脓毒症期间，补体的拮抗剂现在可用于人类， 会被考虑用于治疗感染性休克 布列塔尼猎犬的第三种基因缺陷， 补体（C3）已被用于研究补体在约翰 霍普金斯大学。 这些狗基本上不产生C3（正常值的0.003%）。 通过ELISA测定的水平）。 他们有正常水平的其他 补充因素。 C3是激活补体成分所必需的 C5-C9通过经典和替代途径。 因此，调查 这些动物中的内毒素血症将阐明 补体 本方案建议研究亚致死内毒素的影响 输注给缺乏C3的布列塔尼猎犬。 因为这些动物 很难繁殖，而且非常稀少，有一小部分 有价值的动物进行调查。 为了保护这些动物， 狗会被注射亚致死剂量的内毒素 产生类似于人类败血性休克的心血管特征。

Studies of normal humans given a sublethal dose of endotoxin have shown a cardiopulmonary response similar to the response of humans with septic shock. This normal human model has been used in controlled investigations to elucidate the pathophysiology of septic shock (N Engl J Med 1989;321:280). Septic shock is a highly lethal disease (50-50% mortality) despite optimal antibiotic and cardiovascular supportive therapy. Mortality from septic shock is caused by cardiovascular collapse or multiple organ system failure. Sepsis is the most prevalent cause of death of patients in intensive car units. Endotoxin, a component of the outer cell wall of Gram-negative bacterial, is released into the circulation in patients with septic shock and thought to be the major pathogenic toxin. During sepsis host cells release mediators in response to bacterial toxins (endotoxin). These mediators produce the characteristic cardiopulmonary response of sepsis and septic shock. The complement system is a cascade of host mediators that are activated during sepsis and may be beneficial or harmful to the host. If complement produces, on balance, harmful effects during sepsis, antagonists to complement are now available for humans and would be considered for therapy for septic shock. Brittany spaniels that are genetically deficient in the third component of complement (C3) have been used in investigations of complement at Johns Hopkins University. These dogs produce essentially no C3 (0.003% of normal levels as determined by ELISA). They have normal levels of other complement factors. C3 is required for activation of complement components C5-C9 via classical and alternative pathways. Thus, investigation of endotoxemia in these animals would clarify the pathophysiologic role of complement. This protocol proposes investigation of the effect of a sublethal endotoxin infusion on C3 deficient Brittany spaniels. Because these animals are difficult to breed and extremely scarce, there are a small number of these valuable animals for investigation. In order to preserve these animals, the dogs would be challenged with a sublethal dose of endotoxin that produces cardiovascular profile similar to human septic shock.