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. 这个正常人体模型已用于受控 阐明败血性休克病理生理学的研究（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 最佳抗生素和心血管支持治疗。 死亡率从 败血性休克是由心血管衰竭或多器官衰竭引起的， 系统故障。 脓毒症是导致患者死亡的最常见原因 在重症监护室 内毒素，细胞外壁的一种成分 革兰氏阴性细菌，被释放到患者的循环中， 感染性休克，被认为是主要的致病毒素。 在脓毒症期间，宿主细胞响应细菌感染释放介质。 毒素（内毒素）。 这些介质产生的特征 脓毒症和脓毒性休克的心肺反应。 补体 系统是在脓毒症期间被激活的宿主介质的级联 并且可能对宿主有益或有害。 如果互补产生， 总的来说，脓毒症期间的有害作用，补体拮抗剂是 现在可用于人类，并将被考虑用于治疗败血症 冲击. 布列塔尼猎犬在基因上缺乏第三种成分 补体（C3）的研究已被用于补体的研究， 约翰霍普金斯大学。 这些狗基本上不产生C3（0.003%）。 通过ELISA测定的正常水平）。 他们有正常水平的 其他补偿因素。 C3是激活补体所必需的 组分C5-C9通过经典和替代途径。 因此，在本发明中， 对这些动物内毒素血症的研究将阐明 补体的病理生理作用。 本方案建议研究亚致死剂量 内毒素输注对C3缺乏的布列塔尼猎犬的影响。 因为这些 动物很难繁殖和极其稀缺，有一个小的 这些珍贵动物的数量进行调查。 为了维护 这些狗会被注射亚致死剂量的 产生类似于人类脓毒症的心血管特征的内毒素 冲击.

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. Mortaity 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 care units. Endotoxin, a component of the outer cell wall of Gram-negative bacterial, is released into the circulation in patients with septic shock and is 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 compement 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 animal 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.