ROLE OF COMPLEMENT IN ENDOTOXIC SHOCK

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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.