EFFECT OF CL INHIBITOR ON INFLAMMATORY AND PHYSIOLOGICAL-RESPONSE PATTERNS IN PRIMATES SUFFERING FROM LETHAL SEPTIC SHOCK

We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical pathway of complement and the contact system, on the physiol ogic and inflammatory response in baboons suffering from lethal Escher ichia coli sepsis. Five animals pretreated with 500 U/kg C1-inh (treat ment group; n = 5), followed by a 9-h continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were compared with five cont rols receiving E. coli alone. Of the treatment group, one animal survi ved and another lived beyond 48 h, whereas all control animals died wi thin 27 h. In four of five treated animals, less severe pathology was observed in various target organs. C1-inh administration did not preve nt the hemodynamic or hematologic changes observed upon E. coli infusi on. The activation of fibrinolysis and the development of disseminated intravascular coagulation were essentially unaffected by C1-inh. Howe ver, C1-inh supplementation significantly reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appe arance of C4b/c, indicating substantial inhibition of activation of th e contact system and the classical complement pathway, respectively. F urthermore, treated animals displayed a reduced elaboration of various cytokines including TNF, IL-10, IL-6, and IL-8. Thus, the administrat ion of C1-inh may have a beneficial but modest effect on the clinical course and outcome of severe sepsis in nonhuman primates. We suggest t hat activated complement and/or contact system proteases may, at least in part, contribute to the attendant manifestations of septic shock t hrough an augmentation of the cytokine response.