INHIBITION OF FACTOR-XII IN SEPTIC BABOONS ATTENUATES THE ACTIVATION OF COMPLEMENT AND FIBRINOLYTIC SYSTEMS AND REDUCES THE RELEASE OF INTERLEUKIN-6 AND NEUTROPHIL ELASTASE

In previous studies, we have shown that administration of monoclonal a ntibody (MoAb) C6B7 against human factor XII to baboons challenged wit h a lethal dose of Escherichia coil abrogates activation of the contac t system and modulates secondary hypotension. To evaluate the contribu tion of activated contact proteases to the appearance of other inflamm atory mediators in this experimental model of sepsis, we studied the e ffect of administration of MoAb C6B7 on activation of complement and f ibrinolytic cascades, stimulation of neutrophil degranulation. and rel ease of the proinflammatory cytokines, tumor necrosis factor-alpha (TN F-alpha) and interleukin-6 (IL-6). Activation of the complement system . as reflected by circulating C3b/c and C4b/c levels, was significantl y reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been giv en a lethal challenge only. Inhibition of contact activation also modu lated the fibrinolytic response, since the release of tissue-type plas minogen activator (t-PA) and the appearance of plasmin-alpha(2)-antipl asmin (PAP) complexes into the circulation was significantly attenuate d upon pretreatment with anti-factor XII MoAb. In contrast, plasma lev els of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by cir culating elastase-alpha(1)-protease inhibitor complexes, and release o f IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated a nimals. Observed differences in the inflammatory response between trea tment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulati ng levels of endotoxin after the challenge. were similar for both grou ps. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the infla mmatory response during severe sepsis in nonhuman primates. (C) 1996 b y The American Society of Hematology.