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American Journal of Pathology, Vol 141, 1197-1207, Copyright © 1992 by American Society for Investigative Pathology
REGULAR ARTICLES |
G Jesmok, C Lindsey, M Duerr, M Fournel and T Emerson Jr
Miles Research Center, Miles Inc., West Haven, Connecticut 06516.
Monoclonal antibody against human tumor necrosis factor alpha (TNF MAb) prevents death induced by intravenous gram-negative bacteria or lipopolysaccharide (LPS) in primates. Although these studies have demonstrated that TNF plays a prominent role in the development of lethal septic shock, exploration of dose-response relationships and possible mechanisms of protection have been limited. We addressed these questions in a series of experiments conducted in E. coli-challenged pigs. First, we determined that TNF MAb neutralized the cytotoxic activity found in septic pig plasma and in culture media from pig monocytes incubated with LPS. Second, we demonstrated that pretreatment with TNF MAb promotes survival, in a dose-dependent fashion, in an otherwise lethal E. coli bacteremic pig model. The results of the survival study highly correlate (r = 0.96, P < 0.01) the presence of TNF in the circulation with mortality. In an additional series of physiologic monitoring experiments designed to delineate possible mechanisms of protection, the authors demonstrate that TNF MAb pretreatment abrogates the prolonged leukopenia, thrombocytopenia, and microvascular leakiness resulting from intravenous bacterial challenge and maintains arterial blood pressure while diminishing pulmonary edema. These findings may provide a mechanism whereby neutralization of TNF systemically affords protection against the lethal sequelae of bacteremia.
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