Protective effects of a monoclonal antibody against lipid A in endotoxic shock

Bacterial lipopolysaccharide given intravenously at 30 mg/kg to anesthetized rats results in rapid systemic hypotension and hypovolemia, elaboration of cytokines, increased proteolysis and vascular endothelial dysfunction. When a monoclonal antibody SdJ5-1.17.15 (SdJ5) directed against the lipid A moiety of lipopolysaccharide was administered at (1.25 or 5.0 mg/kg) 5 min prior to the endotoxin, significant protection was afforded to rats. This protection was manifested by a significant reduction in the early hypotension, as well as attenuation of hypovolemia and proteolysis. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats 4 h after endotoxic challenge. Lipopolysaccharide (LPS) significantly reduced superior mesenteric artery vasorelaxation to acetylcholine and A23187, two endothelium-dependent vasodilators, but not to NaNO2, an endothelium-independent vasodilator. SdJ5 significantly preserved vasorelaxation responses to both acetylcholine and A23187, indicating a marked degree of endothelial preservation by this anti-lipid A monoclonal antibody. The protection was dose-dependent since 0.3 mg/kg of SdJ5 did not provide significant protection in any variable measured. Moreover, there was no significant difference between the 1.25 mg/kg and 5.0 mg/kg dose of SdJ5. Furthermore, plasma concentrations of TNF-alpha, a cytokine involved in mediating many of the effects associated with endotoxemia, was significantly reduced in SdJ5-treated animals. Thus, SdJ5 appears to be capable of counteracting many of the in vivo sequelae of endotoxemia in rats.