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.
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
P S
PS
Mead
J P
JP
Guo
A M
AM
Lefer
S
S
Pierce
M
M
Palladino
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001798:Blood Proteins / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000188:drug therapy; D007075:Immunoglobulin M / Q000276:immunology; D008050:Lipid A / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D012977:Sodium Nitrite / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001798:Blood Proteins; D007075:Immunoglobulin M; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin; D012977:Sodium Nitrite; D000109:Acetylcholine