Mediators and vascular effects in response to endotoxin.
Recent experimental findings indicate that endotoxin (i.e. lipopolysaccharide) interacts with specific membrane receptors localized to mononuclear phagocytic cells and neutrophils. Binding of endotoxin to these cells, together with endotoxin-induced activation of host vascular endothelium, initiates a series of signal transduction events that culminate in release of numerous biochemical mediators. The latter include cytokines, platelet-activating factor, thromboxane A2, prostaglandins, leukotrienes, nitric oxide, proteases, toxic O2 radicals, and vasoactive amines. These mediators orchestrate complex biological interactions and amplification signals that lead to cardiopulmonary dysfunction and multi-organ failure within 4-6 h of experimental infusion of endotoxin into animals. The pathophysiological changes include decreased cardiac output, systemic hypotension, decreased blood flow and O2 delivery to tissues, intense pulmonary vasoconstriction and hypertension, bronchoconstriction, increased permeability, pulmonary oedema, ventilation-to-perfusion inequalities, hypoxaemia, and haemoconcentration. Metabolic alterations include increased blood lactate and pyruvate, metabolic acidosis, hyperkalaemia and hypoglycaemia. Potential therapeutic modalities for treatment of endotoxaemia/septic shock include specific antagonists directed against lipopolysaccharide, cytokine, and platelet-activating factor receptors, monoclonal antibodies directed against cytokines and lipid A/core polysaccharides of endotoxin, antiproteases, and agents that block release of toxic O2 and arachidonic acid metabolites.
Olson
N C
NC
Department of Anatomy, Physiological Sciences and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.
Hellyer
P W
PW
Dodam
J R
JR
D000818:Animals; D016470:Bacteremia / Q000503:physiopathology / Q000517:prevention & control / Q000662:veterinary*; D001798:Blood Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D004731:Endotoxins / Q000097:blood* / Q000378:metabolism / Q000633:toxicity; D018836:Inflammation Mediators / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D013552:Swine; D013553:Swine Diseases / Q000503:physiopathology* / Q000517:prevention & control; D014115:Toxemia / Q000503:physiopathology / Q000517:prevention & control / Q000662:veterinary*
D001798:Blood Proteins; D004731:Endotoxins; D018836:Inflammation Mediators; D011956:Receptors, Cell Surface; D009569:Nitric Oxide