MEDIATORS AND VASCULAR EFFECTS IN RESPONSE TO ENDOTOXIN

Recent experimental findings indicate that endotoxin (i.e. lipopolysac charide) interacts with specific membrane receptors localized to monon uclear phagocytic cells and neutrophils. Binding of endotoxin to these cells, together with endotoxin-induced activation of host vascular en dothelium, initiates a series of signal transduction events that culmi nate in release of numerous biochemical mediators. The latter include cytokines, platelet-activating factor, thromboxane A(2), prostaglandin s, leukotrienes, nitric oxide, proteases, toxic O-2 radicals, and vaso active amines. These mediators orchestrate complex biological interact ions and amplification signals that lead to cardiopulmonary dysfunctio n and multi-organ failure within 4-6 h of experimental infusion of end otoxin into animals. The pathophysiological changes include decreased cardiac output, systemic hypotension, decreased blood flow and O-2 del ivery to tissues, intense pulmonary vasoconstriction and hypertension, bronchoconstriction, increased permeability, pulmonary oedema, ventil ation-to-perfusion inequalities, hypoxaemia, and haemoconcentration. M etabolic alterations include increased blood lactate and pyruvate, met abolic acidosis, hyperkalaemia and hypoglycaemia. Potential therapeuti c modalities for treatment of endotoxaemia/septic shock include specif ic antagonists directed against lipopolysaccharide, cytokine, and plat elet-activating factor receptors, monoclonal antibodies directed again st cytokines and lipid A/core polysaccharides of endotoxin, antiprotea ses, and agents that block release of toxic O-2 and arachidonic acid m etabolites.