Mediators and vascular effects in response toendotoxin

• Published in: British veterinary journal 1995, Vol.151 (5), p.489-522
• Main Authors: Olson, N.C., Hellyer, P.W., Dodam, J.R.
• Format: Article
• Language: English
• Subjects: cytokines; eicosanoids; Haemodynamics; lipopolysaccharide receptors; platelet-activating factor
• ISSN: 0007-1935
• DOI: 10.1016/S0007-1935(05)80023-5

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 A 2, prostaglandins, leukotrienes, nitric oxide, proteases, toxic O 2, 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 O 2 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/septicshock 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 O 2 and arachidonic acid metabolites.