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A variety of stimuli can influence the pathophysiology of ischemia, hypoxia, and shock states. Thus, in endotox-emia, macrophages and other cell types become activated and can then release tumor necrosis factor (TNF), a polypeptide cytokine that is cytotoxic for certain cell types and that produces hypotension, hypoglycemia, hyperkalemia, and hemoconcentration. Second, during myocardial ischemia and reperfusion, neutrophils release superoxide free radicals, which are thought to mediate myocardial cell injury. In addition to these actions, both TNF and superoxide radicals share another biologic action: inhibition of the release of endothelium-derived relaxing factor (EDRF), a substance produced by endothelial cells that facilitates vasodilation in response to a variety of vasoactive agents.* TNF inhibits EDRF by inducing the synthesis of a group of endothelial cell surface proteins called endothelium-leuko-cyte adhesion molecules (ELAM), which enable leukocytes to adhere to the endothelium, but even in the absence of leukocytes and other blood cells, one action of ELAM appears to be inhibition of EDRF release. In this situation, endothelial cells may be the source of TNF produced.