Proinflammatory Cytokines Mediating the Induction of iNOS by Endotoxin

Proinflammatory Cytokines Mediating the Induction of iNOS by Endotoxin 

TNF is a primary mediator of circulatory shock (Tracey et ai, 1986, 1987 for a review see Billiau and Vandekerchove, 1991). Administration of TNF alone or in combination with low (otherwise ineffective) doses of endotoxin, produces effects that, mimic several cardiovascular features of circulatory shock, including hypotension, peripheral vasodilatation, and organ damage (for a review see Billiau and Vandekerchove, 1991). Elevated plasma concentrations of TNF are found in endotoxemia (Beutler et al., 1985 Waage, 1987 Michieeta/., 1988 Feuerstein etal., 1990 Klosterhafen et ai, 1992). In addition, antibodies directed against TNF (Tracey et al., 1987 Mathison etal., 1988 Hinshaw etal., 1990 Silva etal., 1990 Walsh et al., 1992) or agents that inhibit the release of TNF, such as pentoxifylline (Schade, 1990), exert protective effects in animal models of endotoxin shock. 

Systemic administration of TNF increases NO production (Kosaka et al., 1992) and causes NO-mediated vasodilatation (Kilbourn et al., 1990a) and vascular hyporeactivity to vasoconstrictors in vivo (Vicaut and Baudry, 

1992) and ex vivo (Takahaski et al., 1992 Foulkes and Shaw, 1992). Like endotoxin, TNF also induces iNOS in vitro (Drapier et al., 1988 Kilbourn and Belloni, 1990). 

Intravenous administration of IL-1, either alone or in combination with low doses of endotoxin or TNF, can also produce a shocklike state. IL-1 is another important endogenous mediator of endotoxin enhances plasma levels of IL-1 and that administration of the endogenous IL-1 receptor antagonist (IL-ljJ protects against the cardiovascular failure caused by endotoxin in various animal models (Okusawa et al., 1988 Dinarello and Thompson, 1991 Bellomo, 1992). 

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