Role of leukotrienes in endotoxin action in vivo.

The cysteinyl leukotrienes LTC4, LTD4, and LTE4 play an important role within the network of mediators of endotoxin shock since they are capable of eliciting the generation of other lipid mediators of shock. Three lines of evidence support the conclusion that the cysteinyl leukotrienes are involved in the lethal shock-inducing action of endotoxin. (1) Endotoxin elicits the systemic production of cysteinyl leukotrienes in vivo. (2) Injection of these leukotrienes into sensitive species causes shock-like reactions, myocardial depression, and extravasation of plasma. (3) Cysteinyl leukotriene receptor antagonists and inhibitors of leukotriene synthesis prevent experimental endotoxin shock. Moreover, endotoxin induces a strong inhibition of the hepatobiliary elimination of cysteinyl leukotrienes, which normally represents the major pathway for deactivation of these mediators. This dual action of endotoxin, comprising enhanced synthesis and simultaneously impaired deactivation of potent mediators, points to a novel type of toxin action. The role of cysteinyl leukotrienes in endotoxin action does not exclude the involvement of additional shock-inducing factors released by endotoxin and their possible contribution to the formation of lipid mediators, including leukotrienes.