ROLE OF LEUKOTRIENES REVEALED BY TARGETED DISRUPTION OF THE 5-LIPOXYGENASE GENE

LEUKOTRIENES constitute a class of potent biological mediators of infl ammation and anaphylaxis (for reviews see refs 1 and 2). Their biosynt hesis derives from 5-lipoxygenase-catalysed oxygenation of arachidonic acid in granulocytes, macrophages and mast cells. To examine the phys iological importance of leukotrienes, we have disrupted the 5-lipoxyge nase gene by homologous recombination in embryonic stem cells. 5-Lipox ygenase-deficient (5LX(-/-)) mice develop normally and are healthy. Th ey show a selective opposition to certain inflammatory insults. Althou gh there is no difference in their reaction to endotoxin shock, the 5L X(-/-) animals resist the lethal effects of shock induced by platelet- activating factor. Reaction to ear inflammation induced by phorbol est er is normal, whereas inflammation induced by arachidonic acid is mark edly reduced. Contrasts mere also found in two models of leukocyte che motaxis in vivo. The phenotype of 5LX(-/-) mice under injurious insult identifies the role for leukotrienes in the pathophysiology of select inflammatory states.