Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene.
Leukotrienes constitute a class of potent biological mediators of inflammation and anaphylaxis (for reviews see refs 1 and 2). Their biosynthesis derives from 5-lipoxygenase-catalysed oxygenation of arachidonic acid in granulocytes, macrophages and mast cells. To examine the physiological importance of leukotrienes, we have disrupted the 5-lipoxygenase gene by homologous recombination in embryonic stem cells. 5-Lipoxygenase-deficient (5LX-/-) mice develop normally and are healthy. They show a selective opposition to certain inflammatory insults. Although there is no difference in their reaction to endotoxin shock, the 5LX-/- animals resist the lethal effects of shock induced by platelet-activating factor. Reaction to ear inflammation induced by phorbol ester is normal, whereas inflammation induced by arachidonic acid is markedly reduced. Contrasts were also found in two models of leukocyte chemotaxis in vivo. The phenotype of 5LX-/- mice under injurious insult identifies the role for leukotrienes in the pathophysiology of select inflammatory states.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
X S
XS
Chen
J R
JR
Sheller
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EN
Johnson
C D
CD
Funk
D000707:Anaphylaxis / Q000503:physiopathology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D005260:Female; D007249:Inflammation / Q000503:physiopathology; D015289:Leukotrienes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010972:Platelet Activating Factor / Q000502:physiology; D012769:Shock / Q000401:mortality / Q000503:physiopathology; D012772:Shock, Septic / Q000503:physiopathology
D015289:Leukotrienes; D010972:Platelet Activating Factor; D001094:Arachidonate 5-Lipoxygenase