Chen X S, Sheller J R, Johnson E N, Funk C D
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
Nature. 1994 Nov 10;372(6502):179-82. doi: 10.1038/372179a0.
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.
白三烯是一类强效的炎症和过敏反应生物介质（综述见参考文献1和2）。它们的生物合成源自粒细胞、巨噬细胞和肥大细胞中5-脂氧合酶催化的花生四烯酸氧化。为了研究白三烯的生理重要性，我们通过胚胎干细胞中的同源重组破坏了5-脂氧合酶基因。5-脂氧合酶缺陷（5LX-/-）小鼠发育正常且健康。它们对某些炎症刺激表现出选择性抵抗。尽管它们对内毒素休克的反应没有差异，但5LX-/-动物能抵抗血小板活化因子诱导的休克致死效应。对佛波酯诱导的耳部炎症反应正常，而花生四烯酸诱导的炎症则明显减轻。在两种体内白细胞趋化模型中也发现了差异。5LX-/-小鼠在损伤刺激下的表型确定了白三烯在特定炎症状态病理生理学中的作用。
