Brock Thomas G, McNish Robert W, Mancuso Peter, Coffey Michael J, Peters-Golden Marc
Department of Internal Medicine, University of Michigan, 6301 MSRB III, Ann Arbor, MI 48109-0642, USA.
Prostaglandins Other Lipid Mediat. 2003 Jul;71(3-4):131-45. doi: 10.1016/s1098-8823(03)00036-4.
Resident rat peritoneal macrophages synthesize a variety of prostanoids and leukotrienes from arachidonic acid. Overnight treatment with lipopolysaccharide (LPS) induces the synthesis of cyclooxygenase-2 (COX-2) and an altered prostanoid profile that emphasizes the preferential conversion of arachidonic acid to prostacyclin and prostaglandin E2. In these studies, we report that exposure to LPS also caused a strong suppression of 5-lipoxygenase but not 12-lipoxygenase activity, indicated by the inhibition of synthesis of both leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE), but not of 12-HETE. Inhibition of 5-lipoxygenase activity by LPS was both time- and dose-dependent. Treatment of macrophages with prostaglandin E2 partially inhibited leukotriene synthesis, and cyclooxygenase inhibitors partially blocked the inhibition of leukotriene generation in LPS-treated cells. In addition to COX-2, nitric oxide synthase (NOS) was also induced by LPS. Treatment of macrophages with an NO donor mimicked the ability of LPS to significantly reduce leukotriene B4 synthesis. Inhibition of NOS activity in LPS-treated cells blunted the suppression of leukotriene synthesis. Inhibition of both inducible NOS and COX completely eliminated leukotriene suppression. Finally, macrophages exposed to prolonged LPS demonstrated impaired killing of Klebsiella pneumoniae and the combination of NOS and COX inhibitors restored killing to the control level. These results indicate that prolonged exposure to LPS severely inhibits leukotriene production via the combined action of COX and NOS products. The shift in mediator profile, to one that minimizes leukotrienes and emphasizes prostacyclin, prostaglandin E2 and NO, provides a signal that reduces leukocyte function, as indicated by impaired killing of Gram-negative bacteria.
大鼠腹膜常驻巨噬细胞可从花生四烯酸合成多种前列腺素和白三烯。用脂多糖（LPS）过夜处理可诱导环氧合酶-2（COX-2）的合成，并使前列腺素谱发生改变，这种改变强调了花生四烯酸优先转化为前列环素和前列腺素E2。在这些研究中，我们报告暴露于LPS还会强烈抑制5-脂氧合酶，但不抑制12-脂氧合酶的活性，这表现为白三烯B4和5-羟基二十碳四烯酸（5-HETE）的合成受到抑制，而12-HETE的合成未受抑制。LPS对5-脂氧合酶活性的抑制具有时间和剂量依赖性。用前列腺素E2处理巨噬细胞可部分抑制白三烯的合成，环氧合酶抑制剂可部分阻断LPS处理细胞中白三烯生成的抑制作用。除了COX-2外，LPS还可诱导一氧化氮合酶（NOS）。用NO供体处理巨噬细胞可模拟LPS显著降低白三烯B4合成的能力。抑制LPS处理细胞中的NOS活性可减弱对白三烯合成的抑制作用。同时抑制诱导型NOS和COX可完全消除对白三烯的抑制作用。最后，长时间暴露于LPS的巨噬细胞对肺炎克雷伯菌的杀伤能力受损，而NOS和COX抑制剂的联合使用可使杀伤能力恢复至对照水平。这些结果表明，长时间暴露于LPS会通过COX和NOS产物的联合作用严重抑制白三烯的产生。介质谱向使白三烯减少并强调前列环素、前列腺素E2和NO的方向转变，这提供了一个降低白细胞功能的信号，如对革兰氏阴性菌杀伤能力受损所示。
