Prolonged exposure to lipopolysaccharide inhibits macrophage 5-lipoxygenase metabolism via induction of nitric oxide synthesis
Prolonged exposure to lipopolysaccharide inhibits macrophage 5-lipoxygenase metabolism via induction of nitric oxide synthesis
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DOI：
10.4049/jimmunol.165.7.3592
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发表时间：
2000-10-01
影响因子：
4.4
通讯作者：
Peters-Golden, M
中科院分区：
文献类型：
--
作者：
Coffey, MJ;Phare, SM;Peters-Golden, M
来自细菌的LPS可导致脓毒症综合征和急性肺损伤的发展。虽然急性暴露于内毒素会使白细胞增强白三烯（LT）的合成，但对慢性暴露的影响知之甚少。因此，我们确定了长时间LPS处理对肺泡巨噬细胞（AM）和外周血单核细胞花生四烯酸5-脂氧合酶（5-LO）代谢的影响，用LPS预处理AM会引起LT合成能力的时间和剂量依赖性抑制。LPS预处理不能抑制花生四烯酸（AA）的释放。LPS对内源性AA合成LT的抑制作用大于对外源性AA合成LT的抑制作用，这表明LPS对5-LO激活蛋白（FLAP）有影响。此外，通过无细胞5-LO酶测定，LPS对AM 5-LO活性有抑制作用。对5-LO和FLAP蛋白的表达均无影响。LPS诱导AM减少5-LO代谢需要新的蛋白质合成，免疫印迹显示明显的NO合成酶（NOS）诱导，LPS的抑制作用被NO供体复制，并被组成型和诱导型NOS抑制剂所消除。LPS对外周血单核细胞的5-LO代谢没有抑制作用，对诱导型NOS也没有诱导作用。我们得出结论，长期暴露于LPS会通过no介导的5-LO和FLAP功能的抑制来损害AM 5-LO代谢。由于肝移植有助于抗微生物防御，这种5-LO代谢的下调可能导致败血症后患者对肺炎的易感性增加。
LPS from bacteria can result in the development of sepsis syndrome and acute lung injury. Although acute exposure to endotoxin primes leukocytes for enhanced synthesis of leukotrienes (LT), little is known about the effect of chronic exposure. Therefore, we determined the effect of prolonged LPS treatment on 5-lipoxygenase (5-LO) metabolism of arachidonic acid in alveolar macrophages (AM) and in peripheral blood monocytes, Pretreatment of AM with LPS caused time- and dose-dependent suppression of LT synthetic capacity. LPS pretreatment failed to inhibit arachidonic acid (AA) release. The fact that LPS inhibited LT synthesis from endogenous AA more than from exogenous AA suggested an effect on 5-LO-activating protein (FLAP), In addition, an inhibitory effect of LPS treatment on AM 5-LO activity was suggested by cell-free 5-LO enzyme assay. No effect on the expression of either 5-LO or FLAP proteins was observed. New protein synthesis was necessary for LPS-induced reduction of 5-LO metabolism in AM, and immunoblotting demonstrated marked induction of NO synthase (NOS), Inhibition by LPS was reproduced by an NO donor and was abrogated by inhibitors of constitutive and inducible NOS. Compared with AM, peripheral blood monocytes exhibited no suppression by LPS of 5-LO metabolism and no induction of inducible NOS. We conclude that prolonged exposure to LPS impairs AM 5-LO metabolism by NO-mediated suppression of both 5-LO and FLAP function. Because LT contribute to antimicrobial defense, this down-regulation of 5-LO metabolism may contribute to the increased susceptibility to pneumonia in patients following sepsis.