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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat.
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Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat.

机译：脂球蛋白1介导地塞米松抑制内毒素对大鼠一氧化氮合酶的诱导。

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Administration of Escherichia coli lipopolysaccharide (LPS; 10 mg/kg i.v.) to male Wistar rats caused within 240 min (i) a sustained fall (approximately 30 mmHg) in mean arterial blood pressure, (ii) a reduction (> 75%) in the pressor responses to norepinephrine (1 microgram/kg i.v.), and (iii) an induction of nitric oxide synthase (iNOS) as measured in the lung. Dexamethasone (1 mg/kg i.p. at 2 h prior to LPS) attenuated the hypotension and the vascular hyporeactivity to norepinephrine and reduced (by approximately 77%) the expression of iNOS in the lung. These effects of dexamethasone were prevented by pretreatment of LPS-treated rats with a neutralizing antiserum to lipocortin 1 (anti-LC1; 60 mg/kg s.c. at 24 h prior to LPS) but not by a control nonimmune sheep serum. Stimulation of J774.2 macrophages with LPS (1 microgram/ml for 24 h) caused the expression of iNOS and cyclooxygenase 2 (COX-2) protein and significantly increased nitrite generation; this was prevented by dexamethasone (0.1 microM at 1 h prior to LPS), which also increased cell surface lipocortin 1. Pretreatment of J774.2 cells with anti-LC1 (1:60 dilution at 4 h prior to LPS) also abolished the inhibitory effect of dexamethasone on iNOS expression and nitrite accumulation but not that on COX-2 expression. A lipocortin 1 fragment (residues 1-188 of human lipocortin 1; 20 micrograms/ml at 1 h prior to LPS) also blocked iNOS in J774.2 macrophages activated by LPS (approximately 78% inhibition), and this too was prevented by anti-LC1. We conclude that the extracellular release of endogenous lipocortin 1 (i) mediates the inhibition by dexamethasone of the expression of iNOS, but not of COX-2, and (ii) contributes substantially to the beneficial actions of dexamethasone in rats with endotoxic shock.
机译：向雄性Wistar大鼠施用大肠埃希氏菌脂多糖（LPS; 10 mg / kg iv）在240分钟内（i）平均动脉血压持续下降（约30 mmHg），（ii）血压下降（> 75％）升压对去甲肾上腺素（1微克/千克，静脉注射）的反应，以及（iii）在肺中测量的一氧化氮合酶（iNOS）的诱导。地塞米松（LPS前2 h腹腔注射1 mg / kg）可减轻低血压和对去甲肾上腺素的血管反应性降低，并降低（降低约77％）iNOS在肺中的表达。地塞米松的这些作用可通过用对脂皮质素1的中和性抗血清（LPS之前24小时抗LC1; 60 mg / kg s.c.）预处理LPS处理的大鼠来预防，但不能通过对照非免疫绵羊血清来预防。用LPS（1微克/毫升，持续24小时）刺激J774.2巨噬细胞引起iNOS和环氧合酶2（COX-2）蛋白的表达，并显着增加亚硝酸盐的生成。地塞米松（在LPS之前1 h时为0.1 microM）可防止这种情况，这也会增加细胞表面脂皮质激素1的水平。用抗LC1预处理J774.2细胞（在LPS之前4 h时以1:60稀释）也消除了这种抑制作用。地塞米松对iNOS表达和亚硝酸盐积累的影响，但对COX-2表达没有影响。脂皮质激素1片段（人脂皮质激素1的残基1-188； LPS之前1 h为20微克/ ml）也阻断了被LPS激活的J774.2巨噬细胞中的iNOS（约78％抑制），并且也被抗-LC1。我们得出的结论是，内源性脂皮质激素1的细胞外释放（i）介导地塞米松抑制iNOS的表达，但不抑制COX-2的表达，并且（ii）大大有助于地塞米松在内毒素性休克大鼠中的有益作用。

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