Wu C C, Croxtall J D, Perretti M, Bryant C E, Thiemermann C, Flower R J, Vane J R
Department of Vascular Biology, William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3473-7. doi: 10.1073/pnas.92.8.3473.
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.
给雄性Wistar大鼠静脉注射大肠杆菌脂多糖（LPS；10mg/kg），在240分钟内导致：（i）平均动脉血压持续下降（约30mmHg）；（ii）对去甲肾上腺素（1μg/kg静脉注射）的升压反应降低（>75%）；（iii）肺中一氧化氮合酶（iNOS）的诱导。地塞米松（在LPS注射前2小时腹腔注射1mg/kg）减轻了低血压和对去甲肾上腺素的血管低反应性，并降低了肺中iNOS的表达（约77%）。用抗脂皮质素1中和抗血清（LPS注射前24小时皮下注射60mg/kg）预处理LPS处理的大鼠可防止地塞米松的这些作用，但对照非免疫绵羊血清则不能。用LPS（1μg/ml处理24小时）刺激J774.2巨噬细胞可导致iNOS和环氧化酶2（COX-2）蛋白的表达，并显著增加亚硝酸盐的生成；这可被地塞米松（LPS注射前1小时0.1μM）阻止，地塞米松还增加了细胞表面脂皮质素1。用抗LC1（LPS注射前4小时1:60稀释）预处理J774.2细胞也消除了地塞米松对iNOS表达和亚硝酸盐积累的抑制作用，但对COX-2表达的抑制作用未消除。脂皮质素1片段（人脂皮质素1的1-188位残基；LPS注射前1小时20μg/ml）也可阻断LPS激活的J774.2巨噬细胞中的iNOS（约78%抑制），这也可被抗LC1阻止。我们得出结论，内源性脂皮质素1的细胞外释放：（i）介导地塞米松对iNOS表达的抑制，但不介导对COX-2表达的抑制；（ii）在很大程度上有助于地塞米松对内毒素休克大鼠的有益作用。
