Da Jiping, Chen Luni, Hedenstierna Göran
Department of Medical Sciences, Clinical Physiology, University Hospital, Uppsala University, Sweden.
Crit Care Med. 2007 Jan;35(1):26-32. doi: 10.1097/01.CCM.0000250319.91575.BB.
Nitric oxide inhibits the expression of many genes involved in inflammatory diseases. Glucocorticoids inhibit similar transcription factors. We hypothesized that there may be an interaction between nitric oxide and glucocorticoids, with the potential to enhance the anti-inflammatory effect when administered simultaneously.
Prospective, randomized, controlled study.
Animal research laboratory.
A total of 45 anesthetized and mechanically ventilated pigs.
Lung and systemic injury was induced by intravenous infusion of endotoxin (lipopolysaccharide) for 6 hrs. After 2.5 hrs, one group received 3.5 mg/kg hydrocortisone, another group inhaled nitric oxide (30 ppm), and still another group received both steroid and nitric oxide. Control groups of healthy and endotoxin-exposed piglets were also studied.
Central hemodynamics and gas exchange were measured. Detection of the glucocorticoid receptor and inflammatory markers in lung, liver, and kidney tissue were made by immunohistochemistry, and morphology was studied with light microscopy. Endotoxin infusion markedly reduced glucocorticoid receptor expression in lung, liver, and kidney and up-regulated activator protein-1 and the inflammatory markers nuclear factor-kappaB and tumor necrosis factor-alpha. When administered separately, steroids and nitric oxide had modest effect on the inflammatory response. However, nitric oxide up-regulated the glucocorticoid receptor expression. Simultaneous administration of steroids and nitric oxide attenuated the inflammatory response and almost preserved or restored normal histology of both lung and systemic organs. When the glucocorticoid receptor was blocked by a receptor antagonist (mifepristone, 600 mg) and inhaled nitric oxide was subsequently administered, no increase in the expression of the glucocorticoid receptor was seen.
We suggest that up-regulation of glucocorticoid receptor expression by nitric oxide made steroid therapy more effective.
一氧化氮可抑制许多参与炎症性疾病的基因表达。糖皮质激素可抑制类似的转录因子。我们推测一氧化氮与糖皮质激素之间可能存在相互作用，同时给药时有可能增强抗炎效果。
前瞻性、随机、对照研究。
动物研究实验室。
总共45只麻醉并机械通气的猪。
通过静脉输注内毒素（脂多糖）6小时诱导肺和全身损伤。2.5小时后，一组接受3.5mg/kg氢化可的松，另一组吸入一氧化氮（30ppm），还有一组同时接受类固醇和一氧化氮。还研究了健康和暴露于内毒素的仔猪对照组。
测量中心血流动力学和气体交换。通过免疫组织化学检测肺、肝和肾组织中的糖皮质激素受体和炎症标志物，并用光学显微镜研究形态学。内毒素输注显著降低了肺、肝和肾中糖皮质激素受体的表达，并上调了激活蛋白-1以及炎症标志物核因子-κB和肿瘤坏死因子-α。单独给药时，类固醇和一氧化氮对炎症反应的影响较小。然而，一氧化氮上调了糖皮质激素受体的表达。同时给予类固醇和一氧化氮可减轻炎症反应，几乎保留或恢复了肺和全身器官的正常组织学。当糖皮质激素受体被受体拮抗剂（米非司酮，600mg）阻断，随后吸入一氧化氮时，未观察到糖皮质激素受体表达增加。
我们认为一氧化氮上调糖皮质激素受体表达使类固醇治疗更有效。
