糖皮质激素受体在大鼠内毒素性急性肺损伤中的作用

Role of glucocorticoid receptor in acute lung injury induced by lipopolysaccharide in rats

目的评价糖皮质激素受体（GR）在大鼠内毒素性急性肺损伤中的作用及可能机制。方法成年雄性sD大鼠60只，体重180～230g，采用随机数字表法，将其随机分为4组：对照组（C组，n=6）、RU486组（GR特异性拮抗剂组，R组，n=6）、急性肺损伤组（ALI组，n=24）、RU486＋Au组（RA组，n=24）。Au组尾静脉注射内毒素（LPS）5mg／kg制备大鼠急性肺损伤模型，C组给予等容量生理盐水，R组皮下注射GR拮抗剂RU48620mg／kg，RA组注射RU48620mg／kg90min后注射LPS。ALI组及RA组分别于注射LPS后1、3和6h（T1-3）时，各组随机取8只大鼠，C组与R组于注射生理盐水、RU4861h后处死取肺，检测p-p38MAPK、丝裂原活化蛋白激酶磷酸酶-1（MKP-1）的表达。T1时回收支气管肺泡灌洗液（BALF），测定蛋白和TNF-α的浓度；计算细胞凋亡指数；观察肺组织病理学结果。另取32只大鼠，体重180～230g，采用随机数字表法，将其随机分为2组（n=16）：急性肺损伤组（ALI1组）、RU486＋ALI组（RA，组），处理方法同上。观察48h内大鼠生存情况。结果与c组相比，ALI组、RA组BALF蛋白浓度和TNF—d浓度、细胞凋亡指数升高（P〈0．05）、病理学损伤加重；T1-3时p-p38MAPK表达上调，ALI组T2，时MKP-1表达下调，RA组T1-3，时MKP-1表达下调（P〈0．05）；与ALI组相比，RA组BALF蛋白浓度和TNF—α浓度、细胞凋亡指数增加，T1-3时p-p38MAPK表达上调（P〈0．05），T2，时MKP-1表达差异无统计学意义（P〉0．05），RA1组大鼠生存率低于ALI1组（P〈0．05）。结论GR参与大鼠内毒素急性肺损伤的发生发展，其机制与抑制p38MAPK信号转导通路，降低肺组织细胞凋亡有关。

Objective To evaluate the role of glucocorticoid receptor （GR） in acute lung injury （ALI） induced by Lipopolysaccharide （LPS） in rats. Methods Sixty male Sprague-Dawley rats, weighing 180-230 g, were randomly divided into 4 groups： control group （group C, n = 6） ; GR specific inhibitor RU486 group （group R, n = 6） ; ALl group （ n = 24） ; RU486 ＋ ALI group （group RA, n = 24）. ALI was induced by injection of LPS 5 mg/kg via the tail vein in groups ALI and RA, while the equal volume of normal saline was given in group C and RU486 20 mg/kg was injected subcutaneously in group R. RU486 20 mg/kg was injected subcutaneously 90 min before LPS administration in group RA, Eight rats were chosen at 1, 3, and 6 h after LPS administration （T1-3） in groups ALI and RA and at 1 h after normal saline or Rug86 administration in groups C and R and sacrificed. The lungs were removed for determination of the expression of phosphorylated p38 mitogen-activated protein kinase （p- p38MAPK） and mitogen-activated protein kinase phosphatase-1 （MKP-1） in lung tissues. The concentrations of al- bumin and TNF〈t in bronchoalveolar lavage fluids （BALF） were detected, histopathological changes in lung tissues were observed and apoptosis index （AI） was calculated at T3 . Another 32 Sprague-Dawley rats, weighing 180-230 g, were randomly divided into 2 groups （ n = 16 each） ： group ALII and group RA1 . The rats were treated as the method mentioned above and observed for the 48 h survival rate. Results Compared with group C, the concentrations of protein and TNF-α in BALF and AI were significantly increased, the histopathological damage was aggravated, and p-p38MAKP expression was up-regulated at T1-3 in groups ALl and RA, and MKP-1 expression was downregulated at T2.3 in group ALI and at T1-3 in group RA （ P 〈 0.05）. Compared with group ALI, the concentrations of protein and TNF-a in BALF and AI were significantly increased, p-p38MAKP expression was up-regulated at T,3 （ P 〈 0.05）, and no significant change was found in MKP-1 expression at T2-3 in group RA （ P 〉 0.05）. The 48 h survival rate was significantly lower in group R＆ than in group ALII （ P 〈 0.05 ）. Conclusion Glucocorticoid receptors are involved in the development of LPS-induced ALI, and the mechanism may be related to the inhibition of p38MAPK signal transdoction pathways and decrease in cell apoptosis in rat lung tissues.