过氧化物酶增殖体激活受体α激活剂对急性肺损伤大鼠肺组织的影响及其机制

The role of peroxisome proliferation activated receptor-α activated ligands in acute lung injury induced by lipopolysaccharide in rats

目的探讨过氧化物酶增殖体激活受体α(PPARα)激活剂WY14643对急性肺损伤(ALI)大鼠肺组织的保护作用及其可能机制。方法将104只雄性Wistar大鼠随机分为对照组、脂多糖(LPS)致伤组(ALI组)、WY14643 1 mg/kg处理组(LW 1 mg组)、WY14643 3 mg/kg处理组(LW 3 mg组)。用LPS(5 mg/kg)静脉注射复制大鼠ALI模型,在静脉注射LPS 15 min后再次静脉注射WY14643 1 mg/kg和3 mg/kg,分别在LPS后1、2、4及8 h时处死大鼠,测定用药前、后各时相点大鼠肺组织湿/干重比(W/D)及肺组织病理变化;采用逆转录聚合酶链反应(RT-PCR)检测肺组织中肿瘤坏死因子-α(TNF-α)mRNA的表达,酶联免疫吸附分析法检测肺组织匀浆中TNF-α浓度。结果WY14643 1 mg与3 mg组在2 h、4 h肺组织W/D比值及病理积分均较ALI组相应时相点下降显著(P均<0.01);WY14643 1 mg组在2、4及8 h,3 mg组在1、2、4及8 h TNF-αmRNA表达及肺组织匀浆上清中的TNF-α均较ALI组相应时相点显著下降(P<0.01);WY14643 1 mg与3 mg组间比较作用有显著性差异(P<0.05)。结论WY14643对ALI大鼠肺组织具有一定的保护作用,其机制可能是PPARα激活后抑制了TNF-α的释放,减轻肺部及全身的炎症反应。

Objective To investigate the role and possible mechanism of a peroxisome proliferator-activated receptors （PPARα） ligand, WY14643, in acute lung injury rat model induced by lipopolysaccharide. Methods 104 male Wistar rats were divided randomly into four groups, ie, control group, acute lung injury group, WY14643 1 mg group and WY14643 3 mg group. Wistar rats were challenged with lipopolysaecharide （5 mg/kg） before intratracheal administration with WY14643 （ 1 mg/kg and 3 mg/kg）. All rats were killed at 1 h,2 h,4 h, and 8 h after LPS challenge. The ratio of lung wet weight to dry weight and pulmonary morphologic changes were measured while the expression of tumor necrosis factor-α（TNF-α） mRNA in lung was detected by semi-quantitative reverse transcription polymerase chain reaction（RT-PCR） and the level of TNF-α in supematant of rats lung homogenate was measured by ELISA. Results WY14643 1mg and WY14643 3 mg treatment at 2 h and 4 h alleviated the pathological changes while the ratio of wet weight to dry weight was significantly lower compared to those in ALI group（ P 〈 0.01 ） .TNF-α mRNA expression and TNF-α concentration in supematant of lung homogenate at 2 h,4 h, and 8 h in WY14643 1 mg group, at I h, 2 h, 4 h, and 8 h in WY 14643 3 mg group were significantly lower than those in ALI group（ P 〈 0.05 , P 〈 0.01 ）.Treatment with WY14643 at a dose of 1mg/kg or 3 mg/kg ameliorated the neutrophilic lung inflammation and pulmonary edema induced by lipopolysaccharide, Conclusions Our data suggest WY 14643 could inhibit the expression of TNF-α mRNA and nuclear translocalization of nuclear factor-kB and AP-1 and ameliorate the neutrophilic lung inflammation and pulmonary edema induced by lipopolysaccharide, WY14643 may be a promising option for therapy of acute lung injury.