17β-雌二醇对慢性低氧性肺动脉高压雌性大鼠模型的治疗作用

The therapeutic effect of 17β-estradiol on chronic hypoxic pulmonary hypertension in female rats

目的研究腹腔注射17-β雌二醇对慢性低氧性肺动脉高压雌性大鼠模型的疗效及安全性。方法 32只SD雌性大鼠随机分为常氧组(A组)、常氧+17β-雌二醇干预组(B组)、低氧组(C组)、低氧+17β-雌二醇干预组(D组)。A组、B组置于SPF级动物房内饲养,而C组、D组置于全自动常压低氧箱中,持续低氧[氧浓度为(10.0±0.5)%]28 d。从实验第1天开始,B组、D组按照100μg/(kg·d)的剂量腹腔注射17β-雌二醇;A组、C组腹腔注射相同体积的麻油。28 d后,测定大鼠右心室收缩压(RVSP)及平均右心室压(mRVP);取心脏测右心肥厚指数;取肺组织包埋切片行HE染色观察,测定管壁厚度占外径的百分比(WT%)和管壁面积占血管总面积的百分比(WA%),观察肺小动脉血管形态组织病理学变化。结果慢性低氧明显诱导了雌性RVSP、mRVP和右心肥厚指数的升高,经过17β-雌二醇干预后,这种升高显著降低(P<0.05)。C组大鼠RVSP和mRVP分别为(33.4±2.4)mm Hg和(15.6±0.8)mm Hg,显著高于A组[(27.7±0.9)mm Hg、(11.5±0.9)mm Hg](P<0.05)。与C组相比,D组RVSP和mRVP显著降低[(27.1±4.9)mm Hg、(13.0±1.7)mm Hg](P<0.05)。A组和B组的右心肥厚指数为0.24±0.06和0.28±0.04;与A组比较,C组右心肥厚指数明显较高(0.39±0.02)(P<0.05);与C组相比,D组的右心肥厚指数(0.35±0.03)较低(P<0.05)。与A组比较,C组的WT%明显较高[(33.2±4.0)%](P<0.05);D组的WT%为(16.6±2.4)%,与C组比较差异有统计学意义(P<0.05)。C组的WA%由(17.91±2.5)%增加至(59.16±5.9)%(P<0.05);D组的WA%为(26.30±2.9)%,与C组比较差异有统计学意义(P<0.05)。与A组和B组对比,C组肺小动脉管壁增生增厚,管腔变窄明显;但D组上述形态学改变较C组减轻。结论 17β-雌二醇能有效降低慢性低氧性肺动脉高压雌性大鼠模型的RVSP、改善右心室肥厚,对慢性低氧中的肺血管的重塑具有一定的改善作用,对低氧引起慢性肺动脉高压雌性大鼠模型具有较好的疗效。

Objective To investigate the efficacy of 17β-estradiol on chronic hypoxic pulmonary hypertension in female rats. Methods Totally 32 female SD rats(250-300 g） were randomized into normoxia group(Group A）,normoxia ＋ 17β-estradiol group(Group B）,hypoxia group(Group C） and hypoxia ＋ 17β-estradiolgroup(Group D） by the random number table. The rats in Group A and B were fed in normoxic cabin,while those in Group C and D were put into the atmospheric hypoxic cabin. 17β-estradiol [100 μg/(kg·d） ] were intraperitoneally infused into rats in Group B and D since the first day after experiment,and placebo sesame oil were given in Group A and C. After successive feeding for 28 d,mean right ventricular pressure(mRVP）,right ventricular systolic pressure(RVSP） and right ventricle hypertrophy index RV/(LV ＋ S） were measured by right cardiac manometric method. Lung tissue sections were constructed.The ratios of wall thickness and wall area to pulmonary arteries were quantified by using the Image Pro Plus6. 0 software.Results The hypoxia significantly induced the increases of mRVP,RVSP and RV/(LV ＋ S）. Nevertheless,the increasing levels of mRVP,RVSP and RV/(LV ＋ S） were obviously decreased after intervention of 17β-estradiol. The RVSP and mRVP in Group C [(33. 4 ± 2. 4）,(15. 6 ± 0. 8） mm Hg] were significantly higher than those in Group A [(27. 7 ±0. 9）,(11. 5 ± 0. 9） mm Hg,P 〈0. 05]. The RVSP and mRVP in Group D [(27. 1 ± 4. 9）,(13. 0 ± 1. 7） mm Hg] were significantly lower than those in Group C(P 〈0. 05）. The RV/(LV ＋ S） in Group C(0. 39 ± 0. 02） was significantly higher than those in Group A and Group B(0. 24 ± 0. 06 and 0. 28 ± 0. 04,respectively,P 〈0. 05）. The RV/(LV ＋ S）in Group D(0. 35 ± 0. 03） was significantly lower than that in Group C(P〈 0. 05）. The wall thickness/artery radius(WT%） in Group C was significantly higher than that in Group A [(10. 0 ± 0. 7） % vs.(33. 2 ± 4. 0） %,P 〈0. 05]. In Group D,WT% [(16. 6 ± 2. 4） %]was significantly lower than that in Group C(P 〈0. 05）. The wall area/total vascular area(WA%） in Group C was significantly higher than that in Group A [(59. 16 ± 5. 9） % vs.(17. 91 ± 2. 5） %,P〈 0. 05]. In Group D WA% [(26. 30 ± 2. 9） %] was significantly lower than that in Group C(P 〈0. 05）. Compared with Group A and B,Group C had increased thickening of small arterial wall and smooth muscle layer,narrowing lumen and much lymphocytes and neutrophil infiltration in peripheral vascular; which were alleviated in Group D. Conclusion 17β-estradiol markedly reduces RVSP,mRVP,RV/(LV ＋ S） and pulmonary vascular remodeling in chronic hypoxia induced pulmonary hypertension female rats.