牛磺酸抗缺氧及防治肺动脉高压的研究及其细胞机制初探

Prevention effects of taurine on hypoxic pulmonary hypertension

目的通过动物模型观察牛磺酸对缺氧性肺动脉高压的治疗作用,同时观察其对体外培养牛肺动脉平滑肌细胞(PASMC)和内皮细胞(PAEC)增殖的影响。方法采用模拟高原5 000 m制作缺氧大鼠模型,缺氧2周。设平原(C组)及缺氧对照组(H组),观察牛磺酸治疗后(T组)的肺动脉压(mPAP)、血浆乳酸脱氢酶(LDH)活性、脂质过氧化产物丙二醛(MDA)、肺匀浆一氧化氮(NO)含量、右心室肥大指数的变化。体外培养PASMC和PAEC用3H-TdR掺入法比较牛磺酸对缺氧PASMC和PAEC增殖的影响。结果H组大鼠LDH活性升高为C的10.1倍(P<0.01);肺匀浆NO含量降低为C组的32%(P<0.01);血浆MDA含量显著升高为C组的1.64倍(P<0.01);mPAP显著增高,约为C组的2.74倍(P<0.01);右心室肥大指数是C组的1.56倍(P<0.01)。T组与H组相比较:LDH活性、血浆MDA、右心室肥大指数均显著降低(P<0.01);mPAP显著降低(P<0.05)。高浓度(10～20 mmol/L)的牛磺酸抑制缺氧内皮及平滑肌细胞的3H-TdR掺入,而低浓度的牛磺酸促进缺氧时PAEC的3H-TdR掺入(P<0.05),抑制缺氧时PASMC的3H-TdR掺入(P<0.05)。结论牛磺酸有抗缺氧及防治肺动脉高压的作用。缺氧抑制内皮细胞的增殖而促进平滑肌细胞的增殖,适当剂量的牛磺酸可以对抗缺氧对PAEC和PASMs的作用:减弱缺氧对PAEC的增殖抑制作用,抑制缺氧的促PASMC增殖作用,使之接近常氧水平。这可能是牛磺酸防治肺动脉高压的细胞机制。提示牛横酸对于高山病缺氧性肺血管收缩和血管结构改建的预防和治疗,可能具有广阔的应用前景。

Objective Exposure to hypoxia induces hypoxic pulmonary hypertension （HPH）, the effects of taurine（T） on prevention of HPH were investigated. Methods Male Wistar rats were divided into three groups： Hypoxia 2 weeks, and control （C）. Hypoxia 2 weeks ＋ Taurine groups （T）. The Taurine therapy groups were given drugs every day orally. After exposed （12 hours every day ） 2 weeks in hypobaric chamber at simulated high altitude of 5 000 meters, the effects of taurine were evaluated. Results The rats of H groups developed remarkable HPH and fight ventricle hypertrophy, with an elevated pulmonary artery pressure （mPAP） of about 25 mmHg and the fight ventricle index of 1.56 folds higher （P〈0.01 vs control group）. Taurine group administered emolliated the elevation of mPAP and right ventricle index, with mPAP14.2% and right ventricle index about 20% lower than those of hypoxic group without drug administered （P〈 0.01 ） .The activities of LDH and levels of MDA in H groups were 10.1 and 1.64 folds higher than those of respective C groups （P〈0.01）, therapy group showed decreases in activities of LDH and levels of MDA （P〈0.01）. NO productions of H was 32% lower than those of C （P〈0.01）. As well effects of taurine and hypoxia （2.5%O2 and 0%O2 ） on proliferation of bovine pulmonary artery endothelial cells （PAEC） and pulmonary artery smooth muscle cells （PASMC） were investigated using ^3H-TdR incorporation method. Taurine dose-dependently inhibited ^3H-TdR incorporation of PAEC in normoxic condition （P〈0.05）. Anoxia and hypoxia inhibited PAEC proliferation significantly （P〈0.01）. taurine （20 and 40 mmol/L） markly inhibited the PASMC ^3H-TdR incorporation （P〈0.01） under normoxia. Anoxia and hypoxia stimulated proliferation of PASMC （P〈0.01）. Conclusion The results suggest that taurine have effects on hypoxic injury, inhibit lipidperoxidation, mitigate hypoxic pulmonary hypertension and reduce right ventricle hypertrophy.