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目的:探讨环孢素A(cyclosporine A,CsA)对野百合碱(monocrotaline,MCT)诱发肺动脉高压的影响及其作用机制。方法:36只雄性Sprague-Dawley(SD)大鼠随机分为正常对照组(n=8)、肺动脉高压模型组(n=12)、CsA低、高剂量组(0.33和1 mg.kg-1,n=8)。后3组大鼠颈背部皮下一次性注射MCT50mg.kg-1诱导肺动脉高压模型,MCT注射后d14~d21,CsA组灌胃给药,模型组灌胃等体积的生理氯化钠溶液(5 mL.kg-1)。MCT注射后d22,右心导管术测肺动脉压,称肺湿重(wW)、右心室自由壁(RV)重和左心室加室间隔(LV+S)重,计算右心肥大指数[RVHI=RV/(LV+S)],肺湿重指数(LI=wW/BW)。HE染色观察肺病理改变;免疫组化方法观察肺动脉平滑肌细胞增殖细胞核抗原(PCNA)阳性表达。用Image-ProPlus 5.1软件分析肺动脉中膜相对厚度及肺动脉平滑肌PCNA阳性细胞的比值。结果:CsA低、高剂量组均能逆转MCT诱导的肺动脉高压(P<0.05或P<0.01),降低RVHI及LI(P<0.05或P<0.01),改善肺动脉重构(P<0.05或P<0.01),减轻肺部炎症,抑制肺动脉平滑肌的增殖(P<0.05或P<0.01),且高剂量组更明显。结论:CsA能明显降低MCT诱导的肺动脉高压,逆转肺动脉重构,其机制与抑制肺动脉平滑肌增殖和抑制肺部炎症有关。
Objective: To investigate the effect of cyclosporine A (CsA) on pulmonary hypertension induced by monocrotaline (MCT) and its mechanism. Methods: Thirty-six male Sprague-Dawley rats were randomly divided into normal control group (n = 8), pulmonary hypertension model group (n = 12), CsA low and high dose group (0.33 and 1 mg.kg-1 , n = 8). Rats in the latter 3 groups were injected subcutaneously with MCT 50mg.kg-1 subcutaneously for 5 days to induce pulmonary arterial hypertension. Rats in d14-d21 and CsA groups were intragastrically administrated with the same volume of physiological sodium chloride solution (5 mL .kg-1). Right ventricular hypertrophy index (RVHI) was calculated on d22 after MCT injection and pulmonary arterial pressure measured by right heart catheterization, weighted as lung wet weight (wW), RV free weight (RV) and left ventricular septum (LV + RV / (LV + S)], pulmonary wet weight index (LI = wW / BW). The pathological changes of lung were observed by HE staining. The expression of proliferating cell nuclear antigen (PCNA) in pulmonary artery smooth muscle cells was observed by immunohistochemistry. The ratio of pulmonary artery media thickness to pulmonary artery smooth muscle PCNA positive cells was analyzed by Image-ProPlus 5.1 software. Results: Both low and high CsA groups could reverse pulmonary hypertension induced by MCT (P <0.05 or P <0.01), reduce RVHI and LI (P <0.05 or P <0.01) and improve pulmonary remodeling <0.01), reduce lung inflammation, inhibit the proliferation of pulmonary artery smooth muscle (P <0.05 or P <0.01), and high-dose group is more obvious. CONCLUSIONS: CsA can significantly reduce MCT-induced pulmonary hypertension and reverse pulmonary remodeling. Its mechanism is related to the inhibition of pulmonary artery smooth muscle proliferation and inhibition of lung inflammation.