抑制PAI-1对大鼠左心疾病所致肺高压的影响

Effect of PAI-1 inhibition on pulmonary hypertension caused by left heart disease in rats

目的探讨纤溶酶原激活物抑制剂1(PAI-1)的抑制剂IMD-1622用于治疗左心疾病所致肺高压(PH-LHD)大鼠的效果。方法SD1月长鼠40只,采用随机数字表法均分为四组:对照组(C组)、假手术组(S组)、模型组(M组)和抑制剂组(I组),每组10只。C组,不做任何处理;S组,麻醉后吸氧,经左侧2~3肋间侧开胸,然后关胸;M组,制作PH-LHD模型;I组,PH-LHD模型建模成功后腹腔注射IMD-162220mg/kg。四组大鼠给予正常实验室饮食和水喂养至8周后,监测CVP、MAP、平均肺动脉压(MPA)、左心房压(LAP),计算肺血管阻力(PVR)和体循环阻力(SVR);取肺组织切片测量肺动脉中膜层厚度;HE染色免疫组化检测PAI-1含量;免疫荧光法检测肺组织中内皮素1(ET-1)及血栓素A2(TXA 2)含量。结果M组和I组MPA、LAP、PVR明显高于C组和S组,M组明显高于I组(P<0.05)。M组和I组肺动脉中膜层厚度明显厚于C组和S组,M组明显厚于I组(P<0.05)。M组和I组肺组织PAI-1含量组化灰度分析数值均明显高于C组和S组,M组明显高于I组(P<0.05)。M组和I组肺组织中ET-1和TXA2荧光表达明显强于C组和S组,M组明显强于I组(P<0.05)。结论PAI-1抑制剂IMD-1622可以减轻肺动脉中膜层增厚,改善左心疾病所致肺高压。

Objective To investigate the effect of PAI-1 inhibitor IMD-1622 in the treatment of PH-LHD rats caused by left heart disease.Methods Forty young SD rats were randomly divided into 4 groups(n=10):control group(group C),sham group(group S),model group(group M)and inhibitor group(group I).Rats in group C received no treatment.Oxygen inhalation after anesthesia,thoracotomy through the left 2 to 3 intercostal sides and then sternal closure in group S.PH-LHO model was established in group M.Rats in group I were treated with IMD-1622(20 mg/kg)intraperitoneally after successful modeling.Four groups of rats were given normal laboratory diet and water for 8 weeks,and central venous pressure(CVP),mean arterial pressure(MAP),mean pulmonary arterial pressure(MPA),left atrial pressure(LAP)were monitored,and calculated PVR and SVR.Pulmonary tissue section to measure the thickness of the middle layer of the pulmonary artery,PAI-1 expression was detected by immunohistochemical staining of HE,the expression of endothelin 1(ET-1)and thromboxane A2(TXA2)in lung tissues were determined by immunofluorescence.Results The MPA,LAP,PVR in group M and I were significantly higher than those in groups C and S,where as group M was significantly higher than that in group I(P<0.05).Middle layer of pulmonary artery in group M and I were significantly thicker than group C and S,and group M was thicker than group I(P<0.05).PAI-1 expression of group M and I were higher than group C and S,while group M was significantly higher than group I(P<0.05).Expression of ET-1 and TXA2 in lung tissue of group M and I were higher than group C and S,and group M was significantly higher than that of group I(P<0.05).Conclusion PAI-1 inhibitor IMD-1622 can reduce the thickness of the middle layer of pulmonary artery,so that improve the pulmonary hypertension caused by left heart disease.