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目的探讨抑制内质网应激肌醇必需酶-1(IRE-1)信号通路在野百合碱诱导大鼠肺动脉高压发生、发展中的作用机制。方法选择Wistar雄性大鼠,随机分为正常对照组、模型组、药物治疗组。采用一次性腹腔注射野百合碱的方法建立肺动脉高压模型。药物治疗组在建模2周后给予灌服4-苯基丁酸2周。检测各组大鼠血流动力学、病理形态学及IRE-1信号通路中关键因子葡萄糖调节蛋白78(GRP78)、IRE-1α的mRNA相对表达量。结果腹腔注射野百合碱建立肺动脉高压模型后,模型组平均肺动脉压力(m PAP)、平均右心室压力(mRVP)较正常对照组显著升高(P<0.001),病理肺血管重塑指标较正常对照组增高(P<0.001),GRP78和IRE-1αmRNA相对表达量较正常对照组升高(P<0.05,P<0.001)。经过化学分子伴侣4-苯基丁酸干预后,药物治疗组血流动力学指标较模型组减低(P<0.01),但未恢复到正常对照组水平(P<0.001);病理检测肺小动脉中膜厚度、管壁面积/管总面积与模型组相比减少(P<0.001),可恢复到正常对照组水平(P>0.05),右室肥厚指数与模型组相比减少(P<0.001),未恢复到正常对照组水平(P<0.001);GRP78、IRE-1α的mRNA相对表达量较模型组降低(P<0.05,P<0.001),可恢复到正常对照组水平(P>0.05)。结论内质网应激IRE-1信号通路在肺动脉高压发生、发展中发挥重要作用,通过化学分子伴侣4-苯基丁酸的抑制,可以有效降低肺动脉高压,减轻肺小动脉重塑。
Objective To investigate the mechanism of inhibition of endoplasmic reticulum intima-in-1 (IRE-1) signaling pathway in monocrotaline-induced pulmonary hypertension in rats. Methods Wistar male rats were randomly divided into normal control group, model group and drug treatment group. A one-time intraperitoneal injection of monocrotaline was used to establish a pulmonary hypertension model. Drug treatment groups were given 4-phenylbutyrate for 2 weeks after modeling for 2 weeks. The hemodynamics, pathomorphology and the relative expression of IRE-1α, the key factor of IRE-1 signal pathway, were detected in each group. Results After pulmonary lupus model was established by intraperitoneal injection of monocrotaline, the average pulmonary arterial pressure (m PAP) and mean RV pressure (mRVP) in model group were significantly higher than those in normal control group (P <0.001) Compared with the normal control group, the relative expression of GRP78 and IRE-1αmRNA increased (P <0.001, P <0.001). After the intervention of chemical molecular chaperone 4-phenylbutyric acid, the hemodynamic parameters of the drug-treated group were lower than those of the model group (P <0.01), but not restored to the level of the normal control group (P <0.001) The thickness of medial membrane and the total area of tube wall / tube decreased compared with model group (P <0.001), and returned to normal control group (P> 0.05). The index of right ventricular hypertrophy decreased compared with model group (P <0.001). The mRNA expression of GRP78 and IRE-1α in model group was lower than that in model group (P <0.05, P <0.001) ). Conclusion Endoplasmic reticulum stress IRE-1 signaling pathway plays an important role in the occurrence and development of pulmonary hypertension. Inhibition of chemical molecular chaperone 4-phenylbutyrate can effectively reduce pulmonary hypertension and alleviate remodeling of pulmonary arterioles.