核因子-κB抑制剂PDTC在肺动脉高压中的作用

Effect of nuclear factor-κB inhibitor PDTC on pulmonary arterial hypertension

目的探讨核因子-κB(NF-κB)及其抑制剂吡咯烷二硫代氨基甲酸盐(PDTC)在野百合碱(MCT)所致肺动脉高压中的作用及其机制。方法大鼠腹腔注射MCT建立肺动脉高压模型,将58只Wistar大鼠随机分为MCT0组、MCT1W组、MCT2W组、MCT3W组、对照/盐水组、MCT/盐水组和MCT/PDTC组。采用右心导管法测定血流动力学指标,用免疫组化法检测细胞间粘附分子-1(ICAM-1)表达及巨噬细胞浸润情况,用电泳迁移率变动分析法(EMSA法)检测NF-κB活化情况。结果MCT注射后1周开始,大鼠肺组织ICAM-1的表达和巨噬细胞浸润明显增加(P<0.01),2周开始,平均右心室压力升高,右心肥厚指数增加(P<0.01)。与对照/盐水组相比,MCT/盐水组平均右心室压力、右心肥厚指数明显增加,NF-κB活化、ICAM-1表达及巨噬细胞浸润明显增多(P均<0.01)。与MCT/盐水组相比,MCT/PDTC组平均右心室压力、右心肥厚指数明显降低,NF-κB活化、ICAM-1表达及巨噬细胞浸润明显减少(P均<0.01)。结论NF-κB/ICAM-1介导的炎症级联反应参与了MCT诱导的肺动脉高压的发展,PDTC可抑制这一炎症反应,减轻肺动脉高压。

Objective To investigate changes and functions of nuclear factor-κB（NF-κB） and its inhibitor PDTC in monocrotaline（MCT）-induced pulmonary arterial hypertension（PAH）.Methods Pulmonary arterial hypertension rat models were established by injecting MCT toxin.A total of 58 Wistar rats were randomly divided into 7 groups ： the MCT0 group,the MCT1W group,the MCT2W group,the MCT3W group,the control/vehicle group,the MCT/ vehicle group,and the MCT/PDTC group.Hemodynamic studies were determined by right cardiac catheterization,activity of NF-κB was determined by EMSA,and expression of intercellular adhesion molecule-1（ICAM-1） and macrophage infiltration were determined by immunohistochemistry.Results ICAM-1 expression and macrophage infiltration were significantly up-regulated from week 1 after injection（P〈0.01）,and the mean right ventricular pressure and indexes of right ventricular hypertrophy increased from week 2 after injection（P〈0.01）.Compared with controls,MCT treatment increased the mean right ventricular pressure（27.8±1.5 mmHg vs 17.2±1.4 mmHg,P〈0.01）,which was reduced by PDTC treatment（18.4±2.2 mmHg,P〈0.01）.Indexes of right ventricular hypertrophy induced by MCT were similarly inhibited（P〈0.01） by PDTC treatment,which was associated with suppression of ICAM-1 expression and macrophage infiltration.Conclusion We conclude that NF-κB activity and ICAM-1 expression are probably associated with the development of MCT-induced PAH,which is ameliorated by administering a NF-κB inhibitor,PDTC.