格列本脲对野百合碱诱导的大鼠肺动脉高压的影响及其可能机制

The effect and mechanism of glyburide on monocrotaline-induced pulmonary hypertension in rats

目的初步探讨格列本脲对野百合碱诱导的大鼠肺动脉高压的作用及其可能机制。方法将8周雄性Sprague-Dawley(SD)大鼠采用数字表法随机分为3组:对照组、野百合碱组、野百合碱+格列本脲组。采用经颈静脉右心导管插管术检测大鼠右心室收缩压,计算右心室肥厚指数,HE染色观察肺血管重构,ELISA、Western blotting法检测Nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3(NLRP3)表达水平及白介素-1β(interleukin-1β,IL-1β)质量浓度。结果用药4周后,与对照组相比,野百合碱组大鼠右心室收缩压明显升高1.66倍(P<0.001),右心室肥厚指数显著增加2.15倍(P<0.001),肺血管中膜厚度增加1.20倍(P<0.001),肺组织NLRP3的表达升高1.57倍(P<0.05),血浆中IL-1β质量浓度明显升高[(1 915.82±316.47)pg/m L vs(118.29±27.60)pg/m L,P<0.001]。与野百合碱组相比,野百合碱+格列本脲组用药4周后右心室收缩压明显下降(33.60±5.14)%(P<0.05),右心室肥厚指数降低(18.26±9.23)%(P<0.05),肺血管中膜厚度减少(21.86±8.64)%(P<0.001),肺组织NLRP3的表达降低(55.96±19.33)%(P<0.01),血中IL-1β质量浓度明显降低[(396.64±237.19)pg/m L vs(1 915.82±316.47)pg/m L,P<0.001]。结论格列本脲可缓解野百合碱诱导的大鼠肺动脉高压,其机制可能与抑制NLRP3/IL-1β的表达有关。

Objective To investigate whether glyburide could prevent monocrotaline（ MCT）-induced pulmonary hypertension（ PH）via inhibiting nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3（ NLRP3） inflammasome activation in rats.Methods Male Sprague-Dawley（ SD） rats were divided into 3 groups： control group,MCT group and MCT ＋ glyburide group.Hemodynamic changes, right ventricular hypertrophy, and lung morphological features were assessed. The levels of NLRP3 and interleukin-1β（ IL-1β） were assessed by Western blotting and ELISA. Results Compared with control group,four weeks after MCT injection,the right ventricular systolic pressure（ RVSP）,the index of right ventricular hypertrophy（ RVHI） and the percentage of medial thickness（ MT%） of pulmonary artery significantly increased by 1. 66（ P〈0. 001）,2. 15（ P〈0. 001） and 1. 20 folds（ P〈0. 001）,respectively. Compared with MCT group,they reduced by（ 33. 60 ± 5. 14） %（ P〈0. 05）,（ 18. 26 ± 9. 23） %（ P〈0. 05） and（ 21. 86± 8. 64） %（ P〈0. 001） in MCT ＋ glyburide group. Compared with control group,the expression of NLRP3 in lung of MCT group increased by 1. 57 folds（ P〈0. 05）,while it decreased by（ 55. 96 ± 19. 33） %（ P〈0. 01） after using glyburide in 4 weeks. The serum level of IL-1β was higher in MCT group than that in control group [（ 1 915. 82 ± 316. 47） pg / m L vs（ 118. 29 ± 27. 60） pg / m L,P〈0. 001],while it was lower in MCT ＋ glyburide group than that in MCT group [（ 396. 64 ± 237. 19） pg / m L vs（ 1 915. 82 ± 316. 47） pg /m L,P〈0. 001]. Conclusion These results suggested that glyburide could ameliorate MCT-induced pulmonary hypertension that was mediated by the NLRP3 / IL-1β pathway.