MCC950在野百合碱诱导大鼠肺动脉高压模型中的治疗作用及其机制研究

doi:10.3969/j.issn.1006-7795.2018.06.014

首都医科大学学报 ›› 2018, Vol. 39 ›› Issue (6): 871-876.doi: 10.3969/j.issn.1006-7795.2018.06.014

MCC950在野百合碱诱导大鼠肺动脉高压模型中的治疗作用及其机制研究

齐先梅¹, 王蕾¹, 张瑞恒², 柳婷¹, 刘杰¹, 杨汀³, 王军¹, 张知非¹, 王辰^1,4

1. 首都医科大学呼吸病学系, 北京 100069;
2. 首都医科大学基础医学院, 北京 100069;
3. 北京中日友好医院呼吸与危重症医学科, 北京 100029;
4. 中国医学科学院北京协和医学院, 北京 100730

收稿日期:2018-03-04 出版日期:2018-11-21 发布日期:2018-12-19
通讯作者: 张知非 E-mail:Zhifeiz@ccmu.edu.cn
基金资助:
国家自然科学基金（81570695），北京市自然科学基金（7182014）。

Rapeutic effect of MCC950 on monocrotaline induced rat pulmonary arterial hypertension and mechanism

Qi Xianmei¹, Wang Lei¹, Zhang Ruiheng², Liu Ting¹, Liu Jie¹, Yang Ting³, Wang Jun¹, Zhang Zhifei¹, Wang Chen^1,4

1. Department of Respirology, Capital Medical University, Beijing 100069, China;
2. School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China;
3. Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, China;
4. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China

Received:2018-03-04 Online:2018-11-21 Published:2018-12-19
Supported by:
This study was supported by National Natural Science Foundation of China (81570695), Natural Science Foundation of Beijing (7182014).

摘要/Abstract

摘要： 目的探讨MCC950是否可缓解野百合碱（monocrotaline，MCT）诱导的大鼠肺动脉高压。方法雄性SD大鼠27只，采用数字表法随机分为对照组、MCT组和MCT+MCC950 3组，MCT+MCC950组于腹腔注射MCT第16天给予MCC950干预，每2 d 1次，共7次。至第31天，检测右心室收缩压、右心肥厚指数；观察肺细小动脉结构，计算血管中膜厚度百分比（media thickness，MT%），检测肺组织中NLRP3、白介素-1β（interleukin-1β，IL-1β）和相关分子的mRNA及蛋白表达情况。结果与对照组比较，MCT组RVSP升高显著［（50.72±3.65）mmHg（1 mmHg=0.133 kPa） vs（24.29±1.28）mmHg，P=0.000］，而MCT+MCC950组与MCT组相比显著降低［（34.19±1.94）mmHg vs（50.72±3.65）mmHg，P<0.01］。对照组右心肥厚指数为0.29±0.01，MCT组（0.61±0.04）明显较高，差异有统计学意义（P=0.000），MCT+MCC950组与MCT组相比降低（0.48±0.03 vs 0.61±0.04，P<0.01）。与对照组比较，MCT组大鼠各级肺血管MT%均显著增高（P=0.000），MCT+MCC950组与MCT组相比降低，且差异有统计学意义（P<0.01）。MCT组大鼠肺组织中NLRP3、IL-1β和相关分子的mRNA及蛋白表达较对照组均上调，而MCT+MCC950组肺组织中NLRP3、IL-1β和相关分子的表达量与MCT组相比均降低。结论 MCC950可能通过抑制NLRP3信号通路明显改善肺血管重塑，延缓肺动脉高压进程，具应用于肺动脉高压治疗的潜在价值。

关键词: 肺动脉高压, MCC950, NLRP3

Abstract: Objective To explore the effect of MCC950, selective inhibitor of NLRP3 inflammasome, on the development of pulmonary hypertension. Methods Male Sprague-Dawley rats were divided into 3 groups:control group, monocrotaline (MCT) group and MCT+MCC950 group. The right ventricular systolic pressure (RVSP), the index of right ventricular hypertrophy (RVHI) and lung morphological feature were assessed. The level of NLRP3, IL-1β and other molecular in lung were assessed by Western blotting and RT-PCR. Results The RVSP, RVHI and the remodeling of the small arteries in the MCT group were significantly higher than control group[(50.72±3.65)mmHg (1 mmHg=0.133 kPa) vs (24.29±1.28)mmHg, P=0.000] and (0.29±0.01 vs 0.61±0.04, P=0.000); while decreased after using MCC950 compared with MCT group[(34.19±1.94)mmHg vs (50.72±3.65)mmHg, P<0.01] and (0.48±0.03 vs 0.61±0.04, P<0.01). The protein expression level and the transcription of NLRP3, IL-1β and other molecular in lung of MCT group were increased. The administration of MCC950 decreased the protein expression level and the transcription of NLRP3, IL-1β and other molecular compared to MCT group. Conclusion MCC950 may attenuates pulmonary vascular remodeling and delaying the process of pulmonary hypertension by inhibit NLRP3 signaling pathway, which has the potential value of use in the treatment of pulmonary hypertension.

Key words: pulmonary hypertension, MCC950, NLRP3

中图分类号:

R543.2

齐先梅, 王蕾, 张瑞恒, 柳婷, 刘杰, 杨汀, 王军, 张知非, 王辰. MCC950在野百合碱诱导大鼠肺动脉高压模型中的治疗作用及其机制研究[J]. 首都医科大学学报, 2018, 39(6): 871-876.

Qi Xianmei, Wang Lei, Zhang Ruiheng, Liu Ting, Liu Jie, Yang Ting, Wang Jun, Zhang Zhifei, Wang Chen. Rapeutic effect of MCC950 on monocrotaline induced rat pulmonary arterial hypertension and mechanism[J]. Journal of Capital Medical University, 2018, 39(6): 871-876.

参考文献

[1] Kumar R, Graham B. How does inflammation contribute to pulmonary hypertension?[J]. Eur Respirat J, 2018, 51(1):pii.
[2] Latz E, Xiao T S, Stutz A. Activation and regulation of the inflammasomes[J]. Nat Revis Immunol, 2013, 13(6):397-411.
[3] Gharagozloo M, Gris K V, Mahvelati T, et al. NLR-dependent regulation of inflammation in multiple sclerosis[J]. Front Immunol, 2017, 8(1):2012.
[4] Gong T, Yang Y, Jin T, et al. Orchestration of NLRP3 inflammasome activation by ion fluxes[J]. Trends Immunol, 2018, 39(5):393-406.
[5] 柳婷,刘亚飞,王望,等. 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[J]. 首都医科大学学报, 2015, 5(36):723-728.
[6] Coll R C, Robertson A A, Chae J J, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases[J]. Nat Med, 2015, 21(3):248-255.
[7] Ye X, Zuo D, Yu L, et al. ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia[J]. Biochem Biophysi Research Communicat, 2017, 485(2):499-505.
[8] Kuebler W M, Bonnet S, Tabuchi A. Inflammation and autoimmunity in pulmonary hypertension:is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)[J]. Pulm Circ, 2018, 8(2):2045893218757596.
[9] Hassoun P M, Mouthon L, Barbera J A, et al. Inflammation, growth factors, and pulmonary vascular remodeling[J]. J Am Coll Cardiol, 2009, 54(Suppl 1):S10-S19.
[10] Tang B, Chen G X, Liang M Y, et al. Ellagic acid prevents monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats[J]. Int J Cardiol, 2015, 180:134-141.
[11] Ren H, Kong Y, Liu Z, et al. Selective NLRP3(pyrin domain-containing protein 3) inflammasome inhibitor reduces brain injury after intracerebral hemorrhage[J]. Stroke, 2018, 49(1):184-192.
[12] Dinarello C A, van der Meer J W M. Treating inflammation by blocking interleukin-1 in humans[J]. Semin Immunol, 2013, 25(6):469-484.

MCC950在野百合碱诱导大鼠肺动脉高压模型中的治疗作用及其机制研究

Rapeutic effect of MCC950 on monocrotaline induced rat pulmonary arterial hypertension and mechanism

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 12

编辑推荐

Metrics

本文评价

[1]	范正阳, 谢江, 李菲, 王婧婷, 帕提古丽·依司拉木, 孙丹册. 睡眠重叠综合征患者发生肺动脉高压的相关因素调查[J]. 首都医科大学学报, 2020, 41(3): 482-487.
[2]	沙宇惠, 高阳, 刘杰, 齐先梅, 韩璐璐, 王望. 卵泡抑素样蛋白1促进肺动脉内皮细胞增生、黏附与血管生成[J]. 首都医科大学学报, 2020, 41(1): 80-86.
[3]	刘萍, 娄可, 文隆, 李慧, 汤渝玲. 氧化应激介导NLRP3炎性反应小体对慢性阻塞性肺疾病的影响研究[J]. 首都医科大学学报, 2020, 41(1): 131-136.
[4]	高阳, 刘杰, 王蕾, 张炜, 刘亚飞, 齐先梅, 王望. 两种低氧性肺动脉高压小鼠模型的建立与比较[J]. 首都医科大学学报, 2018, 39(4): 563-568.
[5]	柳婷, 刘亚飞, 王望, 柴三葆, 刘杰, 王军. 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[J]. 首都医科大学学报, 2015, 36(5): 723-728.
[6]	刘杰, 杜雨轩, 王望, 国桓, 王军, 王辰. 雷帕霉素对野百合碱诱导的大鼠肺动脉高压及肺血管重构的影响[J]. 首都医科大学学报, 2013, 34(4): 554-558.
[7]	李晶;王辰;刘杰;李积凤;;刘岩;顾松;杨媛华;翟振国;甘辉立;王军;. 慢性血栓栓塞性肺动脉高压患者肺血管平滑肌细胞膜电位的改变[J]. 首都医科大学学报, 2011, 32(2): 208-213.
[8]	李积凤;王辰;王军. 纤维蛋白原编码区SNP与血栓性疾病的关系及机制[J]. 首都医科大学学报, 2010, 31(5): 558-562.
[9]	王丛;王辰;王跃秀;刘杰;李积凤;王军. 内皮素通过增强库容性钙内流促进肺血管平滑肌细胞增生[J]. 首都医科大学学报, 2009, 30(2): 161-166.
[10]	李积凤;王丛;刘杰;王跃秀;王军;王辰. 低氧通过Ca²⁺-NFAT信号通路促进肺动脉平滑肌细胞增生[J]. 首都医科大学学报, 2009, 30(2): 172-176.
[11]	于晓敏;王辰;王军. Wnt信号通路的生物学效应及其与肺部疾病的关系[J]. 首都医科大学学报, 2009, 30(2): 182-184.
[12]	张红;周其文;温绍君;孟旭. 先心病合并重度肺动脉高压围术期白细胞相关体液因素在肺损伤中的作用[J]. 首都医科大学学报, 2002, 23(2): 162-165.