吸入CDDO⁃NO对野百合碱诱导的大鼠肺动脉高压的作用
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R544.16

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国家科技重大专项(2018ZX10722301-002);国家自然科学基金(81870054,81273571);江苏省卫生厅重点项目(H201601)


Effects of inhaled CDDO ⁃NO on monocrotaline ⁃induced pulmonary arterial hypertension in rats
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    摘要:

    目的:研究吸入新型一氧化氮供体型甲基巴多索隆(bardoxolone methyl,CDDO-Me)衍生物CDDO-NO对野百合碱 (monocrotaline,MCT)诱导大鼠肺动脉高压(pulmonary arterial hypertension,PAH)的作用。方法:SD雄性大鼠随机分为6组,对照组(Con 组)、MCT 组、MCT+10 μg/kg CDDO-NO 组(MCT+10NO 组)、MCT+30 μg/kg CDDO-NO 组(MCT+30NO 组),以及 MCT+7 μg/kg CDDO-Me组(MCT+7Me组)和MCT+21 μg/kg CDDO-Me组(MCT+21Me组)。MCT组及各治疗组均给予60 mg/kg MCT腹腔注射造模,CDDO-NO及CDDO-Me治疗组在MCT注射1 h后通过口鼻暴露式雾化吸入装置给药。连续雾化吸入给药 28 d后,右心导管测量大鼠右心室收缩压(right ventricular systolic pressure,RVSP),计算右心室肥厚指数(right ventricular hyper- trophy index,RVHI)和大鼠右室/体重比(RV-to-body weight ratio,RV/BW)。苏木素伊红(hematoxylin-eosin,HE)染色检测肺小动脉中膜层厚度(pulmonary artery medial thickness,PAMT)及右心室心肌细胞横截面积(cross-sectional area,CSA),马松三色染色(masson trichrome staining,MTS)评估肺小动脉周围纤维化程度,α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)免疫组化染色检测肺小动脉肌化程度。结果:血流动力学及右室重构指标显示,吸入CDDO-NO或CDDO-Me均可降低MCT诱导PAH大鼠的RVSP、RVHI和RV/BW升高,其中30 μg/kg CDDO-NO降低RVHI和RV/BW的效应优于等量母体化合物CDDO-Me(21 μg/kg)。 此外,病理学研究显示,吸入30 μg/kg CDDO-NO改善MCT诱导的PAH模型大鼠右室心肌细胞肥大和肺血管中膜层肥厚、降低完全肌化型血管比例及肺血管外膜胶原沉积的效果较等量母体化合物CDDO-Me(21 μg/kg)更佳。结论:吸入CDDO-NO可通过抑制肺血管重构减轻MCT诱导的大鼠PAH,效果优于母体化合物CDDO-Me,是一种治疗PAH的潜在化合物。

    Abstract:

    Objective:This study aims to investigate the effects of a novel hybrid compound CDDO -NO from bardoxolone methyl (CDDO-Me)and NO donor isosorbide 5-mononitrate on monocrotaline(MCT)-induced pulmonary arterial hypertension(PAH)in rats. Methods:Male Sprague-Dawley rats were randomly divided into 6 groups:control(Con)group,MCT group,MCT+10 μg/kg CDDO-NO (MCT+10NO)group,MCT+30 μg/kg CDDO-NO(MCT+30NO)group,MCT+7 μg/kg CDDO-Me(MCT+7Me)group and MCT+21 μg/kg CDDO-Me(MCT+21Me)group. PAH in rat was induced by a single dose injection of 60 mg/kg MCT intraperitoneally. The rats in each treatment groups were treated for daily aerosol CDDO -NO or CDDO -Me inhalation for 28 days. Right ventricular systolic pressure (RVSP)by right heart catheter,and right ventricular hypertrophy index(RVHI)as well as RV -to - body weight ratio(RV/BW)were measured. Hematoxylin-eosin(HE)staining was used to detect the pulmonary artery medial thickness(PAMT)and the morphological changes of the right ventricle. And α-smooth muscle actin(α-SMA)immunohistochemistry was used to investigate the muscularization of distal vessels. Masson’s trichrome staining(MTS)was performed to evaluate the fibrosis of arterioles. Results:Right heart catheter and right ventricular remodeling indicators showed that inhalation of either CDDO-NO or CDDO-Me suppressed elevations of RVSP, RVHI and RV/BW induced by MCT in PAH rats. CDDO-NO(30 μg/kg)showed stronger inhibitory effect in RVHI and RV/BW than that of the equal dose of parent compound CDDO-Me(21 μg/kg). Moreover,pathological studies indicated that 30 μg/kg CDDO-NO had better effects in alleviating right ventricular myocardial hypertrophy and PAMT,and reducing the proportion of fully muscularized vessels and the area of collagen deposition than those of CDDO-Me(21 μg/kg). Conclusion:Inhalation of CDDO-NO can ameliorate MCT-induced PAH in rats by inhibiting pulmonary vascular remodeling,and the effect of CDDO-NO is superior to parent compound CDDO-Me. These results suggest that CDDO-NO could be a promising drug for the treatment of PAH.

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伍雪橙,李南,黄文,周淑兰,周宏,黄张建,孔辉,解卫平.吸入CDDO⁃NO对野百合碱诱导的大鼠肺动脉高压的作用[J].南京医科大学学报(自然科学版),2022,42(9):1201-1208

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  • 在线发布日期: 2022-09-14
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