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目的观察低氧性肺动脉高压大鼠肺组织中骨形成蛋白2(BMP-2)的变化及 BMP 在低氧诱导内皮细胞凋亡中的作用,探讨 BMP 在低氧性肺动脉高压发病中的作用。方法将20只雄性 Wistar 大鼠随机分为2组,低氧组经常压低氧处理3周,建立大鼠低氧性肺动脉高压模型,采用免疫组织化学染色法观察大鼠肺组织中 BMP-2的表达。用图像分析技术检测大鼠肺小动脉形态改变及 BMP-2表达强度的变化。建立人脐静脉内皮细胞(HUVEC)低氧培养模型,加入 BMP 阻断剂Noggin,用流式细胞仪检测细胞凋亡率。结果低氧3周后,大鼠平均肺动脉压(mPAP)为(29.5±0.9)mm Hg(1 mm Hg=0.133 kPa),与对照组的(16.3±0.5)mm Hg 比较明显增加;低氧大鼠肺小动脉管壁增厚、管腔狭窄,表现为管壁厚度占外径的百分比(WT%)和管壁面积占血管总面积的百分比(WA%)明显升高,分别为(27±7)%和(80±8)%,对照组分别为(16±5)%和(54±11)%,两组相比差异有统计学意义(P<0.01);低氧组肺小动脉壁 BMP-2积分吸光度值(IA)为13 463±5755,对照组为6124±1199,两组相比差异有统计学意义(P<0.01),且与 WT%和 WA%呈明显正相关(r 值分别为0.744和0.693,P<0.01)。低氧诱导内皮细胞凋亡增加,低氧24 h 时的细胞凋亡率为(14.23±1.01)%,48 h 时为(25.21±8.58)%;低氧前预先加入 Noggin,低氧24 h 时细胞凋亡率为(11.91±0.57)%,48 h 时为(15.01±0.15)%,差异有统计学意义(P<0.01)。结论慢性低氧时 BMP-2表达增多;低氧诱导内皮细胞凋亡,BMP 阻断剂可抑制低氧诱导的内皮细胞凋亡;BMP 在低氧性肺动脉高压发病过程中起一定的作用。
Objective To observe the changes of bone morphogenetic protein 2 (BMP-2) and the role of BMP in endothelial cell apoptosis induced by hypoxia in hypoxic pulmonary hypertensive rats and explore the role of BMP in the pathogenesis of hypoxic pulmonary hypertension. Methods Twenty male Wistar rats were randomly divided into 2 groups. Hypoxia group was treated with hypoxia for 3 weeks. Hypoxic pulmonary hypertension model was established. Immunohistochemical staining was used to observe the expression of BMP-2 expression. Image analysis was used to detect the morphological changes of pulmonary arterioles and the expression of BMP-2 in rats. Hypoxic culture model of human umbilical vein endothelial cells (HUVEC) was established, and BMP antagonist Noggin was added to detect apoptosis rate by flow cytometry. Results After 3 weeks of hypoxia, mean pulmonary arterial pressure (mPAP) in rats was (29.5 ± 0.9) mm Hg (1 mm Hg = 0.133 kPa), which was significantly higher than that of the control group (16.3 ± 0.5) mm Hg. The thickening of the pulmonary arterioles and the narrowing of the lumen showed the percentage of the wall thickness to the outer diameter (WT%) and the percentage of the wall area to the total vascular area (WA%), which were (27 ± (16 ± 5)% and (54 ± 11)% respectively in the control group (P <0.01). In the hypoxia group, pulmonary arterioles The integral absorbance (IA) of the wall was 13 463 ± 5 755 in the wall and 6124 ± 1199 in the control group, the difference was statistically significant (P <0.01), and positively correlated with WT% and WA% r values were 0.744 and 0.693, P <0.01). Hypoxia induced apoptosis of endothelial cells. The rate of apoptosis was (14.23 ± 1.01)% at 24 h after hypoxia and (25.21 ± 8.58)% at 48 h. Noggin was added before hypoxia and 24 h after hypoxia The apoptotic rates were (11.91 ± 0.57)% and (15.01 ± 0.15)% at 48 h, respectively. The difference was statistically significant (P <0.01). Conclusion The expression of BMP-2 is increased in chronic hypoxia. Hypoxia induces endothelial cell apoptosis. BMP blockers can inhibit hypoxia-induced endothelial cell apoptosis. BMP plays a role in the pathogenesis of hypoxic pulmonary hypertension.