阿托伐他汀对大鼠野百合碱肺动脉高压模型肺组织P38MAPK表达的影响
摘要
目的：观察野百合碱(MCT)诱导的肺动脉高压大鼠肺组织P38MAPK的表达及阿托伐他汀对它的影响，探讨P38MAPK在MCT诱导的肺动脉高压发病中的可能作用。
方法：将24只健康雄性SD大鼠随机分为正常对照组(n=8)，MCT诱导的肺动脉高压组(MCT组，n=8)，阿托伐他汀干预组(AS组，n=8)。MCT组和AS组(阿托伐他汀干预组)分别一次性腹部皮下注射MCT(60mg／kg)，对照组以等量生理盐水代替。AS组自注射MCT之日起以阿托伐他汀(10mg／kg)灌胃，每日一次。MCT组以生理盐水(10ml／kg)每日灌胃。3周后达实验终点测定大鼠平均肺动脉压(mPAP)、平均颈动脉压(mCAP)，计算右心室肥大指数(RVHI)。肺组织切片进行苏木素-伊红(HE)染色，光镜下观察肺组织形态学的改变，并计算肺中小动脉管壁厚度占血管外径的百分比(WT％)和肺动脉管壁面积／管总面积的百分比(WA％)，以此反映肺血管重建情况。采用免疫组化法观察大鼠肺组织P38MAPK表达的变化。
结果：
1．MCT组大鼠的mPAP和RVHI均显著高于对照组(P＜0.01)，而AS组大鼠的mPAP和RVHI均较MCT组明显降低(P＜0.01)，但AS组大鼠的mPAP和RVHI均较对照组明显增高(P＜0.05)。三组大鼠的mCAP没有明显差别(P均＞0.05)。
2．对照组大鼠肺中小动脉管壁薄，管腔大；MCT组大鼠肺中小动脉，管壁厚度明显增加，管腔面积明显变小，伴有明显的血管周围炎；AS组大鼠肺中小动脉管壁厚度较MCT组明显减小，管腔面积较MCT组明显增大，血管周围炎明显减轻。
3．MCT组大鼠肺中小动脉WT％和WA％均明显高于对照组(P＜0.01)，AS组大鼠肺中小动脉WT％和WA％均明显低于MCT组(P＜0.01)，但AS组大鼠肺中小动脉WT％和WA％均明显高于对照组(P＜0.01)。
4、MCT组大鼠的肺血管内皮P38MAPK的表达显著高于对照组(P＜0.01)，而AS组大鼠的肺血管内皮P38MAPK的表达与对照组无明显差别(P＞0.05)。
结论：阿托伐他汀可抑制MCT诱导的肺血管内皮P38MAPK的表达，减轻肺部炎症及肺动脉高压。
Objective: To investigate the effect of atorvastatin on monocrotaline(MCT)-induced rats pulmonary hypertension and the expression ofP38MAPK in lung.
Methods: Twenty-four male SD rats were randomly divided intothree groups with eight rats each group: control group, MCT group andatorvastatin group (AS group). The rats in MCT and AS group wereinjected with 60mg/kg of MCT subcutaneously and the rats in controlgroup were injected with saline. Atorvastatin (10mg/kg/d) were givenorally for 21 days to the rats in AS groups and vehicle were given to therats in MCT group since the day when rats were injected MCT. At 22days, mean pulmonary arterial pressure (mPAP), mean carotid pressure(reCAP) and right ventricular hypertrophy index (RVHI) were measured.The index of wall thickness of pulmonary arteriole was measured by acomputerized image analyzer. The expression of P38MAPK in lung wasobserved by immunohistochemistry.
Results:
1. The mPAP and RVHI were increased significantly in MCT groupthan that in control group (P＜0.01). This increase in mPAP and RVHI waspartially prevented by atorvastatin (P＜0.01). There was no significant discrepancy on mCAP between three groups (P＞0.05).
2. The thickness of the medial wall of pulmonary medial arteries andarteriole was significantly increased in MCT group as compared withcontrol group. Large numbers inflammatory cells congregated around thesmall vascular and in the pulmonary interstitial in MCT group.Atorvastatin treatment was associated with a significant reduction ofMCT-induced thickening and the number of inflammatory cells.
3. WT% and WA% of pulmonary medial arteries and arteriole wereincreased significantly in MCT group than that in control group (P＜0.01).This increase in WT% and WA% was partially prevented by atorvastatin(P＜0.01).
4. The expression of P38MAPK in pulmonary vascular endothelialcells were increased significantly in MCT group than that in controlgroup (P＜0.01). There was no significant discrepancy on the expressionof P38MAPK between AS and control group (P＞0.05).
Conclusions: Atorvastatin could inhibit MCT-induced P38MAPKexpression of pulmonary vascular endothelial cells, prevent inflammatoryresponse in lung and the development of pulmonary hypertension.
方法：将24只健康雄性SD大鼠随机分为正常对照组(n=8)，MCT诱导的肺动脉高压组(MCT组，n=8)，阿托伐他汀干预组(AS组，n=8)。MCT组和AS组(阿托伐他汀干预组)分别一次性腹部皮下注射MCT(60mg／kg)，对照组以等量生理盐水代替。AS组自注射MCT之日起以阿托伐他汀(10mg／kg)灌胃，每日一次。MCT组以生理盐水(10ml／kg)每日灌胃。3周后达实验终点测定大鼠平均肺动脉压(mPAP)、平均颈动脉压(mCAP)，计算右心室肥大指数(RVHI)。肺组织切片进行苏木素-伊红(HE)染色，光镜下观察肺组织形态学的改变，并计算肺中小动脉管壁厚度占血管外径的百分比(WT％)和肺动脉管壁面积／管总面积的百分比(WA％)，以此反映肺血管重建情况。采用免疫组化法观察大鼠肺组织P38MAPK表达的变化。
结果：
1．MCT组大鼠的mPAP和RVHI均显著高于对照组(P＜0.01)，而AS组大鼠的mPAP和RVHI均较MCT组明显降低(P＜0.01)，但AS组大鼠的mPAP和RVHI均较对照组明显增高(P＜0.05)。三组大鼠的mCAP没有明显差别(P均＞0.05)。
2．对照组大鼠肺中小动脉管壁薄，管腔大；MCT组大鼠肺中小动脉，管壁厚度明显增加，管腔面积明显变小，伴有明显的血管周围炎；AS组大鼠肺中小动脉管壁厚度较MCT组明显减小，管腔面积较MCT组明显增大，血管周围炎明显减轻。
3．MCT组大鼠肺中小动脉WT％和WA％均明显高于对照组(P＜0.01)，AS组大鼠肺中小动脉WT％和WA％均明显低于MCT组(P＜0.01)，但AS组大鼠肺中小动脉WT％和WA％均明显高于对照组(P＜0.01)。
4、MCT组大鼠的肺血管内皮P38MAPK的表达显著高于对照组(P＜0.01)，而AS组大鼠的肺血管内皮P38MAPK的表达与对照组无明显差别(P＞0.05)。
结论：阿托伐他汀可抑制MCT诱导的肺血管内皮P38MAPK的表达，减轻肺部炎症及肺动脉高压。
Objective: To investigate the effect of atorvastatin on monocrotaline(MCT)-induced rats pulmonary hypertension and the expression ofP38MAPK in lung.
Methods: Twenty-four male SD rats were randomly divided intothree groups with eight rats each group: control group, MCT group andatorvastatin group (AS group). The rats in MCT and AS group wereinjected with 60mg/kg of MCT subcutaneously and the rats in controlgroup were injected with saline. Atorvastatin (10mg/kg/d) were givenorally for 21 days to the rats in AS groups and vehicle were given to therats in MCT group since the day when rats were injected MCT. At 22days, mean pulmonary arterial pressure (mPAP), mean carotid pressure(reCAP) and right ventricular hypertrophy index (RVHI) were measured.The index of wall thickness of pulmonary arteriole was measured by acomputerized image analyzer. The expression of P38MAPK in lung wasobserved by immunohistochemistry.
Results:
1. The mPAP and RVHI were increased significantly in MCT groupthan that in control group (P＜0.01). This increase in mPAP and RVHI waspartially prevented by atorvastatin (P＜0.01). There was no significant discrepancy on mCAP between three groups (P＞0.05).
2. The thickness of the medial wall of pulmonary medial arteries andarteriole was significantly increased in MCT group as compared withcontrol group. Large numbers inflammatory cells congregated around thesmall vascular and in the pulmonary interstitial in MCT group.Atorvastatin treatment was associated with a significant reduction ofMCT-induced thickening and the number of inflammatory cells.
3. WT% and WA% of pulmonary medial arteries and arteriole wereincreased significantly in MCT group than that in control group (P＜0.01).This increase in WT% and WA% was partially prevented by atorvastatin(P＜0.01).
4. The expression of P38MAPK in pulmonary vascular endothelialcells were increased significantly in MCT group than that in controlgroup (P＜0.01). There was no significant discrepancy on the expressionof P38MAPK between AS and control group (P＞0.05).
Conclusions: Atorvastatin could inhibit MCT-induced P38MAPKexpression of pulmonary vascular endothelial cells, prevent inflammatoryresponse in lung and the development of pulmonary hypertension.
引文
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