摘要
目的：探讨球囊损伤大鼠颈动脉白介素-18(IL-18)的表达及阿托伐他汀对球囊损伤后平滑肌增生的抑制作用和对IL-18在损伤血管中表达的调节,为血管再狭窄治疗提供新的治疗途径。
方法：40只雄性SD大鼠,随机分组为假手术组、球囊损伤组和阿托伐他汀治疗组,建立大鼠颈动脉损伤模型。假手术组、球囊损伤组用生理盐水灌胃。阿托伐他汀治疗组以5 mg/kg/d灌胃。三组大鼠颈动脉分别在第3天、第7天及第21天取材,行形态学观察；荧光定量PCR检测组织IL-18的mRNA表达；酶联免疫吸附法(ELISA)检测血清中IL-18的含量。
结果：①形态学观察：假手术组血管内膜仅为一层扁平的内皮细胞,中层平滑肌细胞呈梭形,中膜弹力膜完整。球囊损伤后第3天,可见少量新生内皮细胞呈高柱状、核浓染。内膜下有出血,弹力膜中断。损伤后第7天,可见新生内膜非均匀增厚,多由平滑肌细胞形成；血管中膜平滑肌细胞增殖明显。损伤第21天时血管管腔狭窄。阿托伐他汀治疗组与同期损伤组相比,新生内膜增殖较轻。②荧光定量PCR检测IL-18的表达：在血管损伤后3天,损伤组和假手术组相比,IL-18的mRNA的表达升高(2.01±0.78 vs 0.97±0.19ng／ml,P<0.05)；阿托伐他汀干预后,较损伤组相比,IL-18的mRNA的表达降低(1.29±0.39 vs 2.01±0.78 ng／ml,P<0.05),较假手术组无统计学差异(1.29±0.39 vs 0.97±0.19 ng／ml,P>0.05)；在血管损伤后7天,损伤组和假手术组相比,IL-18的mRNA的表达升高(2.98±0.60 vs 1.06±0.33 ng／ml,P<0.05)；阿托伐他汀干预后,较损伤组相比,IL-18的mRNA的表达降低(2.13±0.51 vs 2.98±0.60 ng／ml,P<0.05),而较假手术组表达仍较高(2.13±0.51 vs 1.06±0.33 ng／ml,P<0.05)；在血管损伤后21天,损伤组和假手术组相比,IL-18的mRNA的表达仍升高(1.43±0.25 vs1.03±0.21 ng／ml,P<0.05)；阿托伐他汀干预后,较损伤组相比,IL-18的mRNA的表达降低(0.99±0.18 vs 1.43±0.25,ng／ml P<0.05),较假手术组则无统计学差异(0.99±0.18 vs 1.03±0.21 ng／ml,P>0.05)。③酶联免疫吸附法(ELISA)检测血清中IL-18的含量：在血管损伤后3天,损伤组和假手术组相比,IL-18的表达明显增高(248.45±26.75 vs 21.23±6.14ng／ml,P<0.05)；阿托伐他汀干预后,较损伤组相比,IL-18明显降低(77.03±20.68 vs 248.45±26.75ng／ml,P<0.05),较假手术组IL-18的表达仍较高(77.03±20.68 vs 21.23±6.14ng／ml,P<0.05)；在血管损伤后7天,损伤组和假手术组相比,IL-18的表达明显增高(339.90±101.26 vs 30.72±3.88ng／ml,P<0.05)；阿托伐他汀干预后,较损伤组相比,IL-18的表达明显降低(199.13±56.00 vs339.90±101.26ng／ml,P<0.05),而较假手术组表达仍较高(199.13±56.00 vs30.72±3.88ng／ml,P<0.05)；在血管损伤后21天,损伤组和假手术组相比,IL-18的表达仍升高(39.23±13.83 vs 18.23±5.30ng／ml,P<0.05)；阿托伐他汀干预后,较损伤组相比,IL-18的表达降低(19.83±0.40 vs 39.23±13.83ng／ml,P<0.05),较假手术组无统计学差异(19.83±0.40 vs 18.23±5.30ng／ml,P>0.05)。
结论：大鼠颈动脉血管球囊损伤后的早期血清IL-18升高明显,说明损伤早期炎症因子参与了刺激平滑肌增殖的过程。而阿托伐他汀可抑制血管损伤早期的炎症反应和炎症因子的表达,可下调IL-18,抑制平滑肌增殖,对预防血管损伤后增殖性病变有一定价值。这将为临床防治介入治疗后血管再狭窄提供了一种新的理论和方法。
Objective:To investigate the expression of IL -18 in vascular tissue of rat carotid arteries after balloon injury, and the explore the effect of atorvastatin on the smooth muscle proliferation after balloon injury and on the inhibition of IL-18 expression in vascular injury.
Methods: Forty male SD rats were randomly assigned into sham operation group,balloon injury group and atorvastatin treatment group. The rat carotid artery injury model, sham operation group and balloon injury group were with normal saline. The dosage of atorvastatin treatment group was 5 mg/kg/d. Three groups of rat carotid arteries at 3rd day,7th day,21th day were obtained for morphological observation, real-time Quantitative PCR detection of mRNA expression of IL-18 and Enzyme-linked immunosorbent assay (ELISA) in serum IL-18's expression.
Results:①Mrphology observation:In sham operation group, intima were only a layer of flat endothelial cells, medial smooth muscle cells were spindle, middle elastic membrane is intact. On 3rd day after balloon injury, a small amount of new endothelial cells were high columnar and nuclear were stain with subintimal bleeding and elastic membrane disruption. On 7th day after balloon injury showed non-uniform thickening of the neointima and mostly were made up by smooth muscle cells,vascular smooth muscle cell proliferated in the clear. On 21th day after balloon injury was artery stenosis. Atorvastatin treatment group which compared with the same injury were less neointimal proliferation.②Real-time Quantitative PCR detection of IL-18 expression:On 3rd day after balloon injury, injury group compared with sham operation group, IL-18 mRNA expression increased(2.01±0.78 vs 0.97±0.19 ng/ml, P <0.05);Atorvastatin treatment group compared with injury group, could decreased the IL-18 mRNA expression(1.29±0.39 vs 2.01±0.78 ng/ml, P <0.05),and compared with sham group was no difference in statistics(1.29±0.39vs 0.97±0.19 ng/ml, P> 0.05);On 7th day after balloon injury, injury group compared with sham operation group, IL-18 mRNA expression increased (2.98±0.60 vs 1.06±0.33 ng/ml, P<0.05);Atorvastatin treatment group compared with injury group, could decreased the IL-18 mRNA expression(2.13±0.51 vs 2.98±0.60 ng/ml, P<0.05),but atorvastatin treatment group was still higher(2.13±0.51 vs 1.06±0.33, P<0.05);On 21th day after balloon injury, injury group compared with sham operation group,IL-18 mRNA expression increased(1.43±0.25 vs 1.03±0.21 ng/ml, P <0.05);Atorvastatin treatment group compared with injury group,could decreased the IL-18 mRNA expression(0.99±0.18 vs 1.43±0.25 ng/ml, P<0.05),compared with sham group was not difference in statistics(0.99±0.18 vs 1.03±0.21 ng/ml, P> 0.05)③ELISA detection of IL-18 levels in serum:On 3rd day after balloon injury, injury group compared with sham operation group, IL-18 levels in serum increased(248.45±26.75 vs 21.23±6.14ng/ml, P<0.05);Atorvastatin treatment group compared with injury group, could decreased IL-18 levels in serum(77.03±20.68 vs 248.45±26.75ng/ml, P <0.05),but the levels of IL-18 in serum is higher than sham operation group(77.03±20.68 vs 21.23±6.14ng/ml, P <0.05);On 7th day after balloon injury, injury group compared with sham operation group, IL-18 levels in serum increased(339.90±101.26 vs 30.72±3.88ng/ml, P<0.05);Atorvastatin treatment group compared with injury group, could decreased IL-18 levels in serum(199.13±56.00 vs 339.90±101.26ng/ml, P<0.05), but the levels of IL-18 in serum is higher than sham operation group(199.13±56.00 vs 30.72±3.88ng/ml, P<0.05);On 21th day after balloon injury, injury group compared with sham operation group, IL-18 levels in serum increased(39.23±13.83 vs 18.23±5.30ng/ml, P<0.05);Atorvastatin treatment group compared with injury group, could decreased IL-18 levels in serum(19.83±0.40 vs 39.23±13.83ng/ml, P<0.05),compared with sham operation group was no difference in statistics(19.83±0.40 vs 18.23±5.30ng/ml, P>0.05).
Conclusions:IL-18 levels of rat carotid arteries after balloon injury in early serum increased significantly, showed that IL-18 could stimulate smooth muscle cells proliferation. Atorvastatin inhibits inflammatory vascular injury and the early expression of inflammatory factors, can reduce the expression of IL-18 mRNA, inhibit smooth muscle cell proliferation and prevent proliferative lesions after vascular injury. This will provide a new theory and methods for prevention and treatment of restenosis,
引文
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