辛伐他汀不同给药方式对大鼠肋骨骨折愈合的影响

发布时间：2018-06-29 08:41

本文选题：肋骨骨折 + 辛伐他汀　；参考：《山西医科大学》2017年硕士论文

【摘要】：目的:通过建立肋骨骨折大鼠模型,观察辛伐他汀不同给药方式(急性停药、逐步减量给药、持续给药)对大鼠骨折愈合的影响,探讨该类药物有无急性停药反跳,为临床合理利用他汀类药物治疗骨折提供实验依据。方法:48只10周龄雄性健康SD大鼠腹腔注射麻醉后,俯卧位手法扪及第六肋骨(切口位置:耳下缘2cm,脊柱旁约1.5cm),分层切开皮肤、皮下组织和肌肉,剥离骨膜,显露肋骨,眼科剪横向剪断肋骨,对位分层缝合。术后大鼠随机分为四组:对照组、给药1周组、减量给药组、给药4周组。对照组予以二甲基亚砜(Dimethyl Sulphoxide,DMSO)灌胃;给药1周组第一周10 mg/kg/d辛伐他汀(simvastatin,SIM)灌胃,剩余三周予以DMSO灌胃;减量给药组第一、二、三、四周依次为10,7.5,5,2.5mg/kg/d SIM灌胃;给药4周组持续4周予以10mg/kg/d SIM灌胃。术后1,2,3,4周每周处死大鼠,取肋骨骨折部位行X线检测观察肋骨骨折对位愈合情况,HE染色分析骨折区域骨改建的状况,同时眼窝采血行酶联免疫吸附实验(Elisa)检测细胞因子核转录因子-κB受体(Receptor activator of nuclear factor-κB ligand,RANKL),骨保护素(Osteoprotegerin,OPG)及OPG/RANKL水平变化情况。结果:X射线检查:各组均对位对线良好,无畸形愈合及成角愈合。术后一周给药组较早出现骨痂;术后2-4周,随时间推移,骨折线变模糊,四周时减量给药组骨折区域与周围骨组织较为相近,部分髓腔已通。而给药1周组四周时骨痂仍较为明显。组织形态学观察:HE染色显示骨折术后一周给药组较早出现小梁骨及软骨;随时间推移,各组小梁骨成熟、粗大,编织样及板层样骨开始形成,但四周时给药1周组编织骨及板层样骨形成慢于减量给药组及给药4周组,且骨排列方向不一致。ELISA检测结果:血清RANKL变化较OPG变化有统计学意义,给药1周组波动幅度大,第三周时达到最高,四周时降低;减量给药组四周变化无统计学意义,各周之间变化较缓和,可能与逐步减量给药有关。OPG经时变化曲线图显示在第二周时给药组OPG水平均升高,证实辛伐他汀促进OPG的表达,然而三周后回落,可能是此期OPG不再发挥主导作用。OPG/RANKL比值与二者单独变化相一致,减量组OPG/RANKL比值无统计学意义。结论:肋骨骨折模型具有非负重的特点,可用于试验用骨折模型。辛伐他汀可以促进骨折愈合,不同给药方式对骨折愈合有一定的影响。辛伐他汀的急性停药可能会减弱骨折愈合,逐步减量给药方式有利于骨折愈合,具体的信号机制仍需进一步深入分析。
[Abstract]:Objective: to observe the effects of different administration modes of simvastatin (acute withdrawal, gradual reduction, continuous administration) on fracture healing of rats with rib fracture, and to investigate whether there is an acute withdrawal rebound of these drugs. To provide experimental evidence for the rational use of statins in the treatment of fracture. Methods Forty eight 10-week-old male Sprague-Dawley rats were anesthetized intraperitoneally, and the sixth rib was palpated in prone position (incision position: 2 cm at the lower ear margin, about 1.5cm next to the spine), skin, subcutaneous tissue and muscle were sliced, periosteum was removed and ribs were exposed. The ophthalmic shears cut the ribs transversely and sutured in the opposite position. Rats were randomly divided into four groups: control group, 1 week group, reduced dose group and 4 week group. In the control group, Dimethyl Sulphoxide (DMSO) was administered intragastric, simvastatin was given 10 mg/kg/d in the first week, and DMSO was given for the remaining three weeks. In the first, second, third and fourth weeks, the first, second, third, and fourth weeks of the control group were 107.52.5 mg / kg / d SIM, respectively. 10mg/kg/d SIM was given orally for 4 weeks in the 4 week group. Four weeks after operation, the rats were killed at 1, 2 and 3 weeks after operation. Bone remodeling in the fracture area was analyzed by HE staining and X-ray examination was performed on the site of rib fracture. At the same time, the changes of receptor activator of nuclear factor- 魏 B ligand RANKL, osteoprotegerin OPG and OPG / RANKL were detected by Elisa. Results: X-ray examination showed that all groups had good alignment, no malunion and angular healing. The callus appeared earlier in the drug group one week after operation, the fracture line became blurred with time at 2-4 weeks after operation, and the fracture area was close to the surrounding bone tissue in the reduced dose group at four weeks, and part of the medullary cavity had been opened. But the callus was still obvious in the 1 week group. Histomorphologic observation showed that trabecular bone and cartilage appeared earlier in the treatment group one week after the operation, and the trabecular bone matured, thickened, braided and laminar bone began to form over time. However, the formation of braided bone and lamellar bone in the 1-week group was slower than that in the control group and 4-week group, and the bone arrangement was not the same. The results of Elisa showed that the changes of serum RANKL were significantly higher than those of OPG, and the fluctuation of serum RANKL in the 1-week group was larger than that in the 1-week group. At the third week, it reached the highest level and decreased at the fourth week, but the changes were not statistically significant in the reduced dose group, but the changes were more moderate during each week. The curve of the time-dependent changes of OPG, which may be related to the gradual reduction of drug administration, showed that the OPG level in the treatment group increased at the second week, and the level of OPG in the control group was increased at the second week. It was confirmed that simvastatin promoted the expression of OPG, but the decrease of OPG three weeks later may be that OPG no longer plays a leading role. The ratio of OPG / RANKL is consistent with the changes of OPG / RANKL ratio, but the ratio of OPG / RANKL has no statistical significance in the group of reduced OPG / RANKL. Conclusion: the rib fracture model has the characteristics of non-load and can be used for experimental fracture model. Simvastatin can promote fracture healing. The acute withdrawal of simvastatin may weaken fracture healing, and gradually reduce the dosage of simvastatin in favor of fracture healing. The signal mechanism of simvastatin still needs to be further analyzed.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R683.1

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