本文選題：肋骨骨折 + 辛伐他汀�。� 參考：《山西醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:通過(guò)建立肋骨骨折大鼠模型,觀察辛伐他汀不同給藥方式(急性停藥、逐步減量給藥、持續(xù)給藥)對(duì)大鼠骨折愈合的影響,探討該類(lèi)藥物有無(wú)急性停藥反跳,為臨床合理利用他汀類(lèi)藥物治療骨折提供實(shí)驗(yàn)依據(jù)。方法:48只10周齡雄性健康SD大鼠腹腔注射麻醉后,俯臥位手法捫及第六肋骨(切口位置:耳下緣2cm,脊柱旁約1.5cm),分層切開(kāi)皮膚、皮下組織和肌肉,剝離骨膜,顯露肋骨,眼科剪橫向剪斷肋骨,對(duì)位分層縫合。術(shù)后大鼠隨機(jī)分為四組:對(duì)照組、給藥1周組、減量給藥組、給藥4周組。對(duì)照組予以二甲基亞砜(Dimethyl Sulphoxide,DMSO)灌胃;給藥1周組第一周10 mg/kg/d辛伐他汀(simvastatin,SIM)灌胃,剩余三周予以DMSO灌胃;減量給藥組第一、二、三、四周依次為10,7.5,5,2.5mg/kg/d SIM灌胃;給藥4周組持續(xù)4周予以10mg/kg/d SIM灌胃。術(shù)后1,2,3,4周每周處死大鼠,取肋骨骨折部位行X線(xiàn)檢測(cè)觀察肋骨骨折對(duì)位愈合情況,HE染色分析骨折區(qū)域骨改建的狀況,同時(shí)眼窩采血行酶聯(lián)免疫吸附實(shí)驗(yàn)(Elisa)檢測(cè)細(xì)胞因子核轉(zhuǎn)錄因子-κB受體(Receptor activator of nuclear factor-κB ligand,RANKL),骨保護(hù)素(Osteoprotegerin,OPG)及OPG/RANKL水平變化情況。結(jié)果:X射線(xiàn)檢查:各組均對(duì)位對(duì)線(xiàn)良好,無(wú)畸形愈合及成角愈合。術(shù)后一周給藥組較早出現(xiàn)骨痂;術(shù)后2-4周,隨時(shí)間推移,骨折線(xiàn)變模糊,四周時(shí)減量給藥組骨折區(qū)域與周?chē)墙M織較為相近,部分髓腔已通。而給藥1周組四周時(shí)骨痂仍較為明顯。組織形態(tài)學(xué)觀察:HE染色顯示骨折術(shù)后一周給藥組較早出現(xiàn)小梁骨及軟骨;隨時(shí)間推移,各組小梁骨成熟、粗大,編織樣及板層樣骨開(kāi)始形成,但四周時(shí)給藥1周組編織骨及板層樣骨形成慢于減量給藥組及給藥4周組,且骨排列方向不一致。ELISA檢測(cè)結(jié)果:血清RANKL變化較OPG變化有統(tǒng)計(jì)學(xué)意義,給藥1周組波動(dòng)幅度大,第三周時(shí)達(dá)到最高,四周時(shí)降低;減量給藥組四周變化無(wú)統(tǒng)計(jì)學(xué)意義,各周之間變化較緩和,可能與逐步減量給藥有關(guān)。OPG經(jīng)時(shí)變化曲線(xiàn)圖顯示在第二周時(shí)給藥組OPG水平均升高,證實(shí)辛伐他汀促進(jìn)OPG的表達(dá),然而三周后回落,可能是此期OPG不再發(fā)揮主導(dǎo)作用。OPG/RANKL比值與二者單獨(dú)變化相一致,減量組OPG/RANKL比值無(wú)統(tǒng)計(jì)學(xué)意義。結(jié)論:肋骨骨折模型具有非負(fù)重的特點(diǎn),可用于試驗(yàn)用骨折模型。辛伐他汀可以促進(jìn)骨折愈合,不同給藥方式對(duì)骨折愈合有一定的影響。辛伐他汀的急性停藥可能會(huì)減弱骨折愈合,逐步減量給藥方式有利于骨折愈合,具體的信號(hào)機(jī)制仍需進(jìn)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.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R683.1

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