桡骨骨折模型兔骨折愈合:特异性环氧化酶2抑制剂与非特异性环氧化酶抑制剂的比较
|
摘要
背景:非特异性环氧化酶抑制剂和特异性环氧化酶抑制剂都是常用的镇痛、消炎类非类固醇类药,两种药物治疗对骨折创伤愈合的效果及用药时间的比较缺乏相关实验依据。目的:对比非特异性环氧化酶2抑制剂与特异性环氧化酶2抑制剂对兔桡骨骨折愈合的效果。方法:3-5月龄新西兰大白兔36只,雌雄不限,实验动物由广西医科大学实验动物中心提供。建立兔单侧桡骨骨折(3 mm)模型共36只,随机分为3组:模型组予以等剂量蒸馏水灌胃;特异性环氧化酶2抑制剂组予以1.15 mg/(kg·d)依托考昔灌胃;非特异性环氧化酶抑制剂组予以7.6 mg/(kg·d)阿司匹林灌胃,每组12只。在术后2,4,8周对各组兔桡骨组织进行大体观察和组织病理切片染色观察,检测兔血清骨钙素及骨组织转化生长因子β1、血管内皮生长因子水平。结果与结论:①术后观察发现非特异性环氧化酶抑制剂组造模侧桡骨组织在骨痂的形成改建及愈合情况上均要优其他2组;②术后的各个时间点非特异性环氧化酶抑制剂组血清骨钙素水平明显高于特异性环氧化酶2抑制剂组(P <0.05);③苏木精-伊红染色结果:非特异性环氧化酶抑制剂组在胶原纤维、软骨组织、骨小梁及骨基质的形成时期均早于特异性环氧化酶2抑制剂组;④术后第4周非特异性环氧化酶抑制剂组转化生长因子β1和血管内皮生长因子免疫组织化学平均吸光度值均明显大于特异性环氧化酶2抑制剂组(P <0.05);⑤结果说明,特异性环氧化酶2抑制剂修复兔桡骨骨折的时间相对非特异性环氧化酶更长,说明环氧化酶2特异性抑制剂对骨折愈合的效率低于非特异性环氧化酶抑制剂。
BACKGROUND: Non-specific cyclooxygenase inhibitor and specific cyclooxygenase inhibitor are commonly used nonsteroidal anti-inflammatory and analgesic drugs, but there is a lack of experimental evidence concerning the effect of these drugs on the fracture healing and the administration time. OBJECTIVE: To investigate the effect of non-specific cyclooxygenase-2 inhibitor versus specific cyclooxygenase-2 inhibitor on the healing of tibial fractures in rabbits. METHODS: Thirty-six 3-5-month-old New Zealand rabbits either in sexes were selected(provided by Laboratory Animal Center of Guangxi Medical University). Rabbit models of unilateral tibial fractures(3 mm) were established and randomly divided into modeling group(same volume of distilled water via gavage), specific cyclooxygenase-2 inhibitor group(1.15 mg/kg?d etoricoxib via gavage), and non-specific cyclooxygenase-2 inhibitor group(7.6 mg/kg?d aspirin via gavage), with 12 rabbits in each group. At 2, 4 and 8 weeks postoperatively, the fracture healing was observed and assessed by gross observation and histopathological sections. The serum level of osteocalcin, and levels of transforming growth factor β1 and vascular endothelial growth factor were detected. RESULTS AND CONCLUSION:(1) The non-specific cyclooxygenase-2 inhibitor group was superior to the other two groups in the formation and remodeling of callus and healing.(2) The serum level of osteocalcin in the non-specific cyclooxygenase-2 inhibitor group was significantly higher than that in the specific cyclooxygenase-2 inhibitor group(P < 0.05).(3) Hematoxylin-eosin staining results: the non-specific cyclooxygenase-2 inhibitor group was earlier than the specific cyclooxygenase-2 inhibitor group in the formation of collagen fibers, cartilage tissue, trabecular bone and bone matrix.(4) The average absorbance value of transforming growth factor and vascular endothelial growth factor in the non-specific cyclooxygenase-2 inhibitor group was significantly higher than those in the specific cyclooxygenase-2 inhibitor group at 4 weeks postoperatively(P < 0.05).(5) These results suggest that specific cyclooxygenase-2 inhibitor for rabbit tibia fractures took longer time than non-specific cyclooxygenase-2 inhibitor, indicating that cyclooxygenase-2 specific inhibitor is less effective than non-specific cyclooxygenase-2 inhibitor in fracture healing.
BACKGROUND: Non-specific cyclooxygenase inhibitor and specific cyclooxygenase inhibitor are commonly used nonsteroidal anti-inflammatory and analgesic drugs, but there is a lack of experimental evidence concerning the effect of these drugs on the fracture healing and the administration time. OBJECTIVE: To investigate the effect of non-specific cyclooxygenase-2 inhibitor versus specific cyclooxygenase-2 inhibitor on the healing of tibial fractures in rabbits. METHODS: Thirty-six 3-5-month-old New Zealand rabbits either in sexes were selected(provided by Laboratory Animal Center of Guangxi Medical University). Rabbit models of unilateral tibial fractures(3 mm) were established and randomly divided into modeling group(same volume of distilled water via gavage), specific cyclooxygenase-2 inhibitor group(1.15 mg/kg?d etoricoxib via gavage), and non-specific cyclooxygenase-2 inhibitor group(7.6 mg/kg?d aspirin via gavage), with 12 rabbits in each group. At 2, 4 and 8 weeks postoperatively, the fracture healing was observed and assessed by gross observation and histopathological sections. The serum level of osteocalcin, and levels of transforming growth factor β1 and vascular endothelial growth factor were detected. RESULTS AND CONCLUSION:(1) The non-specific cyclooxygenase-2 inhibitor group was superior to the other two groups in the formation and remodeling of callus and healing.(2) The serum level of osteocalcin in the non-specific cyclooxygenase-2 inhibitor group was significantly higher than that in the specific cyclooxygenase-2 inhibitor group(P < 0.05).(3) Hematoxylin-eosin staining results: the non-specific cyclooxygenase-2 inhibitor group was earlier than the specific cyclooxygenase-2 inhibitor group in the formation of collagen fibers, cartilage tissue, trabecular bone and bone matrix.(4) The average absorbance value of transforming growth factor and vascular endothelial growth factor in the non-specific cyclooxygenase-2 inhibitor group was significantly higher than those in the specific cyclooxygenase-2 inhibitor group at 4 weeks postoperatively(P < 0.05).(5) These results suggest that specific cyclooxygenase-2 inhibitor for rabbit tibia fractures took longer time than non-specific cyclooxygenase-2 inhibitor, indicating that cyclooxygenase-2 specific inhibitor is less effective than non-specific cyclooxygenase-2 inhibitor in fracture healing.
引文
[1]Elmarakby AA,Katary M,Pollock JS,et al.Influence of the selective COX-2 inhibitor celecoxib on sex differences in blood pressure and albuminuria in spontaneously hypertensive rats.Prostaglandins Other Lipid Mediat.2018;135:16-20.
[2]Cronin-Fenton DP,Heide-J?rgensen U,Ahern TP,et al.Low-dose aspirin,non-steroidal anti-inflammatory drugs,selective COX-2 inhibitors and breast cancer recurrence.Epidemiology.2016;27(4):586.
[3]Yadav DK,Saloni,Sharma P,et al.Studies of the benzopyran class of selective COX-2 inhibitors using 3D-QSAR and molecular docking.Arch Pharm Res.2018;41(12):1178-1189.
[4]Kellinsalmi M,Parikka V,Risteli J,et a.l Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro.Eur JPharmacol.2007;572(2-3):102-110.
[5]Krischak GD,Augat P,B lakytny R,et a.l Thenon-steroida lanti in flamm atoryd rugdiclofenac reduces app earance of osteob lasts in bone defect heal ing in rats.Arch Orthop Traum a Surg.2007;127(6):453-458.
[6]Murnaghan M,L I G,M arsh DR.N onsteroidal anti inflamm atory drug induc-ed fracture nonun ion:an inh ibition of angiogenesis.J Bon e Joint Surg Am.2006;88(Suppl 3):140-147.
[7]Ferrara N,Henzel WJ.Pituitary follicular cells secrete a novel heparin binding growth factor specific for vascular endothelial cells.Biochem Biophys Res Commun.1989;161:851-858.
[8]赵广民,刘强.骨折愈合中转化生长因子β与骨形成的关系[J].山西医科大学学报,2000,31(1):89.
[9]Langdahl B L,Stenkjaer L,Carstens M,et al.A CAG repeat polymorphism in the androgen receptor gene is associated with reduced bone mass and increased risk of osteoporotic fractures.Calcif TissueInt.2003;73(3):237-24.
[10]Shi M,Zhu J,Wang R,et al.Latent TGF-βstructure and activation.Nature.2011;474(7351):343-349.
[11]Frenkel SR,Saadeh PB,Mehrara BJ,et al.Transforming growthfactor beta superfamily members:role in cartilage modeling.Plast Reconstr Surg.2000;105(3):980-990.
[12]Li J,Zhang H,Chao Y,et al.An overview of osteocalcin progress.J Bone Miner Metab.2016;34(4):367-379.
[13]De TL,Di NA,Rocca MS,et al.Osteocalcin,a bone-derived hormone with important andrological implications.Andrology.2017;5(4):664.
[14]Wang JX,Wu HL,Zhu M,et al.Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer:an Update Meta-Analysis of Randomized Clinical Trials.Pathol Oncol Res.2018 Jan 30.
[15]Asahara T,Takahashi T,Masuda H,et al.VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells.EMBO J.1999;18(14):3964-3972.
[16]Li Q,Xia S,Fang H,et al.VEGF treatment promotes bone marrow-derived CXCR4+mesenchymal stromal stem cell differentiation into vessel endothelial cells.Exp Ther Med.2017;13(2):449-454.
[17]Saraf SK,Singh A,Garbyal RS,et al.Effect of Simvastatin on fracture healing--an experimental study.Indian J Exp Biol.2007;45(5):444-449.
[18]梁春雨,张柳,赵文国,等.辛伐他汀对大鼠股骨骨折愈合的影响[J].第四军医大学学报,2006,27(3):284-286.
[2]Cronin-Fenton DP,Heide-J?rgensen U,Ahern TP,et al.Low-dose aspirin,non-steroidal anti-inflammatory drugs,selective COX-2 inhibitors and breast cancer recurrence.Epidemiology.2016;27(4):586.
[3]Yadav DK,Saloni,Sharma P,et al.Studies of the benzopyran class of selective COX-2 inhibitors using 3D-QSAR and molecular docking.Arch Pharm Res.2018;41(12):1178-1189.
[4]Kellinsalmi M,Parikka V,Risteli J,et a.l Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro.Eur JPharmacol.2007;572(2-3):102-110.
[5]Krischak GD,Augat P,B lakytny R,et a.l Thenon-steroida lanti in flamm atoryd rugdiclofenac reduces app earance of osteob lasts in bone defect heal ing in rats.Arch Orthop Traum a Surg.2007;127(6):453-458.
[6]Murnaghan M,L I G,M arsh DR.N onsteroidal anti inflamm atory drug induc-ed fracture nonun ion:an inh ibition of angiogenesis.J Bon e Joint Surg Am.2006;88(Suppl 3):140-147.
[7]Ferrara N,Henzel WJ.Pituitary follicular cells secrete a novel heparin binding growth factor specific for vascular endothelial cells.Biochem Biophys Res Commun.1989;161:851-858.
[8]赵广民,刘强.骨折愈合中转化生长因子β与骨形成的关系[J].山西医科大学学报,2000,31(1):89.
[9]Langdahl B L,Stenkjaer L,Carstens M,et al.A CAG repeat polymorphism in the androgen receptor gene is associated with reduced bone mass and increased risk of osteoporotic fractures.Calcif TissueInt.2003;73(3):237-24.
[10]Shi M,Zhu J,Wang R,et al.Latent TGF-βstructure and activation.Nature.2011;474(7351):343-349.
[11]Frenkel SR,Saadeh PB,Mehrara BJ,et al.Transforming growthfactor beta superfamily members:role in cartilage modeling.Plast Reconstr Surg.2000;105(3):980-990.
[12]Li J,Zhang H,Chao Y,et al.An overview of osteocalcin progress.J Bone Miner Metab.2016;34(4):367-379.
[13]De TL,Di NA,Rocca MS,et al.Osteocalcin,a bone-derived hormone with important andrological implications.Andrology.2017;5(4):664.
[14]Wang JX,Wu HL,Zhu M,et al.Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer:an Update Meta-Analysis of Randomized Clinical Trials.Pathol Oncol Res.2018 Jan 30.
[15]Asahara T,Takahashi T,Masuda H,et al.VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells.EMBO J.1999;18(14):3964-3972.
[16]Li Q,Xia S,Fang H,et al.VEGF treatment promotes bone marrow-derived CXCR4+mesenchymal stromal stem cell differentiation into vessel endothelial cells.Exp Ther Med.2017;13(2):449-454.
[17]Saraf SK,Singh A,Garbyal RS,et al.Effect of Simvastatin on fracture healing--an experimental study.Indian J Exp Biol.2007;45(5):444-449.
[18]梁春雨,张柳,赵文国,等.辛伐他汀对大鼠股骨骨折愈合的影响[J].第四军医大学学报,2006,27(3):284-286.