辛伐他汀不同给药方式对骨折大鼠外周血炎性因子的干预效应
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摘要
目的探讨辛伐他汀不同给药方式对骨折大鼠外周血炎性因子的干预效应。方法将48只雄性SD大鼠建立肋骨骨折模型,并随机分为4组,实验组按10mg/(kg·d)剂量的辛伐他汀分为短期给药组、减撤给药组和长期给药组,对照组给予同体积的DMSO溶剂,分别于1、2、4周ELISA法测定外周血中IL-1β、IL-6和TNF-α的含量。结果短期给药停药1周后,可引起IL-6、TNF-α尤其是IL-1β的反跳性升高。长期给药组和减撤给药组IL-1β、IL-6以及TNF-α表达水平均低于对照组和短期给药组,减撤给药组表达水平均最低。结论辛伐他汀减撤给药方式,可抑制骨折愈合过程中促炎细胞因子IL-1β、IL-6以及TNF-α的表达,降低骨折愈合过程中的炎性反应,有利于骨折的修复。
Objective To evaluate the effect of simvastatin on inflammatory cytokine levels of peripheral blood in a rat fracture model by different administration methods. Methods Forty-eight 10-week-old male Sprague-Dawley(SD) rats were randomly divided into 4 groups. The rib fracture model was established. The rats in experimental group were divided into three groups(short-term administration,tapering administration, long-term administration) and received 10 mg/(kg·d) simvastatin. The rats that received equivalent DMSO served as control. The levels of IL-1β, IL-6 and TNF-α in peripheral blood were examined by ELISA. Results One week after fracture, the expression levels of IL-1β, IL-6 and TNF-α increased in short-term administration group. Compared with control group and short-term administration group, the expression levels of IL-1β, IL-6 and TNF-α were lower in those of long-term administration group and tapering administration group. The tapering administration group expressed the lowerest levels. Conclusion Simvastatin tapering administration has certain effect on inhibiting the expression of inflammatory cytokine IL-1β, IL-6 and TNF-α, which may have potential ability of promoting fracture healing.
Objective To evaluate the effect of simvastatin on inflammatory cytokine levels of peripheral blood in a rat fracture model by different administration methods. Methods Forty-eight 10-week-old male Sprague-Dawley(SD) rats were randomly divided into 4 groups. The rib fracture model was established. The rats in experimental group were divided into three groups(short-term administration,tapering administration, long-term administration) and received 10 mg/(kg·d) simvastatin. The rats that received equivalent DMSO served as control. The levels of IL-1β, IL-6 and TNF-α in peripheral blood were examined by ELISA. Results One week after fracture, the expression levels of IL-1β, IL-6 and TNF-α increased in short-term administration group. Compared with control group and short-term administration group, the expression levels of IL-1β, IL-6 and TNF-α were lower in those of long-term administration group and tapering administration group. The tapering administration group expressed the lowerest levels. Conclusion Simvastatin tapering administration has certain effect on inhibiting the expression of inflammatory cytokine IL-1β, IL-6 and TNF-α, which may have potential ability of promoting fracture healing.
引文
1张军.下颌髁突骨折的诊治进展.北京口腔医学,2016,24(3):170-173.
2 Axelrad TW,Kakar S,Einhorn TA.New technologies for the enhancement of skeletal repair.Injury,2007,38(Suppl 1):S49-S62.
3 Bekelis K,Desai A,Bakhoum SF,et al.A predictive model of complications after spine surgery:the National Surgical Quality Improvement Program(NSQIP)2005-2010.Spine J,2014,14(7):1247-1255.
4 Albert MA,Danielson E,Rifai N,et al.Effect of statin therapy on C-reactive protein levels:the pravastatin inflammation/CRPevaluation(PRINCE):a randomized trial and cohort study.JAMA,2001,286(1):64-70.
5伊藤量基.スタチンの有する抗炎症効果~ヒト樹状細胞サブセットを治療ターゲットとした新たな視点からの解析~.サイトメトリーリサーチ,2015,25(1):19-24.
6 Kwak B,Mulhaupt F,Myit S,et al.Statins as a newly recognized type of immunomodulator.Nat Med,2000,6(12):1399-1402.
7 Mundy G,Garrett R,Harris S,et al.Stimulation of bone formation in vitro and in rodents by statins.Science,1999,286(5446):1946-1949.
8 Yamashita M,Otsuka F,Mukai T,et al.Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2and RANKL through regulating MAPK,AKT and Src signaling.Regul Pept,2010,162(1-3):99-108.
9 Jadhav SB,Jain GK.Statins and osteoporosis:new role for old drugs.J Pharm Pharmacol,2006,58(1):3-18.
10 Tang QO,Tran GT,Gamie Z,et al.Statins:under investigation for increasing bone mineral density and augmenting fracture healing.Expert Opin Investig Drugs,2008,17(10):1435-1463.
11 Türer A,Durmu爧lar MC,爦ener I,et al.The effect of local rosuvastatin on mandibular fracture healing.J Craniofac Surg,2016,27(8):e758-e761.
12 Moshiri A,Sharifi AM,Oryan A.Role of Simvastatin on fracture healing and osteoporosis:a systematic review on in vivo investigations.Clin Exp Pharmacol Physiol,2016,43(7):659-684.
13 Zhang Y,Jia Z,Yuan H,et al.The evaluation of therapeutic efficacy and safety profile of Simvastatin prodrug micelles in a closed fracture mouse model.Pharm Res,2016,33(8):1959-1971.
14 Li X,Wu F,Zhang Y,et al.Discontinuation of simvastatin lead to a rebound phenomenon and result in immediate peri-implant bone loss.Clin Exp Dent Res,2016,2(1):65-72.
15周潇逸,吴随一,张子程,等.巨噬细胞在骨折愈合过程中作用的研究进展.第二军医大学学报,2017,38(12):1556-1561.
16 Marsell R,Einhorn TA.The biology of fracture healing.Injury,2011,42(6):551-555.
17 Qian H,Yuan H,Wang J,et al.A monoclonal antibody ameliorates local inflammation and osteoporosis by targeting TNF-αand RANKL.Int Immunopharmacol,2014,20(2):370-376.
18 Thomas MV,Puleo DA.Infection,inflammation,and bone regeneration:a paradoxical relationship.J Dent Res,2011,90(9):1052-1061.
19崔斌,孙天胜.肿瘤坏死因子和部分白介素对骨折影响的研究进展.中华临床医师杂志(电子版),2013,7(21):9743-9745.
20 Maritz FJ,Conradie MM,Hulley PA,et al.Effect of statins on bone mineral density and bone histomorphometry in rodents.Arterioscler Thromb Vasc Biol,2001,21(10):1636-1641.
2 Axelrad TW,Kakar S,Einhorn TA.New technologies for the enhancement of skeletal repair.Injury,2007,38(Suppl 1):S49-S62.
3 Bekelis K,Desai A,Bakhoum SF,et al.A predictive model of complications after spine surgery:the National Surgical Quality Improvement Program(NSQIP)2005-2010.Spine J,2014,14(7):1247-1255.
4 Albert MA,Danielson E,Rifai N,et al.Effect of statin therapy on C-reactive protein levels:the pravastatin inflammation/CRPevaluation(PRINCE):a randomized trial and cohort study.JAMA,2001,286(1):64-70.
5伊藤量基.スタチンの有する抗炎症効果~ヒト樹状細胞サブセットを治療ターゲットとした新たな視点からの解析~.サイトメトリーリサーチ,2015,25(1):19-24.
6 Kwak B,Mulhaupt F,Myit S,et al.Statins as a newly recognized type of immunomodulator.Nat Med,2000,6(12):1399-1402.
7 Mundy G,Garrett R,Harris S,et al.Stimulation of bone formation in vitro and in rodents by statins.Science,1999,286(5446):1946-1949.
8 Yamashita M,Otsuka F,Mukai T,et al.Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2and RANKL through regulating MAPK,AKT and Src signaling.Regul Pept,2010,162(1-3):99-108.
9 Jadhav SB,Jain GK.Statins and osteoporosis:new role for old drugs.J Pharm Pharmacol,2006,58(1):3-18.
10 Tang QO,Tran GT,Gamie Z,et al.Statins:under investigation for increasing bone mineral density and augmenting fracture healing.Expert Opin Investig Drugs,2008,17(10):1435-1463.
11 Türer A,Durmu爧lar MC,爦ener I,et al.The effect of local rosuvastatin on mandibular fracture healing.J Craniofac Surg,2016,27(8):e758-e761.
12 Moshiri A,Sharifi AM,Oryan A.Role of Simvastatin on fracture healing and osteoporosis:a systematic review on in vivo investigations.Clin Exp Pharmacol Physiol,2016,43(7):659-684.
13 Zhang Y,Jia Z,Yuan H,et al.The evaluation of therapeutic efficacy and safety profile of Simvastatin prodrug micelles in a closed fracture mouse model.Pharm Res,2016,33(8):1959-1971.
14 Li X,Wu F,Zhang Y,et al.Discontinuation of simvastatin lead to a rebound phenomenon and result in immediate peri-implant bone loss.Clin Exp Dent Res,2016,2(1):65-72.
15周潇逸,吴随一,张子程,等.巨噬细胞在骨折愈合过程中作用的研究进展.第二军医大学学报,2017,38(12):1556-1561.
16 Marsell R,Einhorn TA.The biology of fracture healing.Injury,2011,42(6):551-555.
17 Qian H,Yuan H,Wang J,et al.A monoclonal antibody ameliorates local inflammation and osteoporosis by targeting TNF-αand RANKL.Int Immunopharmacol,2014,20(2):370-376.
18 Thomas MV,Puleo DA.Infection,inflammation,and bone regeneration:a paradoxical relationship.J Dent Res,2011,90(9):1052-1061.
19崔斌,孙天胜.肿瘤坏死因子和部分白介素对骨折影响的研究进展.中华临床医师杂志(电子版),2013,7(21):9743-9745.
20 Maritz FJ,Conradie MM,Hulley PA,et al.Effect of statins on bone mineral density and bone histomorphometry in rodents.Arterioscler Thromb Vasc Biol,2001,21(10):1636-1641.