大叶茜草素抑制钛颗粒诱导的人工关节无菌性松动的实验研究
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摘要
目的:通过大叶茜草素干预小鼠air-pouch模型,探讨大叶茜草素对钛颗粒诱导的人工关节无菌性松动的抑制作用及其发生机制。方法:体重25~30 g BALB/c小鼠72只,随机分为6组,分别为空白组(A组)、颗粒组(B组)、低剂量组(C组)、中剂量组(D组)、高剂量组(E组)、溶液对照组(F组),小鼠air-pouch模型构建成功后,运用大叶茜草素对实验各组进行干预,连续14天后,收集气囊囊壁进行大体观察、HE染色、RT-PCR及ELISA检测。结果:小鼠都存活至实验结束,大体观察见A组气囊炎症反应轻,B、C、D、E、F组气囊炎症反应较重,其中B、F组最重,C、D、E组较弱,且D组较C、E组最弱。实验室检测发现,B、F组囊壁炎性细胞密度及TNF-α、IL-1β表达无差异(P>0.05);B、F组囊壁炎性细胞密度及TNF-α、IL-1β表达均较A组明显增加(P<0.05);C、D、E组囊壁炎性细胞密度及TNF-α、IL-1β表达均低于B、F组(P<0.05),其中D组最低,且均高于A组(P<0.05)。结论:钛颗粒能在小鼠air-pouch模型中造成和人工关节无菌性松动类似的炎症反应,大叶茜草素能有效抑制这种炎症反应,从而为临床运用药物抑制人工关节无菌性松动的发生及发展带来新的曙光。
Objective:Through the intervention of mollugin on murine air-pouch model,to investigate the inhibitory effect and mechanism of mollugin on titanium particle induced prosthetic aseptic loosening. Methods:72 BALB/c mice,weighing 25 ~ 30 g,were randomly divided into 6 groups,which were blank group(group A),particle group(group B),low dose group(group C),middle dose group(group D),high dose group(group E),solution control group(group F).After the establishment of murine air-pouch model,mollugin was used to intervene the experimental groups,14 consecutive days later,pouch tissues were harvested to HE staining,RT-PCR and ELISA analyses. Results:All mice survived to the end of the experiment. The gross observation showed that the inflammatory reaction of air pouches were light in the group A,and were much heavier in group B、group C、group D、group E and group F. Among them,group B、group F were the most heaviest,group C、group D、group E were weaker. Compared with group C、group E,group D were the weakest.Laboratory tests found that there were no difference in inflammatory cell density and the expression of TNF-α and IL-1β of air pouches in group B、group F(P > 0. 05); compared with group A,group B、group F were obviously increased(P <0. 05); group C、group E,group D were Lower than group B、group F(P < 0. 05),Among them group D was weaker,and all of them were higher than group A(P < 0. 05). Conclusion:The inflammatory response caused by titanium particles induced in the air-pouch model was similar to aseptic loosening of artificial joints,mollugin could effectively inhibit the inflammatory response,so as to bring about a new dawn for the clinical application of drugs to inhibit the occurrence and development of aseptic loosening of artificial joint.
Objective:Through the intervention of mollugin on murine air-pouch model,to investigate the inhibitory effect and mechanism of mollugin on titanium particle induced prosthetic aseptic loosening. Methods:72 BALB/c mice,weighing 25 ~ 30 g,were randomly divided into 6 groups,which were blank group(group A),particle group(group B),low dose group(group C),middle dose group(group D),high dose group(group E),solution control group(group F).After the establishment of murine air-pouch model,mollugin was used to intervene the experimental groups,14 consecutive days later,pouch tissues were harvested to HE staining,RT-PCR and ELISA analyses. Results:All mice survived to the end of the experiment. The gross observation showed that the inflammatory reaction of air pouches were light in the group A,and were much heavier in group B、group C、group D、group E and group F. Among them,group B、group F were the most heaviest,group C、group D、group E were weaker. Compared with group C、group E,group D were the weakest.Laboratory tests found that there were no difference in inflammatory cell density and the expression of TNF-α and IL-1β of air pouches in group B、group F(P > 0. 05); compared with group A,group B、group F were obviously increased(P <0. 05); group C、group E,group D were Lower than group B、group F(P < 0. 05),Among them group D was weaker,and all of them were higher than group A(P < 0. 05). Conclusion:The inflammatory response caused by titanium particles induced in the air-pouch model was similar to aseptic loosening of artificial joints,mollugin could effectively inhibit the inflammatory response,so as to bring about a new dawn for the clinical application of drugs to inhibit the occurrence and development of aseptic loosening of artificial joint.
引文
[1]Sansone V,Pagani D,Melato M.The effects on bone cells of metal ions released from orthopaedic implants.A review[J].Clin Cases Miner Bone Metab,2013,10(1):34-40.
[2]S.B.Goodman,E.Gibon,J.Pajarinen,et al.Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement[J].J R Soc Interface,2014,11(93):20130962.
[3]Beck RT,Illingworth KD,Saleh KJ.Review of periprosthetic osteolysis in total joint arthroplasty:an emphasis on host factors and future directions[J].J Orthop Res,2012,30(4):541-546.
[4]Jeong GS,Lee DS,Kim DC,et al.Neuroprotective and anti-inflammatory effects of mollugin via up-regulation of heme oxygenase-1 in mouse hippocampal and microglial cells[J].Eur J Pharmacol,2011,4(3):226-34.
[5]Sansone V,Pagani D,Melato M.The effects on bone cells of metal ions released from orthopaedic implants.A review[J].Clin Cases Miner Bone Metab,2013,10(1):34-40.
[6]Vasconcelos DM,Ribeiro-da-Silva M,Mateus A,et al.Immune response and innervation signatures in aseptic hip implant loosening[J].J Transl Med,2016,14(1):205.
[7]de Lange-Brokaar BJ,Ioan-Facsinay A,van Osch GJ,et al.Synovial inflammation,immune cells and their cytokines in osteoarthritis:a review[J].Osteoarthritis Cartilage,2012,20(12):1484-1499.
[8]Zhang L,Jia TH,Chong AC,et al.Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model[J].Gene Ther,2010,17(10):1262-1269.
[9]Zhang H,Ricciardi BF,Yang X,et al.Polymethylmethacrylate particles stimulate bone resorption of mature osteoclasts in vitro[J].Acta Orthop,2008,79(2):281-288.
[10]Kaufman AM,Alabre CI,Rubash HE,et al.Human macrophage response to UHMWPE,Ti Al V,Co Cr,and alumina particles:analysis of multiple cytokines using protein arrays[J].J Biomed Mater Res A,2008,84(2):464-474.
[11]Bukata SV,Gelinas J,Wei X,et al.PGE2 and IL-6production by fibroblasts in response to titanium wear debris particles is mediated through a Cox-2 dependent pathway[J].J Orthop Res,2004,22(1):6-12.
[12]Nakashima Y,Sun DH,Trindade MC,et al.Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression in human macrophages exposed to titaniumalloy particulate debris in vitro[J].J Bone Joint Surg Am,1999,81(5):603-615.
[13]Xiao G,Rabson AB,Young W,et al.Alternative pathways of NF-kappa B activation:a double-edged sword in health and disease[J].Cytokine Growth Factor Rev,2006,17(4):281-293.
[14]Kostenuik PJ.Osteoprotegerin and RANKL regulate bone resorption,density,geometry and strength[J].Curr Opin Pharmacol,2005,5(6):618-625.
[15]Idhayadhulla A,Xia L,Lee YR,et al.Synthesis of novel and diverse mollugin analogues and their antibacterial and antioxidant activities[J].Bioorg Chem,2014,52:77-82.
[16]Do MT,Hwang YP,Kim HG.Mollugin inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2-overexpressing cancer cells[J].J Cell Physiol,2013,228(5):1087-1097.
[17]Morita H,Nishino H,Nakajima Y,et al.Oxomollugin,a potential inhibitor of lipopolysaccharide-induced nitric oxide production including nuclear factor kappa B signals[J].J Nat Med,2015,69(4):608-611.
[18]Zhu ZG,Jin H,Yu PJ,et al.Mollugin inhibits the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages by blocking the Janus kinasesignal transducers and activators of transcription signaling pathway[J].Biol Pharm Bull,2013,36(3):399-406.
[19]Kim KJ,Lee JS,Kwak MK,et al.Anti-inflammatory action of mollugin and its synthetic derivatives in HT-29human colonic epithelial cells is mediated through inhibition of NF-kappa B activation[J].Eur J Pharmacol,2009,622(1-3):52-57.
[20]Baek JM,Kim JY,Jung Y,et al.Mollugin from Rubea cordifolia suppresses receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis and bone resorbing activity in vitro and prevents lipopolysaccharide-induced bone loss in vivo[J].Phytomedicine,2015,22(1):27-35.
[2]S.B.Goodman,E.Gibon,J.Pajarinen,et al.Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement[J].J R Soc Interface,2014,11(93):20130962.
[3]Beck RT,Illingworth KD,Saleh KJ.Review of periprosthetic osteolysis in total joint arthroplasty:an emphasis on host factors and future directions[J].J Orthop Res,2012,30(4):541-546.
[4]Jeong GS,Lee DS,Kim DC,et al.Neuroprotective and anti-inflammatory effects of mollugin via up-regulation of heme oxygenase-1 in mouse hippocampal and microglial cells[J].Eur J Pharmacol,2011,4(3):226-34.
[5]Sansone V,Pagani D,Melato M.The effects on bone cells of metal ions released from orthopaedic implants.A review[J].Clin Cases Miner Bone Metab,2013,10(1):34-40.
[6]Vasconcelos DM,Ribeiro-da-Silva M,Mateus A,et al.Immune response and innervation signatures in aseptic hip implant loosening[J].J Transl Med,2016,14(1):205.
[7]de Lange-Brokaar BJ,Ioan-Facsinay A,van Osch GJ,et al.Synovial inflammation,immune cells and their cytokines in osteoarthritis:a review[J].Osteoarthritis Cartilage,2012,20(12):1484-1499.
[8]Zhang L,Jia TH,Chong AC,et al.Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model[J].Gene Ther,2010,17(10):1262-1269.
[9]Zhang H,Ricciardi BF,Yang X,et al.Polymethylmethacrylate particles stimulate bone resorption of mature osteoclasts in vitro[J].Acta Orthop,2008,79(2):281-288.
[10]Kaufman AM,Alabre CI,Rubash HE,et al.Human macrophage response to UHMWPE,Ti Al V,Co Cr,and alumina particles:analysis of multiple cytokines using protein arrays[J].J Biomed Mater Res A,2008,84(2):464-474.
[11]Bukata SV,Gelinas J,Wei X,et al.PGE2 and IL-6production by fibroblasts in response to titanium wear debris particles is mediated through a Cox-2 dependent pathway[J].J Orthop Res,2004,22(1):6-12.
[12]Nakashima Y,Sun DH,Trindade MC,et al.Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression in human macrophages exposed to titaniumalloy particulate debris in vitro[J].J Bone Joint Surg Am,1999,81(5):603-615.
[13]Xiao G,Rabson AB,Young W,et al.Alternative pathways of NF-kappa B activation:a double-edged sword in health and disease[J].Cytokine Growth Factor Rev,2006,17(4):281-293.
[14]Kostenuik PJ.Osteoprotegerin and RANKL regulate bone resorption,density,geometry and strength[J].Curr Opin Pharmacol,2005,5(6):618-625.
[15]Idhayadhulla A,Xia L,Lee YR,et al.Synthesis of novel and diverse mollugin analogues and their antibacterial and antioxidant activities[J].Bioorg Chem,2014,52:77-82.
[16]Do MT,Hwang YP,Kim HG.Mollugin inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2-overexpressing cancer cells[J].J Cell Physiol,2013,228(5):1087-1097.
[17]Morita H,Nishino H,Nakajima Y,et al.Oxomollugin,a potential inhibitor of lipopolysaccharide-induced nitric oxide production including nuclear factor kappa B signals[J].J Nat Med,2015,69(4):608-611.
[18]Zhu ZG,Jin H,Yu PJ,et al.Mollugin inhibits the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages by blocking the Janus kinasesignal transducers and activators of transcription signaling pathway[J].Biol Pharm Bull,2013,36(3):399-406.
[19]Kim KJ,Lee JS,Kwak MK,et al.Anti-inflammatory action of mollugin and its synthetic derivatives in HT-29human colonic epithelial cells is mediated through inhibition of NF-kappa B activation[J].Eur J Pharmacol,2009,622(1-3):52-57.
[20]Baek JM,Kim JY,Jung Y,et al.Mollugin from Rubea cordifolia suppresses receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis and bone resorbing activity in vitro and prevents lipopolysaccharide-induced bone loss in vivo[J].Phytomedicine,2015,22(1):27-35.
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