CXCR4特异性拮抗剂AMD3100对小鼠角膜碱烧伤新生血管的治疗作用及其机制研究
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摘要
目的:探讨结膜下和腹腔注射AMD3100对于C57/BL小鼠角膜碱烧伤新生血管的治疗作用及其机制。
方法:1)采用碱烧伤建立C57/BL小鼠角膜新生血管动物模型;采用免疫组织化学染色、RT-PCR和Western Blot检测碱烧伤后不同时间点角膜组织中SDF-1和CXCR4的表达情况;2)角膜碱烧伤后通过结膜下和腹腔注射给予CXCR4特异性拮抗剂AMD3100,随机分为4组:结膜下注射组、结膜下注射对照组、腹腔注射组和腹腔注射对照组;在不同时间点观察角膜的炎症反应和新生血管形成情况;检测各组角膜组织中炎症细胞的数量、微血管密度、VEGFR2、CD34、SDF-1和CXCR4的表达情况。3)采用流式细胞技术,检测结膜下注射和腹腔注射AMD3100后不同时间点小鼠外周血液中EPC的数量。
结果:1)正常C57/BL小鼠角膜组织可微量表达SDF-1、CXCR4 mRNA和蛋白。SDF-1、CXCR4 mRNA和蛋白的表达于碱烧伤后3天开始可见增高,7天达高峰,14天时开始下降但仍高于正常水平;2)结膜下注射组AMD3100角膜的炎症指数、微血管密度、VEGFR2和CD34的表达水平等均低于对照组和腹腔注射组,差异有统计学意义。角膜碱烧伤后,各组之间SDF-1和CXCR4的表达水平未见显著性差异。腹腔注射组各时间点外周血中EPC的数量均显著增加,而结膜下注射组EPC的数量与注射前差异无统计学意义。
结论:SDF-1/CXCR4在碱烧伤后小鼠角膜组织中表达增加,可能在角膜碱烧伤的炎症和新生血管的形成和发展过程中发挥重要作用。角膜碱烧伤小鼠腹腔注射AMD3100可显著增加外周血EPCs的数量,而结膜下注射无此效应。结膜下注射AMD3100可减少小鼠角膜碱烧伤后新生血管的形成,其机制可能是通过竞争性拮抗SDF-1与CXCR4之间的结合,阻断其生物学功能,并减少EPCs细胞向损伤部位的聚集有关。
Purpose: To investigate the effects of subconjunctival and intraperitoneal injected AMD3100 on alkali-induced corneal neovascularization and its mechanism.
Methods: Alkali-induced corneal neovascularization animal model were constructed of in C57/BL mice. SDF-1 and CXCR4 expression in the corneal tissue were detect by immunohistochemistry, RT-PCR and Western Blot at different time points after alkali burn; AMD3100 was administrated by subconjunctival and intraperitoneal injection. And the mice were randomly divided into 4 groups: subconjunctival injection group, subconjunctival injection control group, intraperitoneal injection group and intraperitoneal injection control group; The number of inflammatory cells, microvessel density, VEGFR2, CD34, SDF-1 and CXCR4 expression in corneal tissue of each group were detected at different time points after alkali burn; Flow cytometry was used to detect the number of EPC in the peripheral blood of subconjunctival and intraperitoneal injection group at different time points after the injection of AMD3100.
Results: Normal mouse corneal tissues only contain traces of SDF-1, CXCR4 mRNA and protein. Three days after alkali burn, the expression start to increase, and reached the peak at the 7th day, 14 days began to decrease but still higher than normal levels; Corneal inflammation index, microvessel density, VEGFR2 and CD34 level in subconjunctival injection group were all lower than the control group and the intraperitoneal injection group, and the difference of the SDF-1 and CXCR4 expression level among the four groups had no statistically significant. The numbers of EPCs in peripheral blood of intraperitoneal injection group were significantly increased at different time points. And the number of EPCs in peripheral blood at different time points after injection was not increased when compared with the number before injection.
Conclusions: The expressions of SDF-1/CXCR4 are increased after alkali burn in corneal tissue of mice, which may indicated that SDF-1/CXCR4 plays an important role in the formation of corneal neovascular formation in alkali-induced corneal neovascularization. Intraperitoneal injection of AMD3100 could significantly increase the number of EPCs in peripheral blood, while subconjunctival injection was just the opposite. Subconjunctival injection of AMD3100 could reduce alkali-induced corneal neovascularization probably through competitive antagonist the binding of SDF-1 to CXCR4 and blocking its biological function, as well as reducing the EPCs gathered to the injury tissue.
方法:1)采用碱烧伤建立C57/BL小鼠角膜新生血管动物模型;采用免疫组织化学染色、RT-PCR和Western Blot检测碱烧伤后不同时间点角膜组织中SDF-1和CXCR4的表达情况;2)角膜碱烧伤后通过结膜下和腹腔注射给予CXCR4特异性拮抗剂AMD3100,随机分为4组:结膜下注射组、结膜下注射对照组、腹腔注射组和腹腔注射对照组;在不同时间点观察角膜的炎症反应和新生血管形成情况;检测各组角膜组织中炎症细胞的数量、微血管密度、VEGFR2、CD34、SDF-1和CXCR4的表达情况。3)采用流式细胞技术,检测结膜下注射和腹腔注射AMD3100后不同时间点小鼠外周血液中EPC的数量。
结果:1)正常C57/BL小鼠角膜组织可微量表达SDF-1、CXCR4 mRNA和蛋白。SDF-1、CXCR4 mRNA和蛋白的表达于碱烧伤后3天开始可见增高,7天达高峰,14天时开始下降但仍高于正常水平;2)结膜下注射组AMD3100角膜的炎症指数、微血管密度、VEGFR2和CD34的表达水平等均低于对照组和腹腔注射组,差异有统计学意义。角膜碱烧伤后,各组之间SDF-1和CXCR4的表达水平未见显著性差异。腹腔注射组各时间点外周血中EPC的数量均显著增加,而结膜下注射组EPC的数量与注射前差异无统计学意义。
结论:SDF-1/CXCR4在碱烧伤后小鼠角膜组织中表达增加,可能在角膜碱烧伤的炎症和新生血管的形成和发展过程中发挥重要作用。角膜碱烧伤小鼠腹腔注射AMD3100可显著增加外周血EPCs的数量,而结膜下注射无此效应。结膜下注射AMD3100可减少小鼠角膜碱烧伤后新生血管的形成,其机制可能是通过竞争性拮抗SDF-1与CXCR4之间的结合,阻断其生物学功能,并减少EPCs细胞向损伤部位的聚集有关。
Purpose: To investigate the effects of subconjunctival and intraperitoneal injected AMD3100 on alkali-induced corneal neovascularization and its mechanism.
Methods: Alkali-induced corneal neovascularization animal model were constructed of in C57/BL mice. SDF-1 and CXCR4 expression in the corneal tissue were detect by immunohistochemistry, RT-PCR and Western Blot at different time points after alkali burn; AMD3100 was administrated by subconjunctival and intraperitoneal injection. And the mice were randomly divided into 4 groups: subconjunctival injection group, subconjunctival injection control group, intraperitoneal injection group and intraperitoneal injection control group; The number of inflammatory cells, microvessel density, VEGFR2, CD34, SDF-1 and CXCR4 expression in corneal tissue of each group were detected at different time points after alkali burn; Flow cytometry was used to detect the number of EPC in the peripheral blood of subconjunctival and intraperitoneal injection group at different time points after the injection of AMD3100.
Results: Normal mouse corneal tissues only contain traces of SDF-1, CXCR4 mRNA and protein. Three days after alkali burn, the expression start to increase, and reached the peak at the 7th day, 14 days began to decrease but still higher than normal levels; Corneal inflammation index, microvessel density, VEGFR2 and CD34 level in subconjunctival injection group were all lower than the control group and the intraperitoneal injection group, and the difference of the SDF-1 and CXCR4 expression level among the four groups had no statistically significant. The numbers of EPCs in peripheral blood of intraperitoneal injection group were significantly increased at different time points. And the number of EPCs in peripheral blood at different time points after injection was not increased when compared with the number before injection.
Conclusions: The expressions of SDF-1/CXCR4 are increased after alkali burn in corneal tissue of mice, which may indicated that SDF-1/CXCR4 plays an important role in the formation of corneal neovascular formation in alkali-induced corneal neovascularization. Intraperitoneal injection of AMD3100 could significantly increase the number of EPCs in peripheral blood, while subconjunctival injection was just the opposite. Subconjunctival injection of AMD3100 could reduce alkali-induced corneal neovascularization probably through competitive antagonist the binding of SDF-1 to CXCR4 and blocking its biological function, as well as reducing the EPCs gathered to the injury tissue.
引文
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