CCR3拮抗剂在实验性角膜新生血管发生过程中的作用和机制
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摘要
背景与目的
正常角膜的透明性是维持良好视力的重要因素之一。当炎症、外伤、缺氧等因素破坏了促血管生成因子和抑制血管生成因子之间的平衡，促使血管从角膜缘长入角膜，是导致视力减退甚至盲目的一个主要原因。目前关于角膜新生血管(CRNV)的发病机制尚未完全阐明，生长因子、细胞因子、趋化因子等炎症介质发挥的作用一直是研究关注的重点。
CC趋化因子受体3（CCR3）是一个G蛋白偶联受体，主要表达在嗜酸性粒细胞、嗜碱性粒细胞、Th2淋巴细胞、肥大细胞及巨噬细胞，其中嗜酸性粒细胞高表达。既往研究CCR3的主要功能是募集白细胞（主要是嗜酸性粒细胞和Th2细胞）至炎症部位，参与过敏性疾病（如哮喘）的发病机制。此外，CCR3也表达于血管内皮细胞，并参与血管生成。而且CCR3信号在脉络膜新生血管的发展中发挥了关键作用。并参与角膜缝线法诱导小鼠角膜新生血管的生长，但CCR3信号在角膜新生血管中的表达及具体作用机制仍不明确。
碱烧伤诱导的CRNV是一种被普遍认可的角膜新生血管的动物模型。为了明确CCR3信号在角膜新生血管中的表达及作用机制，本课题从建立小鼠碱烧伤CRNV模型着手，应用Real-time PCR方法检测CCR3、Eotaxin mRNA在受损角膜组织中各个时间点上的表达。应用角膜铺片荧光染色法和流式细胞术观察局部应用CCR3小分子拮抗剂SB328437进行早期干预后，对碱烧伤诱导的CRNV形成的影响。采用Real-timePCR和Western blot法从基因水平及蛋白水平检测并比较SB328437早期干预后角膜组织内VEGF表达的变化，明确CCR3信号的作用机制。并应用培养的人视网膜血管内皮细胞株（HREC），通过细胞增殖实验和管腔形成实验，进一步证实CCR3信号在血管发生、发展中的作用，为临床治疗新生血管性眼病提供了一定的理论依据。
研究方法
1. BALB/c小鼠60只，以碱烧伤诱导CRNV模型，收集碱烧伤后0d、2d、4d、7d各时间点的角膜组织，以Real-time PCR检测碱烧伤诱导小鼠CRNV过程中角膜组织内各时间点CCR3、Eotaxin mRNA的表达。
2. BALB/c小鼠60只，随机分为实验组和对照组。碱烧伤后立即予局部点眼干预：实验组使用1μmol/ml CCR3拮抗剂，对照组使用0.2%透明质酸钠，每天3次，每次3μl，共干预1周。在角膜组织碱烧伤2周后，大体拍照初步观察两组角膜新生血管形成情况后处死小鼠并摘除实验眼球，应用角膜铺片CD31荧光染色法检测新生血管区域占整个角膜的面积比例，应用流式细胞术检测角膜组织中CD31阳性细胞数目，观察CCR3拮抗剂对碱烧伤CRNV形成的影响。
3. BALB/c小鼠60只，随机分为实验组和对照组：干预方法同前，碱烧伤后4d，收集各组角膜组织，应用Real-time PCR及Western blot法从基因水平和蛋白水平检测各组角膜组织中VEGF的表达。观测CCR3信号通路与角膜组织内VEGF表达的相关性。
4. HREC细胞铺于96孔培养板中。随机分为五组，分别以0.1μmol/ml，0.2μmol/ml，0.5μmol/ml，1μmol/ml的CCR3-antagonist干预，等量的PBS缓冲液作为对照。干预24h后加入CCK8细胞增殖检测液，分光光度仪450nm波长下检测各孔OD值。通过OD值计算和分析CCR3-antagonist对HREC细胞株增殖的影响。
5. HREC细胞铺于含Matrigel的96孔培养板中，随机分为1μmol/ml CCR3-antagonist干预组和PBS缓冲液对照组。在37℃，50ml/L CO2培养箱中培养24h后，观察管腔形成情况。测定CCR3拮抗剂对HREC血管网形成的影响。
结果
1.碱烧伤后CCR3、Eotaxin mRNA的表达有升高趋势，提示CCR3-Eotaxin信号参与碱烧伤诱导的角膜新生血管的发生发展过程。
2.局部应用CCR3-antagonist能抑制碱烧伤诱导的CRNV。
3. CCR3-antagonist能抑制HREC的增殖，并在一定浓度范围内呈剂量依赖性。而且CCR3-antagonist能够抑制HREC血管网的形成。
结论
CCR3信号通路参与角膜新生血管的发生过程，阻断其信号通路则抑制血管内皮细胞的增殖和抑制血管网的形成，从而抑制新生血管的发生、发展，为临床进一步通过干预CCR3信号通路治疗新生血管性眼病提供有力的理论依据。
Background and Aim
The transparency of cornea is one of the important factors to maintain normal visualacuity. Pathological causes such as inflammation, corneal trauma, misuse of contact lensesand so on can break the balance of pro-angiogenic and anti-angiogenic molecules. Newvessels were then growing into the transparent cornea from corneal limbus, which lead tosevere impaired vision. Until now, the pathogenesis of corneal neovascularization (CRNV)has not been fully understood and the effects of growth factors, cytokines, chemokines andother inflammatory mediators on CRNV were focused.
CC chemokine receptor3(CCR3) is a G protein coupled receptor that expressedmainly in eosinophils, basophils, a subset of Th2lymphocytes, mast cells and macrophage,with the highest levels in eosinophils. It is believed to function in recruiting leukocytes,mainly the Th2cells and eosinophils, to inflammatory sites. In allergic diseases such asasthma, it can also be found expression in vascular endothelial cells, and has been shownto be involved in angiogenesis. Recently studies demonstrate that CCR3signal play pivotalroles in choroidal neovascularization. It also mediates the formation of CRNV in mice, butthe specific mechanism and potential invention role of CCR3signal in CRNV is still notclear.
Alkali-induced CRNV is a widely accepted corneal neovascularization animal models.In this study, alkali induced corneal neovascularization is used to explore the effect ofCCR3signal on the process of corneal neovascularization. Firstly, CCR3and eotaxinmRNA time kinetic expression after alkali injury was detected by Real-time PCR.Secondly, CCR3antagonist was locally administrated after alkali injury immediately andthe whole mount CD31staining and flow cytometry was used to examine the formation ofcorneal neovascular after injury. The mRNA and protein expression of VEGF in burnedcorneas was detected by Real-time PCR and Western blot. Thirdly, the effect of CCR3 antagonist on human retinal endothelial cells (HRECs) tube formation and proliferationwere detected in vitro.
Materials and Methods
1. Corneal neovascularization were induced by alkali injury of60BALB/c mice, thecorneal tissue at0,2,4,7days after alkali injury randomly collected. CCR3andeotaxin mRNA expression at the indicated time were detected by Real-time PCR.
2.60BALB/c mice after alkali injury were randomly divided into2groups and eachgroup were administrated topically with concentration of1μmol/ml CCR3-antagonistor0.2%sodium hyaluronate (HA) respectively, three times a day for1week afteralkali injury immediately.2weeks after alkali injury the experimental corneas weremicroscopically observed with slit lamp for the progression of inflammation, cornealperforation and neovascularization. The mice were killed and corneas were enucleatedand CRNV were detected and compared by corneal whole mount CD31staining orflow cytometric analysis of intracorneal CD31positive cell.
3.60BALB/c mice after alkali injury were randomly divided into experimental group (1μmol/ml CCR3-antagonist group) and control group (0.2%HA group). Theintracorneal expression of VEGF and other relative cytokines were detected andcompared between stimulated groups and vehicle groups by Real-time PCR andWestern blot.
4. To observe the CCR3signal on HREC proliferation, cultured HRECs in96well weredivided into5groups. After24h incubation with different concentrations ofCCR3-antagonist (0.1μmol/ml,0.2μmol/ml,0.5μmol/ml,1μmol/mlCCR3-antagonist) and PBS buffer, CCK8were added into culture cluster and the ODvalue in wave length450nm were measured.
5. To observe the CCR3signal on the tube formation of HREC, cultured HRECs in96well coated with Matrigel were divided into2groups (1μmol/ml CCR3-antagonistgroup and control group). After24h incubation, the tube formation were counted.
Results
1. The time kinetic expression of CCR3and eotaxin mRNA in the process of alkaliinduced corneal neovascularization suggest that CCR3signal was involved in thedevelopment of corneal neovascularization.
2. CCR3-antagonist local administration can inhibit the development of CRNV.
3. CCR3-antagonist inhibited the proliferation of HRECs in a certain range ofconcentration with a dose-dependent manner. CCR3antagonist influenced the tubeformation of HRECs.
Conclusion
Alkali-induced corneal neovascularization was inhibited by CCR3antagonist. CCR3pathway plays an important role in corneal neovascularization by regulating the endothelialcell proliferation and tube formation. CCR3-antagonist may be a new clinical treatment forcorneal neovascularization.
正常角膜的透明性是维持良好视力的重要因素之一。当炎症、外伤、缺氧等因素破坏了促血管生成因子和抑制血管生成因子之间的平衡，促使血管从角膜缘长入角膜，是导致视力减退甚至盲目的一个主要原因。目前关于角膜新生血管(CRNV)的发病机制尚未完全阐明，生长因子、细胞因子、趋化因子等炎症介质发挥的作用一直是研究关注的重点。
CC趋化因子受体3（CCR3）是一个G蛋白偶联受体，主要表达在嗜酸性粒细胞、嗜碱性粒细胞、Th2淋巴细胞、肥大细胞及巨噬细胞，其中嗜酸性粒细胞高表达。既往研究CCR3的主要功能是募集白细胞（主要是嗜酸性粒细胞和Th2细胞）至炎症部位，参与过敏性疾病（如哮喘）的发病机制。此外，CCR3也表达于血管内皮细胞，并参与血管生成。而且CCR3信号在脉络膜新生血管的发展中发挥了关键作用。并参与角膜缝线法诱导小鼠角膜新生血管的生长，但CCR3信号在角膜新生血管中的表达及具体作用机制仍不明确。
碱烧伤诱导的CRNV是一种被普遍认可的角膜新生血管的动物模型。为了明确CCR3信号在角膜新生血管中的表达及作用机制，本课题从建立小鼠碱烧伤CRNV模型着手，应用Real-time PCR方法检测CCR3、Eotaxin mRNA在受损角膜组织中各个时间点上的表达。应用角膜铺片荧光染色法和流式细胞术观察局部应用CCR3小分子拮抗剂SB328437进行早期干预后，对碱烧伤诱导的CRNV形成的影响。采用Real-timePCR和Western blot法从基因水平及蛋白水平检测并比较SB328437早期干预后角膜组织内VEGF表达的变化，明确CCR3信号的作用机制。并应用培养的人视网膜血管内皮细胞株（HREC），通过细胞增殖实验和管腔形成实验，进一步证实CCR3信号在血管发生、发展中的作用，为临床治疗新生血管性眼病提供了一定的理论依据。
研究方法
1. BALB/c小鼠60只，以碱烧伤诱导CRNV模型，收集碱烧伤后0d、2d、4d、7d各时间点的角膜组织，以Real-time PCR检测碱烧伤诱导小鼠CRNV过程中角膜组织内各时间点CCR3、Eotaxin mRNA的表达。
2. BALB/c小鼠60只，随机分为实验组和对照组。碱烧伤后立即予局部点眼干预：实验组使用1μmol/ml CCR3拮抗剂，对照组使用0.2%透明质酸钠，每天3次，每次3μl，共干预1周。在角膜组织碱烧伤2周后，大体拍照初步观察两组角膜新生血管形成情况后处死小鼠并摘除实验眼球，应用角膜铺片CD31荧光染色法检测新生血管区域占整个角膜的面积比例，应用流式细胞术检测角膜组织中CD31阳性细胞数目，观察CCR3拮抗剂对碱烧伤CRNV形成的影响。
3. BALB/c小鼠60只，随机分为实验组和对照组：干预方法同前，碱烧伤后4d，收集各组角膜组织，应用Real-time PCR及Western blot法从基因水平和蛋白水平检测各组角膜组织中VEGF的表达。观测CCR3信号通路与角膜组织内VEGF表达的相关性。
4. HREC细胞铺于96孔培养板中。随机分为五组，分别以0.1μmol/ml，0.2μmol/ml，0.5μmol/ml，1μmol/ml的CCR3-antagonist干预，等量的PBS缓冲液作为对照。干预24h后加入CCK8细胞增殖检测液，分光光度仪450nm波长下检测各孔OD值。通过OD值计算和分析CCR3-antagonist对HREC细胞株增殖的影响。
5. HREC细胞铺于含Matrigel的96孔培养板中，随机分为1μmol/ml CCR3-antagonist干预组和PBS缓冲液对照组。在37℃，50ml/L CO2培养箱中培养24h后，观察管腔形成情况。测定CCR3拮抗剂对HREC血管网形成的影响。
结果
1.碱烧伤后CCR3、Eotaxin mRNA的表达有升高趋势，提示CCR3-Eotaxin信号参与碱烧伤诱导的角膜新生血管的发生发展过程。
2.局部应用CCR3-antagonist能抑制碱烧伤诱导的CRNV。
3. CCR3-antagonist能抑制HREC的增殖，并在一定浓度范围内呈剂量依赖性。而且CCR3-antagonist能够抑制HREC血管网的形成。
结论
CCR3信号通路参与角膜新生血管的发生过程，阻断其信号通路则抑制血管内皮细胞的增殖和抑制血管网的形成，从而抑制新生血管的发生、发展，为临床进一步通过干预CCR3信号通路治疗新生血管性眼病提供有力的理论依据。
Background and Aim
The transparency of cornea is one of the important factors to maintain normal visualacuity. Pathological causes such as inflammation, corneal trauma, misuse of contact lensesand so on can break the balance of pro-angiogenic and anti-angiogenic molecules. Newvessels were then growing into the transparent cornea from corneal limbus, which lead tosevere impaired vision. Until now, the pathogenesis of corneal neovascularization (CRNV)has not been fully understood and the effects of growth factors, cytokines, chemokines andother inflammatory mediators on CRNV were focused.
CC chemokine receptor3(CCR3) is a G protein coupled receptor that expressedmainly in eosinophils, basophils, a subset of Th2lymphocytes, mast cells and macrophage,with the highest levels in eosinophils. It is believed to function in recruiting leukocytes,mainly the Th2cells and eosinophils, to inflammatory sites. In allergic diseases such asasthma, it can also be found expression in vascular endothelial cells, and has been shownto be involved in angiogenesis. Recently studies demonstrate that CCR3signal play pivotalroles in choroidal neovascularization. It also mediates the formation of CRNV in mice, butthe specific mechanism and potential invention role of CCR3signal in CRNV is still notclear.
Alkali-induced CRNV is a widely accepted corneal neovascularization animal models.In this study, alkali induced corneal neovascularization is used to explore the effect ofCCR3signal on the process of corneal neovascularization. Firstly, CCR3and eotaxinmRNA time kinetic expression after alkali injury was detected by Real-time PCR.Secondly, CCR3antagonist was locally administrated after alkali injury immediately andthe whole mount CD31staining and flow cytometry was used to examine the formation ofcorneal neovascular after injury. The mRNA and protein expression of VEGF in burnedcorneas was detected by Real-time PCR and Western blot. Thirdly, the effect of CCR3 antagonist on human retinal endothelial cells (HRECs) tube formation and proliferationwere detected in vitro.
Materials and Methods
1. Corneal neovascularization were induced by alkali injury of60BALB/c mice, thecorneal tissue at0,2,4,7days after alkali injury randomly collected. CCR3andeotaxin mRNA expression at the indicated time were detected by Real-time PCR.
2.60BALB/c mice after alkali injury were randomly divided into2groups and eachgroup were administrated topically with concentration of1μmol/ml CCR3-antagonistor0.2%sodium hyaluronate (HA) respectively, three times a day for1week afteralkali injury immediately.2weeks after alkali injury the experimental corneas weremicroscopically observed with slit lamp for the progression of inflammation, cornealperforation and neovascularization. The mice were killed and corneas were enucleatedand CRNV were detected and compared by corneal whole mount CD31staining orflow cytometric analysis of intracorneal CD31positive cell.
3.60BALB/c mice after alkali injury were randomly divided into experimental group (1μmol/ml CCR3-antagonist group) and control group (0.2%HA group). Theintracorneal expression of VEGF and other relative cytokines were detected andcompared between stimulated groups and vehicle groups by Real-time PCR andWestern blot.
4. To observe the CCR3signal on HREC proliferation, cultured HRECs in96well weredivided into5groups. After24h incubation with different concentrations ofCCR3-antagonist (0.1μmol/ml,0.2μmol/ml,0.5μmol/ml,1μmol/mlCCR3-antagonist) and PBS buffer, CCK8were added into culture cluster and the ODvalue in wave length450nm were measured.
5. To observe the CCR3signal on the tube formation of HREC, cultured HRECs in96well coated with Matrigel were divided into2groups (1μmol/ml CCR3-antagonistgroup and control group). After24h incubation, the tube formation were counted.
Results
1. The time kinetic expression of CCR3and eotaxin mRNA in the process of alkaliinduced corneal neovascularization suggest that CCR3signal was involved in thedevelopment of corneal neovascularization.
2. CCR3-antagonist local administration can inhibit the development of CRNV.
3. CCR3-antagonist inhibited the proliferation of HRECs in a certain range ofconcentration with a dose-dependent manner. CCR3antagonist influenced the tubeformation of HRECs.
Conclusion
Alkali-induced corneal neovascularization was inhibited by CCR3antagonist. CCR3pathway plays an important role in corneal neovascularization by regulating the endothelialcell proliferation and tube formation. CCR3-antagonist may be a new clinical treatment forcorneal neovascularization.
引文
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