选择性非肽类CXCR2抑制剂SB225002对大鼠脉络膜新生血管的抑制作用

Selective non-peptide CXCR2 antagonist SB225002 inhibits choroidal neovascniarization in rat model

目的观察CXC趋化因子受体2（CXCR2）的选择性非肽类抑制剂SB225002对大鼠脉络膜新生血管形成的抑制作用。方法实验研究。使用激光对12只棕色挪威大鼠诱导脉络膜新生血管（CNV），6只光凝术后立即玻璃体腔注射10μmol／L的SB225002，6只给予二甲基亚砜作为对照。3只大鼠未给予激光光凝及眼内注射，作为阴性对照用于定量实时逆转录聚合酶链反应（qRT—PCR）检查。光凝术后7d，采用荧光素眼底血管造影分析CNV损伤荧光素渗漏的变化，脉络膜铺片定量分析CNV面积的变化，qRT-PCR观察视网膜色素上皮一脉络膜复合物CXCR2和血管内皮生长因子（VEGF）mRNA表达水平的变化。荧光素眼底血管造影图像的渗漏评分比较采用Mann—Whitney检验；CNV面积比较采用配对t检验；CXCR2或VEGF的mRNA水平比较采用Wileoxon检验。结果10μmol／L的SB225002能有效抑制CNV损伤造成的荧光素渗漏。光凝术后7d10μmol／L的SB225002组脉络膜铺片的CNV面积为（10531±4627）μm^2，DMSO组为（30974±6762）μm^2，10μmol／L的SB225002组面积较DMSO组缩小66％（t=2．54，P=0．001）。10μmol／LSB225002组CXCR2mRNA和VEGFmRNA相对值分别为1．22±0．92和1．93±0．87，与DMSO组的差异具有统计学意义（t=8．54，3．61；P=0．007，0.002）。结论SB225002在CNV形成早期通过阻断IL-8与CXCR2的结合，能够有效抑制血管的新生，提示治疗CNV的一个新的化疗干预机制。

Objective We tested the applicability of using SB225002, a selective non-peptide CXCR2 inhibitor, for inhibiting experimental choroidal neovascularization （CNV） in Brown Norway （BN） rats. Methods It was an experimental study. CNV was induced in 12 adult BN rats with laser photocoagulation. 10 μmol/L SB225002 was administered into the vitreous of 6 rats right after laser injury. DMSO was used as the control in other 6 rats. Three BN rats were served as non-laser-treated controls in quantitative real-time reverse transcription PCR （qRT-PCR） analysis. Fluorescein angiography was performed on day 7 postoperatively to observe the fluorescein leakage of CNV. Quantitative analysis on choroidal fiat mounts was performed to evaluate the area changes of CNV lesions, qRT-PCR analysis was used to compare the changes shown by the SB225002-, DMSO- and non-laser-treated BN rats with regard to mRNA levels of CXCR2 and vascular endothelial growth factor （VEGF） in the RPE-choroidal complex. Results SB225002 （10 μmol/L） significantly inhibited the fluorescein leakage （P 〈0. 05） , the extent of neovascularization on choroidal flat mount of rat CNV model was decreased up to 66% （ t = 2. 54, P = 0. 001 ）. CXCR2 and VEGF mRNA were reduced significantly following this treatment （t = 8. 54,3.61 ;P = 0. 007,0. 002）. Conclusion SB225002 inhibits angiogenic activity of IL-8 by blocking its binding with CXCR2 in the early stage of CNV, which may provide a potential new therapeutic strategy for CNV.