血小板源性生长因子受体a在兔增殖性玻璃体视网膜病变中的作用

摘要

目的 血小板源性生长因子(platelet-derived growth factor,PDGF)可引起增殖性玻璃体视网膜病变,本研究评价特异性的PDGF-a受体酪氨酸激酶阻断剂AG1295对兔PVR的治疗作用.方法 兔结膜成纤维细胞(rabbit conjunctical fibroblats,RCF)培养,用MTT法检测PDGF-AA和-BB以及AG1295和AG1296对兔RCF增殖状况的影响.眼视网膜电图检查和HE染色分析药物的毒性.建立PVR动物模型,玻璃体腔内分别给予AG1295和AG1296.用牵引性视网膜脱离(tractional ratinal detachment,TRD)t的发生率评价药物的体内疗效.结果 体外10umol/L的AG1295和AG1296和均可显著抑制由PDGF-AA和-BB诱导的成纤维细胞的增生,体内100umol/L AG1295和AG1296均减慢了兔TRD的发生,但AG1295的作用仅持续至14d.相同浓度的AG1296和AG1295相比,作用更持久.在两个治疗组中,均未发现明显的视网膜毒性.结论 特异性的PDGF-a受体酪氨酸激酶抑制剂AG1296可显著抑制兔TRD的发生,其作用明显强于PDGF-a受体酪氨激酶抑制AG1295,提示PDGF对PBR的促进作用主要由a受体介导,这一通路的阻断可能成为治疗PVR的一种方法.%AIM:Receptor tyrosine kinase (RTK) activation is critical for growth factor-mediated cell proliferation. The present study was designed to determine the effect of the tyrphostin AG1295 and AG1296, a selective blocker of PDGF βand αRTK,on proliferative vitreoretinopathy (PVR) development.rn METHODS:Rabbit conjunctival fibroblasts (RCF) cells were cultured.The effects of AG1295, AG1296,PDGF-AA and PDGF-BB on RCF proliferation are evaluated by MTT assay.Homologous rabbit conjunctival fibroblasts were injected intravitreally to make animal PVR model, followed by injection of 100μmol/L of AG1295 or AG1296 respectively. The presence of tractional retinal detachment (TRD) was assessed to evaluate the effect of AG1295 and AG1296 in vivo .Electroretinography and histologic studies were performed after intravitreal injection of AG1295 into untreated eyes to evaluate toxicity. rnRESULTS: Both AG1295 and AG1296 (10μmol/L) significantly inhibited rabbit conjunctival fibroblast cell growth stimulated by PDGF-AA or -BB in vitro.Development of TRD was significantly reduced (P<0.05) with 100 μmol/L of AG1295 or AG1296 in vivo, but the effect of AG1295 only present till day 14. Inhibitive effect of AG1296 is longer than that of AG1295.No significant histologic or retinal functional damage was found in both drug-treated groups. rnCONCLUSION: PDGF αand βreceptor specific inhibitor AG1296 and AG1295 attenuated PVR without significant side effects in rabbits, and AG1296 was better than AG1295. The much longer and stronger therapeutic effect from PDGFαreceptor inhibitor indicated that PDGF α receptor is more important in the development of PVR, and inhibition of this pathway could be a useful treatment alternative to prevent PVR.