血小板源性生长因子α和β受体酪氨酸激酶抑制剂对兔PVR的治疗作用

Therapeutic effect of platelet-derived growth factor α and β receptor tyrosine kinase inhibitor on rabbit proliferative vitreoretinopathy

目的 评价特异性的血小板源性生长因子 (PDGF) α受体酪氨酸激酶阻断剂AG12 96和 β受体酪氨酸激酶阻断剂AG12 95对兔PVR的治疗作用。 方法 兔结膜成纤维细胞结膜成纤维细胞培养 ,用MTT法检测PDGF AA和 BB以及AG12 95和AG12 96对兔结膜成纤维细胞的增殖状况的影响。建立PVR动物模型 ,玻璃体腔内分别给予AG12 95和AG12 96 ,用牵引性视网膜脱离 (tractionalretinaldetachment,TRD)的发生率评价药物的体内疗效。眼视网膜电图检查和HE染色分析药物的毒性。结果 体外 10 μmol·L-1的AG12 95和AG12 96均可显著抑制由PDGF AA和 BB诱导的成纤维细胞的增生 ,体内 10 0 μmol·L-1AG12 95和AG12 96均减缓了兔TRD的发生 ,但AG12 95的作用仅持续至 14d。相同浓度的AG12 96和AG12 95相比 ,作用更持久。在 2个治疗组中 ,均未发现明显的网膜毒性。结论 特异性的PDGF α受体酪氨酸激酶抑制剂AG12 96可显著抑制兔TRD的发生 ,其作用明显强于PDGF β受体酪氨酸激酶抑制剂AG12 95 ,提示PDGF对PVR的促进作用主要由α受体介导 。

Objective To determine the effect of the tyrphostin AG1296 and AG1295,selective blockers of platelet derived growth factor(PDGF)α and β receptor tyrosine kinase, on PVR development.Methods Rabbit conjunctival fibroblasts cells were cultured. The effect of AG1295,AG1296,PDGF AA and PDGF BB on rabbit conjunctival fibroblasts proliferation was evaluated by MTT assay.Homologous rabbit conjunctival fibroblasts were injected intravitreally to make animal PVR model,followed by injection of 100 μmol·L -1 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. Results Both AG1295 and AG1296(10μmol·L -1 ) 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 -1 of AG1295 or AG1296, but the effect of AG1295 only lasted 14 days.Inhibitive effect of AG1296 was longer than that of AG1295. No significant histologic or retinal functional damage was found in both drug treated group.Conclusion PDGF α and β receptor 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 PDGF α RTK inhibitor indicated that PDGF α receptor is more important in the development of PVR, and inhibition of this path could be a useful way to prevent PVR.