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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。酪氨酸激酶的激活对生长因子介导的细胞增殖起着重要作用。本研究评价特异性的PDGF-α受体酪氨酸激酶阻断剂AG1296和β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 conjunctival fibroblasts,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 retinal detachment, TRD)的发生率评价药物的体内疗效。结果:体外10μmol/L的AG1295和AG1296均可显著抑制由PDGF-AA和-BB诱导的成纤维细胞的增生,体内100μmol/LAG1295和AG1296均减缓了兔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-α受体酪氨酸激酶抑制剂AG129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AG1295,提示PDGF对PVR的促进作用主要由α受体介导,这一通路的阻断可能成为治疗PVR的一种方法。
Objective: Platelet-derived growth factor (PDGF) can cause proliferative vitreoretinopathy. Activation of tyrosine kinases plays an important role in growth factor-mediated cell proliferation. This study evaluated the therapeutic effect of specific PDGF-α receptor tyrosine kinase inhibitor AG1296 and β receptor tyrosine kinase inhibitor AG1295 on PVR in rabbits. Methods: Rabbit conjunctival fibroblasts (RCF) were cultured. The effects of PDGF-AA and -BB, AG1295 and AG1296 on the proliferation of RCF were detected by MTT assay. Electroretinography and HE staining were used to analyze the toxicity of the drug. The animal model of PVR was established. AG1295 and AG1296 were given respectively in the vitreous cavity. The in vivo efficacy of the drug was evaluated by the incidence of tractional retinal detachment (TRD). RESULTS: Both AG1295 and AG1296 inhibited the proliferation of fibroblasts induced by PDGF-AA and -BB in vitro. Both in vivo and in vivo, 100 μmol / L AG1295 and AG1296 attenuated TRD in rabbits, however, the effect of AG1295 only lasted until 14d. The same concentration of AG1296 compared with AG1295, the role of more durable. In both treatment groups, no significant retinal toxicity was found. CONCLUSION: Specific PDGF-α receptor tyrosine kinase inhibitor AG129 can significantly inhibit the occurrence of TRD in rabbits and its effect is stronger than that of PDGF-β receptor tyrosine kinase inhibitor AG1295, suggesting that PDGF promotes PVR Mainly mediated by alpha receptors, blockade of this pathway may be a treatment for PVR.