基于NFκB/NRF-1/CXCR4信号通路研究川芎嗪调控青光眼术后滤过通道瘢痕化的作用机制

Scarring of the filtration channel is the main cause of failure of glaucoma filtration surgery. Mitomycin C, as the most classic anti-scarring drug for assisted glaucoma filtration surgery, is facing the dilemma of the drugs' big toxicity and side effects, the discontinuation of domestic drug production and the high price of imported drugs. Previous studies by the project team had confirmed that tetramethylprazine (TMP) could inhibit bleomycin-induced pulmonary fibrosis through transcription factor CXCR4 in rats. And the developed TMP eye drops had been shown to inhibit the proliferation of Tenon’s fibroblasts in glaucoma patients and alkali burn-induced corneal neovascularization in rats through NFκB/NRF-1/CXCR4. In order to further explore the fibrosis inhibition effect of TMP and CXCR4 in the glaucoma field, it is finally seeking a filtration channel scar-regulating drug with high efficiency, small side effects and convenient use, the hypothesis that "TMP regulates scarring of filtration channels after glaucoma surgery by NFκB/NRF-1/CXCR4"was been proposed. In this project, we intend to culture Tenon's fibroblasts from glaucoma patients in vitro, and conduct a living experiment by using a chronic high intraocular pressure monkey model that highly mimic the pathogenesis of open-angle glaucoma, to observe the effect of TMP eye drops on the growth of fibroblasts and scarring of filtering channels after glaucoma surgery. In this project, TMP eye drops were innovatively used to interfere with Tenon's capsule fibroblasts from glaucoma patients, and conduct a living experiment by using a chronic high intraocular pressure monkey model that highly mimic the pathogenesis of open-angle glaucoma, to observe the effect of TMP eye drops on the scarring of filtering channels after glaucoma surgery.

滤过通道瘢痕化是青光眼滤过性手术失败的主要原因。丝裂霉素C是辅助该手术最经典的抗瘢痕化药物，正面临药物副作用大和国产药物停产、进口药物价高的窘境。项目组前期研究已证明川芎嗪（TMP）通过TGF-β抑制Tenon's囊成纤维细胞增殖；通过下调转录因子CXCR4抑制博来霉素诱导的鼠肺纤维化；证实TMP滴眼液通过NFκB/NRF-1/CXCR4抑制碱烧伤诱导的鼠角膜新生血管。为进一步探索TMP和CXCR4在青光眼领域的纤维化抑制作用，为寻求一种高效率、副作用小、方便使用的瘢痕化调控药物，本项目提出“TMP通过NFκB/NRF-1/CXCR4调控青光眼术后滤过通道瘢痕化”的假设。项目创新性的使用TMP滴眼液干预体外培养的青光眼患者Tenon’s囊成纤维细胞，并应用高度模拟开角型青光眼发病机制的慢性高眼压猴模型开展活体实验，观察TMP滴眼液调控青光眼滤过术区瘢痕化的疗效性。为探索瘢痕调控提供新思路。

自1983年将抗代谢药物引入青光眼滤过手术以提高成功率以来，丝裂霉素C（MMC）已成为目前辅助青光眼滤过手术最经典的抗瘢痕化的药物。由于MMC的细胞周期非特异性抑制的药物特性，致使其在抑制术区成纤维细胞增殖的同时，还会对周围组织的其他正常细胞（如结膜细胞、杯状细胞、角膜缘干细胞）产生毒副作用。且近年来，国产MMC 药物停止生产，进口MMC药物存在价高等各种问题，MMC目前在国内应用尚被制约。因此，寻求替代药物是最直接的解决途径，也是青光眼治疗中迫切需要解决的问题。. 祖国医药博大精深，本项目探索了中药川芎嗪，实验结果表明川芎嗪具有抑制转化生长因子-β2诱导的人眼Tenon’s囊成纤维细胞增殖、抑制 TGF-β2 诱导的 a-SMA在 HTF 中的表达、减弱 TGF-β2 介导的 B-肌动蛋白在 HTF 中重构、下调TGF-β2诱导的细胞外基质蛋白FN， TMP可以通过NFκB/NRF-1信号通路减轻TGF-β2的纤维化作用。川芎嗪滴眼液使用方便，TMP组术后28天眼前段照相和眼前段OCT 均提示滤过泡良好的隧道空间，TMP能维持良好的滤过功能，有望抑制猴青光眼手术后滤过术区瘢痕化，提高青光眼手术疗效，活体角膜内皮检测提示川芎嗪对眼部组织的安全性。川芎嗪为青光眼瘢痕化这一难题提供新的治疗方案，有望能替代MMC去处理青光眼滤过术区瘢痕化问题。