The treatment of uveitic cystoid macular edema with topical Interferon gamma

我们假设，正常的视网膜水化是通过视网膜色素上皮上干扰素-γ的双峰功能的平衡来维持的。越来越多的证据有力地表明，免疫系统在血管生成中发挥着重要作用。促炎症细胞因子，如IFNG、IL-6、TNFa和IL-1b是眼部炎症性疾病发病机制中的主要细胞因子，并被证明在RPE上有受体。肿瘤坏死因子α、IL-6和IL-1b被认为是促血管生成因子。然而，IFNG被广泛认为是一种抗血管生成的细胞因子，因为它对其他器官系统的内皮细胞生长和毛细血管形成有抑制作用。我们评估了干扰素对JAK/STAT通路的影响，JAK/STAT通路也存在于人RPE细胞中。进行液体转运试验，以检查干扰素是否引起通过hfRPE单层的液体转运的变化。在基础浴中加入IFNG(10 ng/ml)使JV增加8.6 ulcm-2hr-1，反映了从视网膜到组织脉络膜一侧液体吸收的增加。跨皮细胞电位(TEP)和总组织阻力(RT)检测细胞活性无明显变化。在10个实验中，平均JV从12.9±1.6增加到20.5±3.1 ulcm-2hr-1(Mean+-S.E.M.，P&lt；0.01)。使用先前测试的视网膜脱离的在体啮齿动物模型来测量INFg对视网膜脱离后再吸收的影响。最初的脱离是通过向视网膜下间隙(SRS)注入大约1UL的渗透平衡的改良磷酸盐缓冲盐水(MPBS)溶液来造成的。使用在前30分钟内体积变化不超过10%的分离装置来测试INFg效应。在OCT成像测量脱离稳定体积后，通过滴眼液(Celluvisc)将INFg(40ul 100 ng/ml)滴入眼前表面。在不同时间点记录一系列三维OCT图像。在观察的第一个小时内，在眼球前表面添加INFg导致视网膜脱离体积显著、迅速地减少50%。这一结果与观察到的RPE细胞体外液体转运增加是一致的。我们假设，在正常的RPE细胞中，这两条通路同时发挥作用，以维持正常的视网膜水化。Jak/Stat通路如果从基底侧受到刺激，就会诱导液体吸收，从而解决水肿症的异常蓄积。因此，使用INFg可以逆转葡萄膜炎相关的病理改变。

We hypothesize that proper retinal hydration is maintained by a balance of the bimodal functions of interferon gamma on the retinal pigment epithelium. Mounting evidence strongly suggests that the immune system plays an important role in angiogenesis. Pro-inflammatory cytokines, such as IFNg, IL-6, TNFa and IL-1b are the major cytokines in the pathogenesis of ocular inflammatory diseases and been shown to have receptors on RPE. TNFa, IL-6 and IL-1b are regarded as pro-angiogenic factors. However, IFNg is widely accepted as an anti-angiogenic cytokine due to its inhibitory effect on endothelial cell growth and capillary formation in other organ systems. We have evaluated the effect of interferon gamma on the JAK/STAT pathway, a signal transduction pathway also present in Human RPE cells. Fluid transport assays were performed to examine whether IFN&#61543; induced changes in fluid transport across hfRPE monolayers. IFNg (10 ng/ml) addition to the basal bath increased JV by 8.6 ulcm-2hr-1, reflecting an increase in fluid absorption from the retinal to the choroidal side of the tissue. There were no apparent changes in cell viability as measured by transepithelial potential (TEP) and total tissue resistance (RT). In 10 experiments, the mean JV increased from 12.9 +_ 1.6 to 20.5 +_ 3.1 ulcm-2hr-1 (mean +- s.e.m., P< 0.01). A previously tested in vivo rodent model of retinal detachment was used to measure the effect of INFg on re-absorption following retinal detachment. Initial detachment was created by injecting approximately 1ul of osmotically-balanced, modified phosphate-buffered saline (MPBS) solution into the sub-retinal space (SRS). Detachments that did not change in volume more than 10% in the first 30 minutes were used to test INFg effects. After detachment stabilization volume was measured by OCT imaging, INFg (40ul of 100ng/ml) was added to the anterior surface of the eye via eye drops (Celluvisc). A series of 3D OCT images were recorded at different time point. Addition of INFg to the anterior eye surface caused a significant, rapid 50% decrease in retinal detachment volume in the first hour of observation. This result is consistent with the observed fluid transport increase in RPE cells in vitro. We hypothesize that in the normal RPE cell, both pathways are functioning simultaneously to maintain the normal retinal hydration. The Jak/Stat pathway, if stimulated from basal side, will induce fluid absorption to resolve the abnormal accumulation of edema. Therefore using INFg can provide therapeutic effect to reverse pathological changes associated with uveitis.