Role Of Retinal Pigment Epithelium In Retinal Disorders

视网膜色素上皮（RPE）是存在于眼睛中的视网膜和脉络膜之间的单层细胞，对于视网膜的正常功能至关重要。视网膜的许多炎性、感染性和遗传性疾病与RPE的变性和/或功能障碍有关。我们已经开发了人RPE细胞培养系统，并以此为模型来研究RPE在视网膜疾病的病理生理学中的各种作用。我们将注意力集中在转化生长因子-β（TGF-β）上，因为TGF-β参与增殖性、炎症性和感染性病因的视网膜疾病。弓形虫（Toxoplasma gondii，T.弓形虫），一种原生动物寄生虫，感染导致视网膜的炎症和坏死，并且是葡萄膜炎的常见原因之一。当T.弓形虫感染体外培养的RPE细胞后，我们观察到TGF-β（一种天然抗炎剂）的mRNA和蛋白分泌增加。这些结果表明宿主视网膜细胞和T.在视网膜脉络膜炎的发病机制中可能起积极作用。 脉络膜新生血管（CNV）是老年性黄斑变性（ARMD）的主要病变之一，ARMD是老年人视力损害的主要原因。TGF-β在玻璃体、视网膜和RPE中的高表达与视网膜纤维化和脉络膜新生血管形成密切相关。由于血管内皮生长因子（VEGF）与CNV相关，我们研究了RPE在VEGF表达中的作用。发现TGF-β是VEGF分泌的有效诱导剂。RT-PCR分析表明VEGF的121、165和189个氨基酸的异构体的存在，其被TGF-β上调。通过使用丝裂原活化蛋白激酶的特异性抑制剂，我们发现TGF-β似乎通过MAPK和smad途径转录激活VEGF。TGF-β对VEGF表达的调节强烈提示TGF-β在ARMD的CNV中起重要作用。

Retinal pigment epithelium (RPE), a single layer of cells present between the retina and choroid in the eye, is vital for the normal functioning of the retina. Many of the inflammatory, infectious and hereditary diseases of the retina are associated with the degeneration and /or dysfunction of the RPE. We have developed human RPE cell culture system and have used this as a model to investigate the various roles of RPE in the pathophysiology of retinal disorders. We have focussed our attention on Transforming Growth factor-beta (TGF-b), since TGF-b is involved in retinal disorders of proliferative, inflammatory and infectious etiology. Retinochoroiditis induced by Toxoplasma gondii (T. gondii ), a protozoan parasite, infections results in inflammation and necrosis of the retina, and is one of the common causes of uveitis. When T. gondii infects RPE cells in vitro, we observed an elevated mRNA and protein secretion of TGF-b, a native anti-inflammatory agent. These results indicate interactions between host retinal cells and T. gondii that may play an active role in the pathogenesis of retinochoroiditis. Choroidal neovascularization (CNV) is one of the major events in the age related macular degeneration (ARMD), a leading cause of visual impairment in the aged population. Elevated expression of TGF-b in vitreous, retina and RPE has been closely correlated with the retinal fibrosis and choroidal neovascularization. Since vascular endothelial growth factor (VEGF) is associated with CNV, we have examined the role of RPE in VEGF expression. TGF-b is found to be the potent inducer of VEGF secretion. RT-PCR analyses indicated the presence of 121,165 and 189 aa isoforms of VEGF, which are up regulated by TGF-b. By using specific inhibitors of mitogen activated protein kinases, we found that TGF-b appears to transcriptionally activate VEGF through MAPK and smad pathway. Regulation of the expression of VEGF by TGF-b strongly suggests an important role for TGF-b in CNV in ARMD.