Role of Retinal Pigment Epithelium In Retinal Disorders

视网膜色素上皮在视网膜疾病中的作用

• 批准号: 6968487
• 负责人: CHANDRASEK N NAGINENI
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6968487
• 关键词: aging; angiogenesis; cytokine; diabetic retinopathy; enzyme inhibitors; fibroblasts; gene expression; growth factor receptors; human tissue; inflammation; macular degeneration; mitogen activated protein kinase; necrosis; platelet derived growth factor; polymerase chain reaction; proliferative vitreoretinopathy; receptor expression; retina circulation; retina detachment; retina disorder; retinal pigment epithelium; tissue /cell culture; transforming growth factors; uvea disorder; uveitis; vascular endothelial growth factors

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 other diseases of the retina are associated with the degeneration and /or dysfunction of the RPE. We have developed a 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 focused our attention on Transforming Growth factor-beta (TGF-b), since TGF-b is involved in retinal disorders of proliferative, inflammatory and infectious etiology. Retinal and Choroidal neovascularization (CNV), observed during age related macular degeneration (ARMD) and proliferative vitreoretinopathy (PVR) associated with retinal detachments, are the leading causes of visual impairment. Elevated expression of TGF-b in vitreous, retina and RPE has been closely correlated with the retinal fibrosis and CNV. Platelet derived growth factors (PDGF) are known to be associated with retinal proliferative and angiogenic disorders such as PVR and ARMD. PDGF promotes proliferation and migration of fibroblasts, pericytes and smooth muscle cells. Our studies indicated that TGF-b is a potent inducer of PDGF-AA and PDGF-AB in RPE cells while choroidal fibroblasts (CHF) do not produce PDGF. Receptors for PDGF are highly expressed on CHF but not on RPE. Human recombinant PDGF-isoforms (AA, AB, BB) significantly enhanced CHF proliferation, elongation and migration. In contrast no significant effects on RPE proliferation and migration were observed. These results show that PDGF secreted by RPE cells (stimulated by TGF-b) act on nearby connective tissue cells (fibroblasts) and possibly on vascular pericytes and smooth muscle cells. Consequent promotion of proliferation and migration of these target cells results in the pathogenesis of PVR and CNV in ARMD. Regulation of the expression of PDGF in RPE by TGF-b strongly suggests an important role for TGF-b in neovascularization associated with retinal disorders such as PVR and ARMD. Our previous and ongoing studies have shown a prominent role for TGF-b in many of the retinal diseases such as ARMD, PVR, and diabetic retinopathy as well as in inflammatory diseases. However, the sources and production of TGF-b by retinal resident cells were not clearly known. We have examined the role of various cytokines and other mediators in the regulation of the expression of TGF-b by RPE. Our results demonstrated a differential role for interferon-g, which enhanced TGF-b1 but inhibited TGF-b2 production. Interestingly, other inflammatory mediators such as tumor necrosis factor-a and interleukin-1 enhanced the secretion of both TGF-b1 and TGF-b2. These observations were corroborated by mRNA analyses by Real-time and conventional RT-PCR methods. These contrasting effects of IFN-g on TGF-b1 and TGF-b2 sheds new light on the possible differential actions of TGF-b1 and TGF-b2 in the pathophysiology of retinal diseases. Further studies are in progress to evaluate the potential role of TGF-b1 and TGF-b2 and their receptors in the retinal diseases.

视网膜色素上皮(RPE)是视网膜和眼部脉络膜之间的单层细胞，对视网膜的正常功能至关重要。许多炎症性、感染性和其他视网膜疾病都与RPE的退化和/或功能障碍有关。我们已经开发了一个人类RPE细胞培养系统，并将其作为一个模型来研究RPE在视网膜疾病的病理生理学中的各种作用。由于转化生长因子-β与增殖性、炎症性和感染性视网膜病变有关，我们将注意力集中在转化生长因子-β。在老年性黄斑变性(ARMD)和增殖性玻璃体视网膜病变(PVR)合并视网膜脱离时观察到的视网膜和脉络膜新生血管(CNV)是导致视力损害的主要原因。转化生长因子-β在玻璃体、视网膜和RPE中的高表达与视网膜纤维化和新生血管的形成密切相关。已知血小板衍生生长因子(PDGF)与视网膜增生性疾病和血管生成疾病有关，如PVR和ARMD。PDGF促进成纤维细胞、周细胞和平滑肌细胞的增殖和迁移。我们的研究表明，在RPE细胞中，转化生长因子-β是一种有效的PDGF-AA和PDGF-AB的诱导剂，而脉络膜成纤维细胞(CHF)不产生PDGF。PDGF受体在CHF中高表达，但在RPE中低表达。人重组PDGF异构体(AA、AB、BB)显著促进CHF的增殖、延长和迁移。相反，未观察到对RPE的增殖和迁移有明显影响。这些结果表明，由RPE细胞分泌的PDGF(在转化生长因子-b的刺激下)作用于附近的结缔组织细胞(成纤维细胞)，并可能作用于血管周细胞和平滑肌细胞。随后这些靶细胞的增殖和迁移的促进导致了ARMD的PVR和CNV的发病。转化生长因子-β对视网膜色素上皮中PDGF表达的调节强烈提示转化生长因子-β在PVR和ARMD等视网膜病变相关的新生血管形成中起重要作用。 我们之前和正在进行的研究表明，转化生长因子-b在许多视网膜疾病中发挥着重要作用，如ARMD、PVR、糖尿病视网膜病变以及炎症性疾病。然而，视网膜驻留细胞产生转化生长因子-β的来源和产生尚不清楚。我们研究了各种细胞因子和其他介质在RPE调节转化生长因子-β表达中的作用。我们的结果显示了干扰素-g的不同作用，它促进了转化生长因子-β1的产生，但抑制了转化生长因子-β2的产生。有趣的是，其他炎症介质，如肿瘤坏死因子-a和白介素1，促进了转化生长因子-β1和转化生长因子-β2的分泌。这些观察结果得到了Real-Time和常规RT-PCR方法的信使核糖核酸分析证实。这些干扰素-β对转化生长因子-β1和转化生长因子-β2的对比作用为揭示转化生长因子-β1和转化生长因子-β2在视网膜疾病的病理生理过程中可能的不同作用提供了新的线索。进一步的研究正在评估转化生长因子-β1和转化生长因子-β2及其受体在视网膜疾病中的潜在作用。