Ocular Inflammatory Mediators in the Pathophysiology of Diabetic Retinopathy

项目摘要 糖尿病视网膜病变（DR）是全球范围内致盲的主要原因。许多患者的DR进展， 预防措施，如血糖和血压控制。其他可用的治疗方法需要 侵入性眼部注射并且通常无效-DR仍然是法律的失明的主要原因， 工作年龄的成年人。目前的诊断测试无法识别早期疾病阶段或预测疾病进展。 因此，需要新的生物标志物和治疗策略。 DR是一种确定的炎症性疾病，涉及白细胞。许多炎性细胞因子（产物 白细胞）在晚期DR和糖尿病患者的房水和玻璃体中持续升高 黄斑水肿（DME）。炎症介质是可能预测DR的直接生物标志物的候选者 进展以及治疗反应。迄今为止，唯一有效的预后DR生物标志物是 循环血红蛋白标志物糖化血红蛋白（HbA 1C）。然而，HbA 1C筛查反映了葡萄糖 对照，其指示与DR病理相反的疾病风险。 我们的中心假设是眼内炎症介质如PGE 2、IL-6和IL-8是眼内炎症的标志物。 DR严重程度，从而预测疾病进展的风险。同样重要的是，它们代表了潜在的新颖性， 抑制的目标。我们最近证明，局部应用酮咯酸，一种非甾体抗- 炎性药物，达到治疗玻璃体水平，并显着降低几个升高 这些观察结果及其商业可用性为DR眼的炎症介质提供了理论基础， 研究炎症介质与DR严重程度的关系以及慢性炎症反应的长期影响。 在糖尿病患者中局部施用酮咯酸。 我们目前的目标包括确认炎症介质是系统性糖尿病和DR的生物标志物 在水中的进展。像玻璃体液一样，房水反映局部眼部炎症， 然而，在技术上更容易收集，风险更小。我们还将确定长期的影响， 酮咯酸应用对眼内细胞因子水平、DR进展和DME发生率的影响。我们的建议是 首次使用角膜渗透性NSAID治疗DR。 我们相信眼部局部炎症控制将改变糖尿病患者未来的治疗选择 面对失明在DR的所有阶段跟踪和抑制局部炎症介质具有能力 每年减少或预防数百万患者的残疾。

Project Summary Diabetic retinopathy (DR) is a major cause of blindness worldwide. DR progresses in many patients despite preventable measures such as blood sugar and blood pressure control. Other available treatments require invasive eye injections and are often ineffective—DR remains the leading cause of legal blindness among working-age adults. Current diagnostic tests fail to identify early disease stages or predict disease progression. Consequently, new biomarkers and therapeutic strategies are needed. DR is an established inflammatory disease with leukocyte involvement. Many inflammatory cytokines (products of leukocytes) are consistently elevated in the aqueous and vitreous of patients with advanced DR and diabetic macular edema (DME). Inflammatory mediators are candidates for direct biomarkers that may predict DR progression as well as treatment response. To date the only validated prognostic DR biomarker is the circulating glycemia marker glycated hemoglobin (HbA1C). HbA1C screening, however, reflects glucose control, which indicates disease risk as opposed to DR pathology. Our central hypothesis is that intraocular inflammatory mediators such as PGE2, IL-6, and IL-8 are markers of DR severity and therefore predict risk of disease progression. Equally important, they represent potential novel targets for inhibition. We have recently demonstrated that topically applied ketorolac, a nonsteroidal anti- inflammatory drug, achieves therapeutic vitreous levels and significantly reduces several elevated inflammatory mediators in eyes with DR. These observations and its commercial availability provide rationale to investigate the relationship of inflammatory mediators with DR severity and the long-term effects of chronic topical administration of ketorolac in diabetic patients. Our current goals include confirming inflammation mediators are biomarkers of both systemic diabetes and DR progression in the aqueous. Like the vitreous humor, the aqueous reflects localized ocular inflammation, however, is technically easier to collect with less risk. We will also determine the long-term effects of sustained ketorolac application on intraocular cytokine levels, DR progression, and DME incidence. Our proposal is the first to use a cornea-permeable NSAID for the treatment of DR. We believe local inflammation control in the eye will transform future treatment options for diabetic patients facing blindness. Tracking and inhibiting local inflammatory mediators through all DR stages has the capacity to reduce or prevent disability in millions of patients per year.