OCULAR PATHOGENESIS AND THERAPY OF BACTERIAL KERATITIS

我们的目的是探讨眼部致病假单胞菌 铜绿假单胞菌性角膜炎的目的是限制化疗， 细菌因素和宿主免疫和非免疫因素， 间质损伤细菌性角膜炎通常会导致严重的炎症， 不可逆的角膜疤痕，失明，需要角膜 移植细菌性角膜炎的发病率一直在大幅度上升 部分原因是隐形眼镜的使用越来越多。假单胞菌性角膜炎 发展迅速，导致角膜瘢痕和视力丧失。激烈 抗生素治疗最终阻止了感染的扩散， 消除细菌，但不能防止疤痕。疤痕结果 从一个不明确的细胞变化序列开始， 传染过程我们的总体目标是找到一种 与抗生素治疗相容的方案，其抑制细菌 以及引起角膜瘢痕形成的急性感染的宿主反应物。 具体目标是：1）确定东道国因素对 组织损伤和炎症; 2）确定细菌因素的作用 组织损伤和炎症; 3）开发新的化疗药物 假单胞菌角膜炎的治疗方案。检查贡献主机 各种现有药物的有效性 将测试它们限制组织损伤和炎症的能力 在同时接受杀菌抗生素治疗的眼中。药物来 测试包括类固醇和非甾体抗炎药（NSAID）， 抑制破坏性宿主非特异性免疫反应和蛋白酶抑制剂 以抑制宿主和细菌的蛋白水解酶。评价 细菌因子（碱性蛋白酶、外毒素A、弹性蛋白酶和蛋白酶 IV）将使用野生型菌株和外蛋白缺陷假单胞菌 诱导炎症反应能力不同的突变体， 组织损伤关联外蛋白缺陷突变体的毒力 其胞外蛋白的产生将允许鉴定特定的 参与细菌性角膜炎发病机制的外蛋白。 这些突变体在正常和 免疫功能低下的宿主将提供更多关于 介导角膜损伤的特异性外蛋白。开发新 化疗方案将涉及已建立的和新的 根据细菌因子的鉴定开发药物 介导组织损伤和炎症反应。改善药物释放 方法（胶原蛋白屏蔽和离子电渗疗法）将用于最大化 提供抗生素以杀死细菌和辅助治疗， 以限制角膜炎症和损伤。最终， 预防或减轻角膜瘢痕形成将提供显著的益处， 减少视力损害的发生率和手术的需要， 角膜病理损伤患者的干预 细菌性角膜炎

Our objective is to investigate the ocular pathogenesis of Pseudomonas aeruginosa keratitis with the goal of limiting by chemotherapy the bacterial factors and host immune and nonimmune factors that produce stromal damage. Bacterial keratitis often results in intense inflammation, irreversible scarring of the cornea, blindness, and the need for a corneal transplant. The incidence of bacterial keratitis has been rising in large part because of the increased use of contact lenses. Pseudomonas keratitis evolves rapidly, resulting in corneal scarring and loss of vision. Intense antibiotic therapy arrests the spread of the infection, ultimately eliminating the bacteria, but fails to prevent scarring. Scarring results from an ill-defined sequence of cellular changes initiated by the infectious process. Our overall goal is to identify a chemotherapeutic regimen compatible with antibiotic therapy which inhibits the bacterial and host reactants of the acute infection that induce corneal scarring. The specific aims are to: 1) determine the contribution of host factors to tissue damage and inflammation; 2) determine the role of bacterial factors in tissue damage and inflammation; and 3) develop new chemotherapeutic regimens for Pseudomonas keratitis. To examine the contributory host factors, the effectiveness of a variety of presently available medications will be tested for their ability to limit tissue damage and inflammation in eyes concurrently treated with bactericidal antibiotics. Medications to be tested include steroids and nonsteroidal anti-inflammatories (NSAID) to inhibit damaging host nonspecific immune reactions and protease inhibitors to inhibit both host and bacterial proteolytic enzymes. Evaluation of bacterial factors (alkaline protease, exotoxin A, elastase, and protease IV) will employ wild-type strains and exoprotein-deficient Pseudomonas mutants that vary in their ability to induce inflammatory reactions and tissue damage. Correlating the virulence of exoprotein-deficient mutants and their exoprotein production will allow identification of specific exoproteins involved in the pathogenesis of bacterial keratitis. Evaluation of the virulence of these mutants in normal and immunocompromised hosts will provide further information on the role of specific exoproteins in mediating cornea damage. Development of new chemotherapeutic regimens will involve both established and newly developed medications based on the identification of bacterial factors mediating tissue damage and inflammatory reactions. Improved drug delivery methods (collagen shields and iontophoresis) will be used to maximize delivery of antibiotics to kill bacteria and of adjunct therapies designed to limit corneal inflammation and damage. Ultimately, the ability to prevent or mitigate corneal scarring will provide significant benefits by reducing the incidence of visual impairment and the need for surgical intervention in patients with corneas damaged by the pathologic processes of bacterial keratitis.