OCULAR PATHOGENESIS AND THERAPY OF BACTERIAL KERATITIS

描述：（来自摘要）假单胞菌引起的细菌性角膜炎 铜绿假单胞菌是一种严重的眼部感染，可以迅速进展， 在严重的眼部炎症，不可逆的角膜基质瘢痕， 失明和需要角膜移植。 的目的 该项目旨在提高我们对细菌因素和 宿主免疫和非免疫因素导致基质损伤，如 一个基础的发展化疗方案，防止 角膜疤痕 虽然假单胞菌的强烈抗生素治疗 角膜炎杀死细菌并对角膜进行消毒，但仍会发生损伤; 瘢痕形成是由一系列细胞变化引起的， 宿主角膜的炎症反应。 所以，任何治疗， 临床上成功的，必须抑制细菌和宿主因子。 因此，具体的目的是检验关于 以及宿主因子和细菌因子对角膜上皮细胞增殖的影响 炎症和组织损伤，以及必须 控制以减少疤痕。 拟议的实验，无论是在体外和在 体内，将1）定义细菌外蛋白在体内的致病作用， 宿主组织，特别是蛋白酶; 2）评估 使用抗生素限制细菌和非甾体类药物产生角膜炎 抗炎药（NSAID），以抑制炎症介导的基质 3）评估蛋白酶抑制剂作为化疗剂以减少 细菌和宿主蛋白酶介导组织损伤的能力;以及4） 测试新的化疗方案，使用各种组合的抗生素 包括非甾体抗炎药、类固醇和蛋白酶抑制剂， 同时抑制宿主和细菌因子。 方法包括 野生型假单胞菌菌株与外蛋白缺陷型假单胞菌菌株相比的用途 假单胞菌菌株，以确定特定的蛋白质， 角膜损伤，以及最近鉴定的假单胞菌蛋白酶在 以鉴定和测试合适的蛋白酶抑制剂。

DESCRIPTION: (from abstract) Bacterial keratitis caused by Pseudomonas aeruginosa is a severe ocular infection that can progress rapidly, resulting in intense ocular inflammation, irreversible stromal scarring of the cornea, blindness, and the need for corneal transplantation. The objective of this project is to improve our understanding of both the bacterial factors and the host immune and nonimmune factors that contribute to stromal damage, as a basis for the development of a chemotherapeutic regimen that prevents corneal scarring. Although intense antibiotic therapy of Pseudomonas keratitis kills the bacteria and sterilizes the cornea, damage still occurs; scarring results from a sequence of cellular changes mediated by an inflammatory response in the host cornea. Thus, any therapy, to be clinically successful, must inhibit both bacterial and host factors. Therefore, the specific aims are to test hypotheses concerning the nature of and the contributions of host factors and bacterial factors to corneal inflammation and tissue damage, as well as the mechanisms that must be controlled to reduce scarring. Proposed experiments, both in vitro and in vivo, will 1) define the pathogenic role of bacterial exoproteins in the host tissues, especially proteases; 2) assess combination chemotherapy of keratitis using antibiotics to limit production of bacteria and nonsteroidal anti-inflammatory drugs (NSAID) to inhibit inflammation-mediated stromal damage; 3) evaluate protease inhibitors as chemotherapeutic agents to reduce the ability of bacterial and host proteases to mediate tissue damage; and 4) test new chemotherapeutic regimens using antibiotics in various combinations that include NSAIDs, steroids, and protease inhibitors in order to simultaneously inhibit both host and bacterial factors. Methods include the use of wild-type Pseudomonas strains compared to exoprotein-deficient Pseudomonas strains in order to identify the specific proteins that produce corneal damage, and the use of recently identified Pseudomonas proteases in order to identify and test appropriate protease inhibitors.