OCULAR PATHOGENESIS AND THERAPY OF BACTERIAL KERATITIS

描述：(摘自)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，进展迅速，导致 严重的眼部炎症，不可逆的角膜基质疤痕， 失明，以及角膜移植的需要。这样做的目的是 这个项目是为了提高我们对细菌因素和 导致基质损伤的宿主免疫和非免疫因素，如 开发一种化疗方案的基础，以防止 角膜上的疤痕。尽管加强对假单胞菌的抗生素治疗 角膜炎杀死细菌，使角膜消毒，损害仍会发生； 疤痕形成是由一系列细胞变化引起的，这些变化是由 宿主角膜的炎症反应。因此，任何治疗方法，都是 临床成功，必须同时抑制细菌和宿主因素。 因此，具体的目的是测试有关性质的假设 以及宿主因素和细菌因素对角膜的贡献 炎症和组织损伤，以及必须 控制住以减少疤痕。拟议中的实验，包括体外实验和 活体，将1)定义细菌外源蛋白在 宿主组织，特别是蛋白酶；2)评估联合化疗 角膜炎使用抗生素限制细菌和非类固醇的产生 抗炎药物(NSAID)抑制炎症介导的基质 损害；3)评价作为化疗药物的蛋白水解酶抑制剂 细菌和宿主蛋白酶介导组织损伤的能力；以及4) 使用不同组合的抗生素测试新的化疗方案 包括非类固醇抗炎药、类固醇和蛋白酶抑制剂，以便 同时抑制寄主和细菌因素。方法包括 野生型假单胞菌与外源蛋白缺陷型的比较 假单胞菌菌株，以鉴定产生 角膜损伤，以及最近发现的假单胞菌蛋白水解酶在 以鉴定和测试合适的蛋白水解酶抑制剂。

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.