OCULAR PATHOGENESIS AND THERAPY OF BACTERIAL KERATITIS

细菌性角膜炎的眼部发病机制和治疗

• 批准号: 6150761
• 负责人: JAMES M HILL
• 金额: $ 28.61万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150761
• 关键词: Pseudomonas aeruginosa; antibiotics; antiinflammatory agents; bacterial cytopathogenic effect; combination chemotherapy; corneal stroma; drug screening /evaluation; enzyme biosynthesis; enzyme therapy; eye disorder chemotherapy; eye pharmacology; host organism interaction; inflammation; keratitis; laboratory rabbit; microscopy; necrosis; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; protease inhibitor; scars

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.

描述：（摘要）假单胞菌引起的细菌性角膜炎 Aeruginosa是一种严重的眼部感染，可以迅速发展，导致 在强烈的眼部炎症中，角膜的不可逆性基质疤痕， 失明以及对角膜移植的需求。 这个目的 项目是为了提高我们对两个细菌因素和 宿主免疫和非免疫因子会导致基质损害，如 开发化学治疗方案的基础 角膜疤痕。 虽然假单胞菌的强烈抗生素疗法 角膜炎杀死细菌并使角膜消毒，仍会发生损伤。 疤痕是由一系列由一个细胞变化介导的。 宿主角膜中的炎症反应。 因此，任何疗法 临床成功，必须抑制细菌和宿主因素。 因此，具体目的是检验有关性质的假设 以及宿主因素和细菌因子对角膜的贡献 炎症和组织损伤，以及必须是的机制 受控以减少疤痕。 提出的实验，无论是体外还是在 Vivo，将1）定义细菌异蛋白在 宿主组织，尤其是蛋白酶； 2）评估组合化疗 使用抗生素限制细菌和非甾体类生产的角膜炎 抗炎药（NSAID）以抑制炎症介导的基质 损害; 3）评估蛋白酶抑制剂作为化学治疗剂以减少 细菌和宿主蛋白酶介导组织损伤的能力；和4） 在各种组合中使用抗生素测试新的化学治疗方案 其中包括NSAID，类固醇和蛋白酶抑制剂，以便 同时抑制宿主和细菌因子。 方法包括 与缺乏蛋白质相比，使用野生型假单胞菌菌株 为了鉴定产生的特定蛋白质，假单胞菌菌株 角膜损伤，以及最近确定的假单胞菌蛋白酶的使用 为了识别和测试适当的蛋白酶抑制剂。