OCULAR PATHOGENESIS AND THERAPY OF BACTERIAL KERATITIS

描述(改编自申请人的摘要)：目标是 研究细菌性角膜炎的眼部发病机制 通过化疗限制细菌和宿主因素产生 间质损伤。细菌性角膜炎常常导致不可逆转的疤痕。 眼角膜、失明和角膜移植的需要。这个 细菌性角膜炎的发病率一直在上升，很大程度上是因为 隐形眼镜使用量的增加。细菌性角膜炎常见的治疗方法 需要至少住院七天；在大多数情况下，药物 治疗包括局部使用氨基糖苷类药物和 头孢菌素。尽管这种疗法最终会导致细菌 死亡，它一般不能防止角膜疤痕形成。结疤涉及到 由传染性疾病引发的一系列定义不清的细胞事件 进程。调查员的总体目标是了解 引发不可逆的间质损伤的事件，无论是 细菌的机制和宿主反应的机制，以及 将这些知识应用到治疗策略的开发中。这些 研究将采用新的药物输送方法(离子导入和 胶原蛋白屏蔽物)能够在 短时间，以及两种铜绿假单胞菌兔模型 角膜炎，最具破坏性和迅速蔓延的眼部疾病之一 感染。眼前的目标是测试最佳交付(时间安排 和剂量)的抗生素和炎症抑制剂 联合使用，可最大限度地减少角膜疤痕形成。此外, 细菌毒力因子将进行测试，以确定它们在 造成角膜损伤。利用毒力不足的假单胞菌突变株 白细胞减少兔角膜中的因子、研究者和他的研究人员 同事们会定义为角膜损伤最小的角膜炎。这个 具体目标是：1)确定细菌毒力的贡献 角膜炎期间产生的因子(碱性蛋白酶和外毒素A)对 不可逆的角膜瘢痕形成过程；2)确定类固醇是否 (地塞米松或强的松龙)加抗生素(环丙沙星或 妥布霉素)可以减少不可逆的角膜疤痕；3)确定其他 非类固醇抗炎药(氟比洛芬或 螯合剂)，可减少PMN的渗透，可与 抗生素以减少不可逆转的角膜疤痕；以及4)确定 蛋白酶抑制剂(三肽和抗胶原酶抗体)加 抗生素可减少角膜不可逆性瘢痕形成 假单胞菌角膜炎。细菌性角膜炎患者将收获 从特定治疗方案的开发中获得显著好处 这可以最大限度地减少角膜疤痕。

DESCRIPTION (adapted from applicant's abstract): The objective is to investigate the ocular pathogenesis of bacterial keratitis with the goal of limiting by chemotherapy the bacterial and host factors that produce stromal damage. Bacterial keratitis often results in 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. Therapy of bacterial keratitis often requires a minimum of seven days in the hospital; in most cases, drug therapy includes topical administration of an aminoglycoside and a cephalosporin. Although this therapy ultimately results in bacterial death, it does not generally prevent corneal scarring. Scarring involves an ill-defined sequence of cellular events initiated by the infectious process. The investigator's overall goal is to understand the nature of the events that initiate the irreversible stromal damage, both the mechanisms due to the bacteria and those due to the host response, and to apply this knowledge to the development of therapeutic strategies. These studies would employ novel drug delivery methods (iontophoresis and collagen shields) capable of delivering large amounts of antibiotic in a short time, as well as two rabbit models of Pseudomonas aeruginosa keratitis, one of the most destructive and rapidly spreading ocular infections. The immediate goals are to test the optimal delivery (timing and dose) of antibiotics and inhibitors of inflammation, separately and in combination, for efficacy in minimizing corneal scarring. In addition, bacterial virulence factors would be tested to determine their role in producing corneal damage. Using Pseudomonas mutants deficient in virulence factors in corneas of leukopenic rabbits, the investigator and his coworkers would define a keratitis with minimal corneal damage. The specific aims are to: 1) Determine the contribution of bacterial virulence factors (alkaline protease and exotoxin A) produced during keratitis to the process of irreversible corneal scarring; 2) Determine if steroids (dexamethasone or prednisolone) plus antibiotics (ciprofloxacin or tobramycin) can reduce irreversible corneal scarring; 3) Determine if other agents such as nonsteroidal anti-inflammatory drugs (flurbiprofen or chelators), which reduce PMN infiltrates, can be used in combination with antibiotics to reduce irreversible corneal scarring; and 4) Determine if protease inhibitors (tripeptides and anti-collagenase antibodies) plus antibiotics can reduce the irreversible corneal scarring produced by Pseudomonas keratitis. Patients with bacterial keratitis would reap significant benefits from the development of a specific therapeutic regimen that minimizes corneal scarring.