OCULAR PATHOGENESIS AND THERAPY OF BACTERIAL KERATITIS

描述（改编自申请人摘要）：目的是 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， 间质损伤 细菌性角膜炎往往导致不可逆的疤痕 眼角膜，失明，需要角膜移植。 的 细菌性角膜炎的发病率一直在上升，这在很大程度上是因为 隐形眼镜的使用越来越多。 细菌性角膜炎的治疗 需要在医院至少住七天;在大多数情况下， 治疗包括局部施用氨基糖苷类和 头孢菌素。 虽然这种疗法最终导致细菌感染， 死亡，它通常不能防止角膜瘢痕形成。 疤痕包括 一系列由感染性病毒引发的不明确的细胞事件 过程 研究者的总体目标是了解 引发不可逆基质损伤的事件， 由于细菌的机制和那些由于宿主反应，以及 将这些知识应用于治疗策略的开发。 这些 研究将采用新的药物递送方法（离子电渗疗法和 胶原蛋白屏障）能够以一种 短时间内，以及两种铜绿假单胞菌的家兔模型 角膜炎是最具破坏性和迅速蔓延的眼部疾病之一， 感染. 近期目标是测试最佳交付（时机 和剂量）的抗生素和炎症抑制剂，分别在 组合，用于最小化角膜瘢痕形成的功效。 此外，本发明还提供了一种方法， 将测试细菌毒力因子以确定它们在 造成角膜损伤。 使用毒力缺陷的假单胞菌突变体 白细胞减少兔角膜中的因子，研究者及其 同事将角膜炎定义为最小角膜损伤。 的 具体目标是：1）确定细菌毒力的贡献 因子（碱性蛋白酶和外毒素A）产生的角膜炎， 不可逆的角膜瘢痕形成过程; 2）确定类固醇是否 （地塞米松或泼尼松龙）加抗生素（环丙沙星或 妥布霉素）可以减少不可逆的角膜瘢痕形成; 3）确定其他 例如非甾体抗炎药（氟比洛芬或 螯合剂），其减少PMN浸润，可以与 抗生素，以减少不可逆的角膜疤痕;和4）确定是否 蛋白酶抑制剂（三肽和抗胶原酶抗体）加 抗生素可以减少不可逆转的角膜瘢痕形成， 假单胞菌角膜炎。 患有细菌性角膜炎的患者 开发特定治疗方案的显著益处 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.