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: 3266221
• 负责人: JAMES M HILL
• 金额: $ 15.46万
• 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 1994-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3266221
• 关键词: Pseudomonas; aminoglycoside antibiotics; antibiotics; antiinflammatory agents; bacterial cytopathogenic effect; blindness; cephalosporins; chelating agents; collagenase; combination chemotherapy; cornea disorder; corneal stroma; dexamethasone; drug delivery systems; exotoxins; eye disorder chemotherapy; host organism interaction; keratitis; laboratory rabbit; mutant; prednisolone; protease inhibitor; steroids

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.

描述（根据申请人的摘要改编）：目的是 研究细菌性角膜炎的眼科发病机理，目的是 通过化学疗法限制产生的细菌和宿主因子 基质伤害。 细菌性角膜炎通常导致不可逆的疤痕 角膜，失明以及对角膜移植的需求。 这 细菌性角膜炎的发生率一直在上升，在很大程度上是因为 隐形眼镜的使用增加。 经常治疗细菌性角膜炎 医院至少需要7天；在大多数情况下，药物 治疗包括局部给药氨基糖苷和A 头孢菌素。 尽管这种疗法最终导致细菌 死亡，通常不会防止角膜疤痕。 疤痕涉及 由传染性发起的细胞事件定义不明的序列 过程。 研究者的总体目标是了解 引发不可逆的基质损害的事件，既 由于细菌和由于宿主反应而引起的机制，以及 将此知识应用于治疗策略的发展。 这些 研究将采用新颖的药物输送方法（离子噬菌体和 胶原蛋白盾牌）能够在A中输送大量抗生素 短时间以及两种兔铜绿兔模型 角膜炎，最具破坏性和迅速传播的眼 感染。 直接的目标是测试最佳交付（时机） 抗生素和炎症抑制剂的剂量分别 组合，以最大程度地减少角膜疤痕。 此外， 将测试细菌毒力因子，以确定其在 产生角膜损伤。 使用毒力不足的假单胞菌突变体 白细胞减少兔子角膜的因素，调查员及其 同事将定义角膜炎，其角膜损害最小。 这 具体目的是：1）确定细菌毒力的贡献 因素（碱性蛋白酶和外毒素A）在角膜炎期间产生的因素 不可逆的角膜疤痕的过程； 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 毒素）可以减少不可逆的角膜疤痕； 3）确定是否其他 诸如非甾体类抗炎药（Flurbiprofen或 螯合剂）可减少PMN浸润，可与 抗生素可减少不可逆的角膜疤痕； 4）确定是否 蛋白酶抑制剂（三肽和抗胶原酶抗体）加上 抗生素可以减少不可逆的角膜疤痕 假单胞菌角膜炎。 细菌性角膜炎患者会收获 特定治疗方案的开发带来了重大好处 这可以最大程度地减少角膜疤痕。