Our objective is to investigate the ocular pathogenesis of Pseudomonas aeruginosa keratitis with the goal of limiting by chemotherapy the bacterial factors and host immune and nonimmune factors that produce stromal damage. Bacterial keratitis often results in intense inflammation, 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. Pseudomonas keratitis evolves rapidly, resulting in corneal scarring and loss of vision. Intense antibiotic therapy arrests the spread of the infection, ultimately eliminating the bacteria, but fails to prevent scarring. Scarring results from an ill-defined sequence of cellular changes initiated by the infectious process. Our overall goal is to identify a chemotherapeutic regimen compatible with antibiotic therapy which inhibits the bacterial and host reactants of the acute infection that induce corneal scarring.
The specific aims are to: 1) determine the contribution of host factors to tissue damage and inflammation; 2) determine the role of bacterial factors in tissue damage and inflammation; and 3) develop new chemotherapeutic regimens for Pseudomonas keratitis. To examine the contributory host factors, the effectiveness of a variety of presently available medications will be tested for their ability to limit tissue damage and inflammation in eyes concurrently treated with bactericidal antibiotics. Medications to be tested include steroids and nonsteroidal anti-inflammatories (NSAID) to inhibit damaging host nonspecific immune reactions and protease inhibitors to inhibit both host and bacterial proteolytic enzymes. Evaluation of bacterial factors (alkaline protease, exotoxin A, elastase, and protease IV) will employ wild-type strains and exoprotein-deficient Pseudomonas mutants that vary in their ability to induce inflammatory reactions and tissue damage. Correlating the virulence of exoprotein-deficient mutants and their exoprotein production will allow identification of specific exoproteins involved in the pathogenesis of bacterial keratitis. Evaluation of the virulence of these mutants in normal and immunocompromised hosts will provide further information on the role of specific exoproteins in mediating cornea damage. Development of new chemotherapeutic regimens will involve both established and newly developed medications based on the identification of bacterial factors mediating tissue damage and inflammatory reactions. Improved drug delivery methods (collagen shields and iontophoresis) will be used to maximize delivery of antibiotics to kill bacteria and of adjunct therapies designed to limit corneal inflammation and damage. Ultimately, the ability to prevent or mitigate corneal scarring will provide significant benefits by reducing the incidence of visual impairment and the need for surgical intervention in patients with corneas damaged by the pathologic processes of bacterial keratitis.
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