IOVS Journal of Bacteriology
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(Investigative Ophthalmology and Visual Science. 2004;45:3177-3184.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-0041
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Caspase-1 Inhibitor Reduces Severity of Pseudomonas aeruginosa Keratitis in Mice

Archana Thakur,1 Ronald P. Barrett,1 Jeffery A. Hobden,2 and Linda D. Hazlett1,2

1From the Departments of Anatomy and Cell Biology, and 2Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan.

PURPOSE. To test an inhibitor of IL-1ß converting enzyme (ICE), with or without ciprofloxacin, in a C57BL/6 mouse model of keratitis induced by Pseudomonas aeruginosa in which corneal perforation is expected.

METHODS. Clinical score, histopathology, myeloperoxidase (MPO) activity, bacterial counts, and ELISA analysis were used to assess the efficacy of treatment initiated at 18 hours postinfection (p.i.) with ICE inhibitor versus placebo; and with ICE inhibitor plus ciprofloxacin versus placebo plus ciprofloxacin. Efficacy of the ICE inhibitor was also tested and evaluated for clinical score in experimental corneal infection induced by a clinical isolate and a ciprofloxacin-resistant bacterial strain.

RESULTS. Clinical scores were reduced at 3, 5, and 7 days p.i. in ICE inhibitor versus placebo-treated mice; reduced scores also were observed with a combined treatment (ICE inhibitor and ciprofloxacin). Further testing (MPO assay) revealed reduced PMN number, particularly striking in ICE inhibitor and ciprofloxacin versus placebo and ciprofloxacin-treated mice. Corneal protein levels for IL-1ß and MIP-2 also were reduced in mice treated with the ICE inhibitor versus placebo and in ICE inhibitor and ciprofloxacin versus ciprofloxacin and placebo-treated mice. Treatment with ICE inhibitor also reduced clinical scores after corneal infection with a clinical isolate, KEI-1025, and with a ciprofloxacin-resistant P. aeruginosa strain.

CONCLUSIONS. Downregulation of IL-1ß by ICE together with ciprofloxacin to kill bacteria may provide alternate therapy to current treatment.




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