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A. Thakur, R.P. Barrett, L.D. Hazlett; Caspase–1(ICE) inhibitor treatment reduces severity of Pseudomonas keratitis in mice. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1003.
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Purpose: Previous studies have shown that IL–1ß plays a key role in the pathogenesis of P. aeruginosa corneal infection. Therefore, the purpose of this study was to experimentally test an inhibitor of IL–1ß converting enzyme (ICE), VRT–043198, with or without (+/–) ciprofloxacin in a murine model of keratitis in which perforation is the expected outcome. Methods: Clinical scores, histopathology, MPO activity, bacterial plate counts and ELISA analysis were used to assess the efficacy of treatment (at 18h p.i.) with the ICE inhibitor vs. placebo +/– ciprofloxacin in C57BL/6 (B6) mice after corneal infection with P. aeruginosa strain 19660. Efficacy of the ICE inhibitor also was similarly tested in experimental corneal infection induced by a clinical isolate of P. aeruginosa or a ciprofloxacin resistant P. aeruginosa strain. Results: Clinical scores were significantly reduced at 3, 5 and 7 days post–infection (p.i.) in the ICE inhibitor vs. placebo +/– ciprofloxacin treated mice. The decreased inflammatory response also was evidenced by reduced MPO activity and protein levels of IL–1ß and MIP–2 at 7 days p.i. in the cornea of the ICE inhibitor vs. placebo +/– ciprofloxacin treated mice. Similarly bacterial load was reduced in the cornea at 7 days p.i. in the ICE inhibitor vs. placebo without ciprofloxacin treated mice. The ICE inhibitor also was efficacious in reducing clinical scores after corneal infection induced by a clinical isolate–1025 or a ciprofloxacin resistant P. aeruginosa strain. Conclusions: Administration of an ICE inhibitor either alone or + ciprofloxacin significantly reduced corneal disease severity and suggest that the host inflammatory response after bacterial infection can be successfully managed by therapeutic strategies targeting IL–1ß. Support: Vertex Pharmaceuticals Inc., Cambridge, MA.
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