Caspase-1 inhibitor reduces severity of pseudomonas aeruginosa keratitis in mice.
OBJECTIVE
To test an inhibitor of IL-1beta 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-1beta 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-1beta by ICE together with ciprofloxacin to kill bacteria may provide alternate therapy to current treatment.
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48230, USA..
Archana
A
Thakur
Ronald P
RP
Barrett
Jeffery A
JA
Hobden
Linda D
LD
Hazlett
D000818:Animals; D061945:Caspase Inhibitors; D018925:Chemokines / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007634:Keratitis / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D011552:Pseudomonas Infections / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000235:genetics; D012720:Severity of Illness Index; D013045:Species Specificity
D061945:Caspase Inhibitors; D018925:Chemokines; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines