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A. Thakur, R.P. Barrett, L.D. Hazlett; Further Studies of P. aeruginosa Corneal Infection in Caspase-1 Deficient Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3238.
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Purpose: The purpose of this study was to examine production of pro- and anti-inflammatory cytokines and nitric oxide (NO) to characterize further the disease response of ICE-/- mice to P. aeruginosa challenge. Methods: RT-PCR analysis, immunostaining for peroxynitrite, the end product of NO + superoxide, MPO assay for PMN quantitation and bacterial plate count were used. Results: RT-PCR analysis revealed a significant increase in IL-1 receptor antagonist (IL-1Ra) and iNOS mRNA at day 1 p.i. in ICE -/- mice vs. B6 wild type (wt) (P=0.001 and 0.03, respectively), but levels were similar at day 5 p.i. Peroxynitrite immunostaining in the infected cornea of ICE-/- vs. B6 wt mice was of greater intensity at 1 and 5 days p.i. and higher levels of nitrite/nitrate (Griess reaction) also were seen at 1-5 days p.i. The cornea of ICE-/- mice had a significantly lower number of bacteria at 3 (P=0.001) and 5 (P=0.0059) days p.i., as well as a significantly lower number of PMN at 1-5 days p.i. (P = 0.0152, 0.038, 0.0029, respectively) compared to B6 wt mice. mRNA expression levels of IL-12 p40 and TNF-α also were measured, but no difference between ICE-/- and B6 wt mice was detected. Conclusion: These data suggest that in ICE-/- mice early upregulation of IL-1Ra may block the action of IL-1ß activated by bacterial and/or host proteases other than ICE, reducing PMN infiltration and corneal disease when compared to B6 wt mice. Early up-regulation of NO production and increased levels of peroxynitrite in cornea may expedite bacterial clearance and provide anti-inflammatory activity, respectively, decreasing disease in ICE-/- mice. Support: Vertex Pharmaceuticals Inc., Cambridge, MA.
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