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Sharon A. McClellan, Xi Huang, Ronald P. Barrett, Shahrzad Lighvani, Yunfan Zhang, Dawn Richiert, Linda D. Hazlett; Matrix Metalloproteinase-9 Amplifies the Immune Response to Pseudomonas aeruginosa Corneal Infection. Invest. Ophthalmol. Vis. Sci. 2006;47(1):256-264. doi: 10.1167/iovs.05-1050.
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purpose. The purpose of this study was to determine the role of matrix metalloproteinases (MMP) in Pseudomonas aeruginosa keratitis.
methods. Gene array and selective real-time PCR examined MMP expression in the cornea of susceptible (C57BL/6, B6) versus resistant (BALB/c) mice before and after infection; zymography tested enzyme activity for MMP-2 and -9. Clinical score, Langerhans cell (LC), and Neutrophil (PMN) quantitation were done in recombinant (r) MMP-9, antibody neutralized, and MMP-9−/− mice. The chemotactic potential of MMP-9 was tested in a Boyden chamber assay; light and transmission microscopy and immunostaining for collagen IV and MMP-9 were used to examine the effects and the source of MMP-9 after infection. ELISA was used to assess IL-1β and MIP-2 levels.
results. Gene array (confirmed by PCR) revealed sixfold more MMP-9, and zymography showed greater enzyme activity in the infected cornea of B6 over BALB/c mice. rMMP-9 injection of BALB/c mice enhanced, whereas MMP-9 antibody neutralization in B6 mice and its absence in MMP-9−/− mice decreased corneal disease. MMP-9−/− and antibody neutralized mice had fewer LCs in cornea; rMMP-9-treated mice had more. A myeloperoxidase (MPO) assay showed a similar pattern for PMN. MMP-9 was not chemotactic for LC or PMN. The basement membrane was more intact in MMP-9−/− over wild-type infected mice and correlated with staining for collagen IV; PMN was a source of MMP-9. IL-1β and MIP-2 were increased in rMMP-9 but decreased in MMP-9 antibody neutralized and MMP-9−/− over control groups.
conclusions. MMP-9 regulates immune function in cornea by proteolysis, potentiating P. aeruginosa keratitis by degrading collagen IV and upregulating chemotactic cytokines/chemokines IL-1β and MIP-2.
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