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Nan Gao, Fushin Yu; Matrix Metalloproteinase 13 as a target for suppressing corneal ulceration caused by Pseudomonas aeruginosa infection. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1728.
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This study investigated whether MMP-13 is involved in P. aeruginosa infection caused corneal tissue destruction and therefore can be targeted for prevention of corneal ulceration associated with microbial keratitis.
Genome-wide cDNA array was performed using epithelial cells isolated from normal, P. aeruginosa infected, and flagellin pretreated/P. aeruginosa infected B6 mouse corneas 6 h post infection. The cDNA array detected MMP expression patterns were verified by realtime PCR and immunohistochemistry. To assess the role of MMP13 B6 mice were subconjunctivally injected with 50 ng MMP-13 inhibitor 16 hours prior to pathogen inoculation and inoculated with 104 ATCC19660 strain. At 1 and 3 dpi, severities of keratitis were monitored. To determine if MMP13 inhibitor can be used for adjuvant therapy, B6 mouse corneas were inoculated with 104 ATCC19660. Topical solution containing gatifloxacin and gatifloxacin/MMP-13 inhibito were applied 16 hpi and after then every hour in the remaining day, 2 h at day 2 dpi and 4 h 3 days post infection. The corneal opacity was examined and photographed using slit lamp microscopy. At the end of observation, the corneas were processed for H&E stained for morphology examination and immunostaining with collagen IV of and type III.
PA01 infection greatly increased MMP-13 expression 6 hpi and this elevated expression was almost totally attenuated by flagellin pretreatment which prevented microbial keratitis in B6 mice. While gatifloxacin applied 24 h or early is sufficient to eradicate pathogens from the cornea, the inflammation persisted for at least three days. Topical co-application of MMP13 inhibitor with gatifloxacin greatly improved disease outcome including accelerated dissolution of opacity, reduced tissue inflammation, and rapid functional recovery. Fewer disorganization of collagen fibers were seen in antibicotic-MMP-13 co-treated corneas.
Downregulation of infection induced MMP13 expression might be an underlying mechanism for flagellin induced protection against microbial infection and MMP-13 inhibitor(s) could potential be used as an adjunctive therapy to treat microbial keratitis and other mucosal infection.
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