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H.L. Chandler, D.F. Kusewitt, C.M. Colitz; Enhanced Protease Production in Refractory Corneal Ulcers . Invest. Ophthalmol. Vis. Sci. 2003;44(13):914.
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Purpose: 1) To test the hypothesis that inappropriate protease activity, specifically involving matrix metalloproteinases 9 and 2 (MMP-9, MMP-2) and urokinase-type plasminogen activator (uPA), at the margins of non-healing canine corneal ulcers prevents the establishment of epithelial cell-substrate interactions essential for epithelial cell attachment and locomotion during the healing process. 2) To test the ability of ultraviolet radiation (UVR) to influence corneal wound healing by altering net protease production by corneal epithelial cells and fibroblasts. Methods: In one study, debrided material from the unattached epithelial rims of non-healing corneal ulcers was collected from canine patients undergoing treatment. Immunohistochemistry was performed to determine the location and relative intensity of MMP-9, MMP-2 and uPA production. In a second study, freshly isolated canine corneal stromal cells were exposed to UVR (0, 300, 600, 1200 J/m2) and harvested 24 hours later. Semi-quantitative determination of secreted and cell-associated uPA, MMP-9 and MMP-2 was preformed by gelatin zymography. Results: MMP-9, MMP-2 and uPA production and activity were localized to the epithelium forming the margins of corneal ulcers. UVR treatment enhanced the production of MMP-9, MMP-2 and uPA in cultured canine corneal stromal cells. Conclusions: Unlike other MMPs, MMP-9 and, possibly, MMP-2 slow the rate of corneal wound healing. Higher levels of uPA are also found in ulcerating corneas than in normal corneas. Our studies show that MMP and uPA production and activity are localized to the epithelium forming the margin of the ulcer. This indicates that these proteases are appropriately positioned to inhibit corneal re-epithelialization. MMP and uPA were induced in corneal stromal cells in response to UVR, thus, UVR exposure may impact corneal wounding healing. In future studies, the ability of inhibitors to block the induction of protease activity will provide relevant information on the pathways leading to protease induction by UVR.
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