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Cintia S De Paiva, Caterina Camodeca, Elisa Nuti, Armando Rossello, Stephen C Pflugfelder, De-Quan Li, Fang Bian; Dexamethasone Protects Cornea From Alkali-Induced and Dry eye Injury Through an Increase of Metalloproteinase-8. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5617.
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We have shown that Dexamethasone significantly increased MMP-8 mRNA transcripts (~330 fold) in a concomitant dry eye and alkali burn murine model. The purpose was to investigate if the protective effects of pDex are mediated through an increase of MMP-8.
C57BL/6 (B6) mice were subjected to unilateral alkali burn with desiccating stress for 2 or 5 days and topically treated either with 2µL of 0.1% Dexamethasone (pDex), or BSS QID and received either 100nM CAM12 (an MMP-8 synthetic inhibitor) or vehicle (Veh) IP, Q.D. A separate group of MMP-8KO mice were subjected to topical treatment (pDex or BSS) and compared to B6 mice. Corneal clarity was graded daily using a 4-point scale. Presence of wound closure was investigated using 0.1% sodium fluorescein. Mice were euthanized after 2 or 5 days. qPCR was performed to measure expression of inflammatory cytokines and MMPs in whole cornea lysates. Myeloperoxidase activity (MPO) was measured using a commercial kit in cornea lysates.
pDex treatment in MMP-8KO and B6+CAM12 animals significantly increased total wound closure rate (50% closure at 5 days vs. 25% controls, P<0.05), but failed to improve corneal clarity compared to controls after 5 days. After 2 days after lesion, pDex+Veh treatment significantly decreased IL-1β (41 vs. 3.36 fold), IL-6 (100 vs. 32.75 fold), MMP-1 (174 vs.65 fold), MMP-3 (140 vs. 78.5 fold), MMP-9 (77 vs. 21 fold), MMP-13 (28 vs. 23.23 fold) while increased MMP-8 levels (153 vs.377 fold) compared to BSS+Veh group. pDex+CAM12 treatment significantly increased IL-1β (6.65 fold), IL-6 (55.18 fold), MMP-1 (84 fold) and MMP-9 (31.5 fold) while had no effect on MMP-8 (378 fold) and MMP-13 (22 fold) and decreased MMP-3 (70 fold) mRNA transcripts compared to pDex+Veh. In B6 mice, MPO activity was significantly decreased in pDex group compared to BSS (4.10±0.96 vs. 8.84±1.73 mU/mL, p<0.05). Although pDex in MMP-8KO animals decreased MPO activity by half compared to BSS treatment (7.94±0.70 vs. 16.25±3.09 mU/ml, p<0.01), it was still significantly higher than pDex levels in B6 animals.
Inhibiting MMP-8 in corneas subjected to alkali burn+ dry eye accelerated wound healing, worsened corneal clarity, increased IL-1β and IL-6 and MMP-1 and MMP-9 and neutrophil infiltration, suggesting that some of the anti-inflammatory effects of Dexamethasone are mediated through increased MMP-8.
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