MMP-8 Is Critical for Dexamethasone Therapy in Alkali-Burned Corneas Under Dry Eye Conditions

Abstract

Our previous studies have shown that Dexamethasone (Dex) reduced the expression of matrix-metalloproteinases (MMPs -1,-3,-9,-13), IL-1β and IL-6, while it significantly increased MMP-8 mRNA transcripts in a concomitant dry eye and corneal alkali burn murine model (CM). To investigate if MMP-8 induction is responsible for some of the protective effects of Dex in CM, MMP-8 knock out mice (MMP-8KO) were subjected to the CM for 2 or 5 days and topically treated either with 2 μl of 0.1% Dexamethasone (Dex), or saline QID. A separate group of C57BL/6 mice were topically treated with Dex or BSS and received either 100 nM CAM12 (MMP-8 inhibitor) or vehicle IP, QD. Here we demonstrate that topical Dex treated MMP-8KO mice subjected to CM showed reduced corneal clarity, increased expression of inflammatory mediators (IL-6, CXCL1, and MMP-1 mRNA) and increased neutrophil infiltration at 2D and 5D compared to Dex treated WT mice. C57BL/6 mice topically treated with Dex and CAM12 IP recapitulated findings seen with MMP-8KO mice. These results suggest that some of the anti-inflammatory effects of Dex are mediated through increased MMP-8 expression.

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

“…98 Studies with gene KO and pharmacologic inhibitors showed that part of the beneficial effects from dexamethasone in this model were through an increase in MMP-8. 84 Nonpreserved topical methylprednisolone administered three to four times per day significantly improved signs and symptoms of dry eye in patients with SS. 109 Clinically, prolonged use of topical corticosteroids is plagued by frequent side effects, such as cataract induction and glaucoma, that limit their wide use in dry eye; 109 however, the introduction of "soft-steroids" that carry a markedly reduced risk of sightthreatening side effects has led to community acceptance of corticosteroid therapy on a limited basis.…”

“…[82][83][84][85] This simulated the most severe burn cases, where extensive facial and eyelid thermal injury results in eye exposure and desiccation due to loss of protection from the eyelids and reduced blinking. We found there was an additive pathogenic effect of dry eye to alkali burn, with amplification of MMP-3, -8, -9 and -12, IL-6 and IL-1β mRNA expression and sterile corneal perforation in ~30% of animals subjected to the chemical burn and desiccating conditions.…”

Matrix metalloproteinase functioning in case of esophagus acid burn

“…MMP functioning in processes of normal and pathological wound healing is currently under active research [9,10]. We determined the MMP-1, MMP-2, MMP-3, MMP-8 and MMP-9 content in the esophageal mucosal (Table 1) and serum (Table 2) of rats after the esophagus 2 nd degree acid burn simulation.…”

Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)

“…The expression of MMP and TIMP proteins is tightly regulated to maintain adequate balance between ECM synthesis and degradation, which is essential for healthy tissues. Disorders in the regulation of the MMP/TIMP complex have been implicated in many pathological conditions including cancer, Alzheimer’s, cardiovascular or rheumatologic diseases [ 89 , 90 , 91 ], as well as eye diseases such as retinal dystrophies [ 92 , 93 , 94 ], retinal detachment [ 95 ] and proliferative vitreoretinopathy (PVR) [ 49 , 96 , 97 , 98 ], wound corneal healing [ 99 , 100 , 101 ], glaucoma [ 102 , 103 , 104 , 105 ], diabetic retinopathy (DR) [ 106 , 107 , 108 , 109 , 110 ], ocular tumors [ 111 , 112 , 113 , 114 ], pseudoexfoliation syndrome [ 115 , 116 , 117 ], and epiretinal membranes formation [ 118 ]. It is thought that the lack of stability in the regulation of MMPs may play a key role in the pathogenesis of AMD [ 5 , 17 , 50 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ].…”