Abstract
Purpose:
Dry eye disease is known to involve an increase in multiple matrix metalloproteinases (MMPs), particularly MMP-9, at the ocular surface. Increased MMP-9 levels are associated with corneal epithelial barrier dysfunction that causes ocular irritation and visual dysfunction in dry eye disease. The aim of this study was to determine the effect of mapracorat on MMP levels in human corneal epithelial cells (HCEpiC) exposed to hyperosmolarity and IL-1β.
Methods:
HCEpiC were challenged with 1 ng/ml IL-1β or 480 mOsm hyperosmolar media (by the addition of sucrose) in the presence of mapracorat or dexamethasone, both at 6 doses (1 - 300 nM). After 24 h, culture medium was collected and evaluated for MMP release [MMP-1 MMP-2, MMP-3, MMP-9, MMP-10, MMP-12, and MMP-13] by Luminex. Dose response data were fitted to a 4 parameter logistic equation to determine IC50 and efficacy.
Results:
IL-1β increased levels of all measured MMPs in the conditioned medium, while hyperosmolarity increased release of 4 out of the 7 measured MMPs (MMP-1, 3, 9 and 13). Both IL-1β- (MMP-1, 2, 3, 9, 10, 12 and 13) and hyperosmolarity-induced (MMP-1, 3, 9, and 13) levels of MMPs were inhibited by mapracorat. Calculated IC50 values for inhibition of IL-1β and hyperosmolarity-induced MMPs for mapracorat were below 10 nM and were not statistically significant from dexamethasone IC50 values. Mapracorat was fully efficacious (>80% for the majority of MMPs) at reducing IL-1β and hyperosmolarity-induced cytokine release and no statistically significant differences were identified when comparing MMP levels with those following dexamethasone treatment.
Conclusions:
Mapracorat potently reduced IL-1β and hyperosmolarity-induced MMP release to a similar extent as dexamethasone in HCEpiC. These data, together with mapracorat’s ability to potently inhibit pro-inflammatory cytokines, and propensity for an improved side effect profile as compared to traditional steroids warrant investigation of this novel drug as a clinically effective treatment for dry eye disease.
Keywords: 480 cornea: basic science •
557 inflammation •
675 receptors: pharmacology/physiology