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Direct Matrix Metalloproteinase Enhancement of Transscleral Permeability

From the Hamilton Glaucoma Center and Department of Ophthalmology, University of California San Diego, La Jolla, California.

PURPOSE. Previous studies have shown that increased trans-scleral permeability after exposure to certain prostaglandins is associated with increased intrascleral matrix metalloproteinases (MMPs). The present study was undertaken to determine whether these MMPs could directly alter transscleral permeability.

METHODS. Freshly enucleated mouse eyes were incubated with human MMP-1, -2, and -14 for 4 hours at 37°C. The eyes then were incubated with 10 or 70 kDa dextran-tetramethylrhodamine-lysine for 16 to 32 minutes at 37°C. Two methods of analysis were used. In the first, quickly isolated retinas were homogenized and centrifuged. Fluorescence in the supernatants was determined by microspectrofluorimetry. In the second, the eyes were fixed in 4% paraformaldehyde, and frozen sections were prepared. After the identity of the sections was masked, the intensity of fluorescence in anterior, middle, and posterior regions of the outer retina and inner retina was scored with a 7-point grading scheme.

RESULTS. The concentration of 10-kDa fluorescent dextran was 5.14 ± 1.61 µg/mL (mean ± SD, n = 33) in the control retinal supernatants, and 6.37 ± 2.67 µg/mL (n = 40) in the retinal supernatants from the MMP-treated eyes. This increase was statistically significant (P < 0.02, t-test). The structural organization of the retina and other ocular tissues was maintained in all experimental conditions. Histologic scoring of fluorescence found significantly increased dextran in the outer retina of eyes treated with MMPs for 32 minutes (the score of control eyes was 2.5 ± 0.4 and of MMP-treated eyes was 3.5 ± 0.1, mean ± SD; P = 0.02, n = 3). Analysis by region found greater scores in the third of the retina nearest to the optic nerve head.

CONCLUSIONS. These results show that MMP-1, -2, and -14 can directly increase transscleral permeability and support the view that the increased MMP-1 and -2 observed after topical PG treatment could contribute to increased uveoscleral outflow.