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G. P. Lewis, E. A. Chapin, G. Luna, J. Byun, G. Zahn, S. K. Fisher; Suppression of Intraretinal Proliferation and Glial Scar Formation Following Experimental Retinal Detachment (RD) Using an Alpha5Beta1 Integrin Antagonist. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4888.
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Proliferation of non-neuronal retinal cells is a common event following RD and can result in the human disease, proliferative vitreoretinopathy (PVR). The alpha5Beta1 antagonist, JSM6427 has previously been shown to be an effective inhibitor of choroidal neovascularization in mice. Here we sought to determine the effects of JSM6427 on intraretinal proliferation and glial scar formation following experimental RD.
Experimental RDs were created in the right eyes of pigmented rabbits. One mg of JSM6427 in 50 ul PBS or the vehicle was injected intravitreally on day 0 (immediately after the detachment) or day 1, and 10 µg of BrdU was given on day 3. The retinas were harvested on day 3 (4 hr after the BrdU injection) or 7. The tissue was fixed, embedded in agarose and sectioned at 100 microns. The sections were labeled with anti-BrdU (to detect dividing cells), anti-vimentin (to label Mueller cells), and the Isolectin B4 (to label macrophages and microglia). The number of BrdU labeled cells, and the number and length of subretinal scars were counted and measured from images collected using an Olympus FluoView confocal microscope.
At both 3 days and 7 days, there was a statistically significant decrease in the number of BrdU labeled cells in treated animals, however, the drug was more effective when given on day 1 after detachment rather than at day 0. At both time points, Mueller cells comprised the majority of BrdU labeled cells and they showed the greatest decrease in BrdU labeling following drug treatment. There was a slight, but significant, decrease in the number of BrdU labeled microglia and macrophages at day 3 in animals treated on day 1 but the difference was not significant at day 7. However, the total number of Isolectin B4 labeled immune cells (whether BrdU labeled or not) did show a statistically significant decrease at day 7 in animals treated on day 1. No glial scars were observed at day 3, however, there was a significant decrease in the number and size of subretinal glial scars in the drug treated animals at day 7.
These data indicate that JSM6427 can be an effective inhibitor of intraretinal proliferation as well as subretinal glial scar formation following retinal detachment. In addition, they point to a role for alpha5Beta1 integrin in the proliferative response suggesting that it may be a target for the treatment of PVR in human patients.
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