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Marion K. Gordon, Lakshmi Raman, Rita A. Hahn, John J. Schlager, Ronald Gordon, Donald R. Gerecke, Michael C. Babin, Kathy K. Svoboda; Rabbit Corneal Epithelia and Keratocytes Respond to Sulfur Mustard Exposure by Increasing Autophagy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3553.
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Sulfur mustard (SM) injury to the cornea can lead to blindness. SM is an alkylating agent known to crosslink proteins of the epidermal basement membrane into aggregates (Zhang Z, Peters BP, Monteiro-Riviere NA, Cell Biol Tox. 11:89-101, 1995). In models of protein-aggregating neurodegenerative diseases, it has been demonstrated that autophagy is induced to clear the aggregates (Ravikumar et al, 2002; Webb et al., 2003). Therefore, we hypothesized that similar mechanisms would be present in corneal wound healing after SM exposure. To test the hypothesis, we analyzed the exposed and unexposed corneal tissue for their numbers of autophagosomes.
Neat sulfur mustard (0.4 microliter) was applied to the central corneas of New Zealand white rabbits. Rabbits were sacrificed at 1, 3, 7 and 28 days post-exposure, and the corneas were dissected, fixed, embedded in epon plastic, and sectioned for transmission electron microscopy (TEM) analysis. Unexposed rabbit eyes were controls.
TEM analysis (n > 100 epithelial and >50 stromal keratocytes/time point) revealed that both unexposed and SM-exposed corneal cells contained autophagosomes; however, these structures were more prevalent in the SM-exposed corneal cells. Three and 7 days after SM exposure corneal epithelial cells had ~7 times more autophagosomes than unexposed corneal epithelial cells. For keratocytes, exposed corneas had ~5 times more autophagosomes than unexposed corneas 3 and 7 days post SM exposure. At 28 days post exposure, exposed corneal epithelia and keratocytes contained ~4 times more autophagosomes than unexposed corneas.
The results suggest that autophagy in SM-exposed corneas may be one mechanism used to degrade vesicant-alkylated proteins in both the epithelial and keratocyte populations.
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