ADAM17 Inhibitors Attenuate Corneal Epithelial Detachment Induced by Mustard Exposure.
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PURPOSE: Sulfur mustard, nitrogen mustard (NM), and 2-chloroethyl ethyl sulfide all cause corneal injury with epithelial-stromal separation, differing only by degree. Injury can resolve in a few weeks or develop into chronic corneal problems. These vesicants induce microbullae at the epithelial-stromal junction, which is partially caused by cleavage of transmembranous hemidesmosomal collagen XVII, a component anchoring the epithelium to the stroma. ADAM17 is an enzyme involved in wound healing and is able to cleave collagen XVII. The activity of ADAM17 was inhibited in vesicant-exposed corneas by four different hydroxamates, to evaluate their therapeutic potential when applied 2 hours after exposure, thereby allowing ADAM17 to perform its early steps in wound healing. METHODS: Rabbit corneal organ cultures exposed to NM for 2 hours were washed, then incubated at 37C for 22 hours, with or without one of the four hydroxamates (dose range, 0.3-100 nmol in 20 L, applied four times). Corneas were analyzed by light and immunofluorescence microscopy, and ADAM17 activity assays. RESULTS: Nitrogen mustard-induced corneal injury showed significant activation of ADAM17 levels accompanying epithelial-stromal detachment. Corneas treated with hydroxamates starting 2 hours post exposure showed a dose-dependent ADAM17 activity inhibition up to concentrations of 3 nmol. Of the four hydroxamates, NDH4417 (N-octyl-N-hydroxy-2-[4-hydroxy-3-methoxyphenyl] acetamide) was most effective for inhibiting ADAM17 and retaining epithelial-stromal attachment. CONCLUSIONS: Mustard exposure leads to corneal epithelial sloughing caused, in part, by the activation of ADAM17 at the epithelial-stromal junction. Select hydroxamate compounds applied 2 hours after NM exposure mitigated epithelial-stromal separation.
Invest Ophthalmol Vis Sci
author list (cited authors)
DeSantis-Rodrigues, A., Chang, Y., Hahn, R. A., Po, I. P., Zhou, P., Lacey, C. J., ... Gordon, M. K.
complete list of authors
DeSantis-Rodrigues, Andrea||Chang, Yoke-Chen||Hahn, Rita A||Po, Iris P||Zhou, Peihong||Lacey, C Jeffrey||Pillai, Abhilash||C Young, Sherri||Flowers, Robert A||Gallo, Michael A||Laskin, Jeffrey D||Gerecke, Donald R||Svoboda, Kathy KH||Heindel, Ned D||Gordon, Marion K