Hydroxamates Inhibit EMMPRIN as well as ADAM17/TACE and MMPs
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To study corneal wound healing, organ cultures were injured with nitrogen mustard (NM). This blistering agent causes the epithelium to separate from the stromal layer. Separation is in part due to the activation of ADAM17/TACE. We found that ADAM17 is activated in rabbit corneal organ cultures immediately after NM exposure, and remains activated even at 24 hr post exposure. To inhibit ADAM17 and promote epithelialstromal integrity after NM exposure, the hydroxamates olvanil OH (NDH4409) and retro olvanil 8 (NDH4417) were tested for their ability to inhibit ADAM17 and reduce collagen XVII cleavage. The hydroxamates were applied 4 times to organ cultures over the course of 22 hrs, beginning 2 hours post NM exposure. Epithelialstromal separation at 24 hr was significantly reduced by the hydroxamate treatments. Surprisingly, both drugs also reduced expression of the matrix metalloproteinase (MMP) inducer, EMMPRIN. Thus, the inhibition of MMP9 observed after hydroxamate treatment was likely caused by both direct inhibition of the catalytic zinc as well as the reduction of EMMPRIN. In conclusion, hydroxamates inactivate ADAM17, MMPs, and also preserve corneal epithelialstromal integrity by attenuating the vesicantinduced upregulation of EMMPRIN. Supported by UMDNJRutgers Counteract Center of Excellence NIAMSD U54AR055073; NIH NEI EY009056; and NIEHS P30ES005022
