Development of Protective Agent Against Sulfur Mustard-Induced Skin Lesions
Abstract
Previous studies demonstrated the protective effect of our novel iodine formulation against SM-induced skin lesions. In order to improve the preparation we investigated the inflammatory processes occurring upon SM exposure and particularly those involve cyclooxygenase activity. To evaluate the role of cyclooxygenas-l and -2 (COX-l, COX-2) in sulfur mustard-induced skin toxicity, we applied the agent to the ears of wildtype (WI) and COX-l- and COX-2-deficient mice. In the latter, ear swelling 24 and 48 h after exposure was significantly reduced by 55% and 30%, respectively, compared to WT These findings were confirmed by histopathological evaluation. The COX-2 inhibitor celecoxib resulted in significant reductions of 27% and 28% in ear swelling at intervals of 40 and 60 min between exposure and treatment, respectively. These findings encouraged us to introduce celecoxib, together with the steroidal anti-inflammatory agent clobetasol, into our iodine preparation. After optimization procedures, the ointment was efficacious 60 min (or less) following exposure. The ability of low iodine concentrations to scavenge reactive oxygen species and to inhibit oxidative burst of activated mouse neutropils might explain the protective mechanism of action of iodine. Previous results have shown that prophylactic injection of H2A histone fragment protected against SM-induced skin lesions. In the present report we found that the T1/2 of the peptide in mouse and humans serum was 7 and 14 min. We also identified the cleavage sites of the peptide by mouse and human serum proteinases; and accordingly synthesized N-methylated analogs for stabilizing the peptide against this proteolytic activity. Injection of the peptide 30 min after exposure significantly reduced ear swelling in the mouse edema model.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2004
- Accession Number
- ADA423301
Entities
People
- Uri Wormser
Organizations
- Hebrew University of Jerusalem