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Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries.
- Source :
-
Toxicology [Toxicology] 2014 Jun 05; Vol. 320, pp. 25-33. Date of Electronic Publication: 2014 Mar 12. - Publication Year :
- 2014
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Abstract
- The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) exposure, are poorly understood. Neutrophils which accumulate at the site of injury, abundantly express myeloperoxidase (MPO), a heme protein that is implicated in oxidant-related antimicrobial and cytotoxic responses. Our previous studies have shown that exposure to SM analog 2-chloroethyl ethyl sulfide (CEES) or NM results in an inflammatory response including increased neutrophilic infiltration and MPO activity. To further define the role of neutrophil-derived MPO in NM-induced skin injury, here we used a genetic approach and examined the effect of NM exposure (12h and 24h) on previously established injury endpoints in C57BL/6J wild type (WT) and B6.129X1-MPOtm1Lus/J mice (MPO KO), homozygous null for MPO gene. NM exposure caused a significant increase in skin bi-fold thickness, epidermal thickness, microvesication, DNA damage and apoptosis in WT mice compared to MPO KO mice. MPO KO mice showed relatively insignificant effect. Similarly, NM induced increases in the expression of inflammatory and proteolytic mediators, including COX-2, iNOS and MMP-9 in WT mice, while having a significantly lower effect in MPO KO mice. Collectively, these results show that MPO, which generates microbicidal oxidants, plays an important role in NM-induced skin injuries. This suggests the development of mechanism-based treatments against NM- and SM-induced skin injuries that inhibit MPO activity and attenuate MPO-derived oxidants.<br /> (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Animals
Blister chemically induced
Blister pathology
Cyclooxygenase 2 metabolism
DNA Damage drug effects
Male
Matrix Metalloproteinase 9 metabolism
Mechlorethamine administration & dosage
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase Type II metabolism
Peroxidase genetics
Skin pathology
Time Factors
Apoptosis drug effects
Chemical Warfare Agents toxicity
Mechlorethamine toxicity
Metabolism, Inborn Errors metabolism
Skin drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3185
- Volume :
- 320
- Database :
- MEDLINE
- Journal :
- Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 24631667
- Full Text :
- https://doi.org/10.1016/j.tox.2014.02.013