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Published on: October 22, 2012
Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries
Anil K Jain1, Neera Tewari-Singh1, Swetha Inturi1
1Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA.
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.
Insights
Myeloperoxidase (MPO) significantly worsens skin injuries from nitrogen mustard (NM) exposure by generating harmful oxidants. Inhibiting MPO may offer new treatments for chemical skin damage.
Area of Science:
- Toxicology
- Dermatology
- Biochemistry
Background:
- Pathologic mechanisms of skin injuries from vesicating agents like sulfur mustard (SM) and nitrogen mustard (NM) are not fully understood.
- Neutrophils, key in inflammation, express myeloperoxidase (MPO), involved in oxidant-related responses.
- Previous studies linked SM analog (CEES) and NM exposure to inflammation and increased MPO activity.
Purpose of the Study:
- To investigate the specific role of neutrophil-derived MPO in NM-induced skin injury.
- To compare NM effects on wild-type (WT) mice versus MPO-deficient (MPO KO) mice.
Main Methods:
- Used a genetic approach comparing WT and MPO KO mice.
- Exposed mice to nitrogen mustard (NM).
- Assessed skin injury endpoints, including thickness, microvesication, DNA damage, apoptosis, and inflammatory mediator expression at 12 and 24 hours.
Main Results:
- NM exposure significantly increased skin and epidermal thickness, microvesication, DNA damage, and apoptosis in WT mice compared to MPO KO mice.
- MPO KO mice exhibited significantly lower levels of NM-induced inflammatory mediators (COX-2, iNOS, MMP-9).
- MPO KO mice showed a markedly reduced response to NM exposure, indicating MPO's critical role.
Conclusions:
- Neutrophil-derived MPO plays a significant role in the pathogenesis of NM-induced skin injuries.
- MPO generates microbicidal oxidants that contribute to tissue damage.
- Inhibiting MPO activity and its derived oxidants could be a therapeutic strategy for NM- and SM-induced skin injuries.
