title: Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: anil.jain@ucdenver.edu.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: Neera.Tewari-Singh@ucdenver.edu.
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: Swetha.Inturi@ucdenver.edu.
authors.forename: Swetha
authors.initials: S
authors.lastname: Inturi
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: David.Orlicky@ucdenver.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: Carl.White@ucdenver.edu.
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: Rajesh.Agarwal@ucdenver.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001768:Blister / Q000139:chemically induced / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008466:Mechlorethamine / Q000008:administration & dosage / Q000633:toxicity*; D008661:Metabolism, Inborn Errors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: D002619:Chemical Warfare Agents; D008466:Mechlorethamine; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9
keywords: Apoptosis; DNA damage; Inflammation; Myeloperoxidase; Nitrogen mustard; Sulfur mustard