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ToxSci Advance Access published online on December 15, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn261
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide (CEES)-induced skin injury in SKH-1 hairless mice

Neera Tewari-Singh*, Sumeet Rana*, Mallikarjuna Gu*, Arttatrana Pal*, David J. Orlicky{dagger}, Carl W. White{ddagger} and Rajesh Agarwal*,1

* Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, CO 80045, USA {dagger} Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA {ddagger} Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA

1 Corresponding author: Rajesh Agarwal, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Box C238 P-15 Research 2, Aurora, CO 80045, USA; Phone: 303-724-4055, Fax: 303-724-7266 Email: Rajesh.Agarwal{at}ucdenver.edu

Received October 16, 2008; revision received December 5, 2008; accepted December 10, 2008


  Abstract

Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, CEES, we identified quantifiable inflammatory biomarkers of CEES-induced skin injury in dose- (0.05-2 mg) and time- (3 h to 168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages and mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by TUNEL and proliferative cell nuclear antigen (PCNA) stainings, respectively. Following an increase in the mast cells, myeloperoxidase (MPO) activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.

Key Words: CEES; inflammatory biomarkers; SKH-1 hairless mouse; epidermal thickness; mast cells; macrophages.

Neera Tewari-Singh: Neera.Tewari-Singh{at}ucdenver.edu; Sumeet Rana: rana.sumeet{at}yahoo.com; Mallikarjuna Gu: Gu.Mallikarjuna{at}ucdenver.edu; Arttatrana Pal: Arttatrana.Pal{at}ucdenver.edu; Davis J. Orlicky: David.Orlicky{at}ucdenver.edu; Carl W. White: whitec{at}njc.org


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