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ToxSci Advance Access originally published online on September 1, 2005
Toxicological Sciences 2006 90(2):549-557; doi:10.1093/toxsci/kfi306
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Characterization of the Initial Response of Engineered Human Skin to Sulfur Mustard

Shari Greenberg*, Padmaja Kamath*, John Petrali{dagger}, Tracey Hamilton{dagger}, Jackie Garfield{ddagger} and Jonathan A. Garlick*,§,1

* Department of Oral Biology and Pathology, School of Dental Medicine, SUNY at Stony Brook, Stony Brook, New York 11794-8702; {dagger} US Army Medical Research and Material Command, Fort Detrick, Maryland, {ddagger} LifeCell Inc., One Millenium Way, Branchburg, New Jersey 08876; and § Department of Dermatology, School of Medicine, SUNY at Stony Brook, Stony Brook, New York 11794

Received July 21, 2005; accepted August 24, 2005

We have used a new approach to identify early events in sulfur mustard-induced, cutaneous injury by exposing human, bioengineered tissues that mimic human skin to this agent to determine the morphologic, apoptotic, inflammatory, ultrastructural, and basement membrane alterations that lead to dermal-epidermal separation. We found distinct prevesication and post-vesication phases of tissue damage that were identified 6 and 24 h after sulfur mustard (SM) exposure, respectively. Prevesication (6 h) injury was restricted to small groups of basal keratinocytes that underwent apoptotic cell death independent of SM dose. Immunoreactivity for basement membrane proteins was preserved and basement membrane ultrastructure was intact 6 h after exposure. Dermal-epidermal separation was seen by the presence of microvesicles 24 h after SM exposure. This change was accompanied by the dose-dependent induction of apoptosis, focal loss of basement membrane immunoreactivity, increase in acute inflammatory cell infiltration, and ultrastructural evidence of altered basement membrane integrity. These studies provide important proof of concept that bioengineered, human skin demonstrates many alterations previously found in animal models of cutaneous SM injury. These findings further our understanding of mechanisms of SM-induced damage and can help development of new countermeasures designed to limit the morbidity and mortality caused by this chemical agent.

Key Words: sulfur mustard; basement membrane; bioengineered human skin; human keratinocytes.


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