Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Adrienne T. Black, Patrick J. Hayden, Robert P. Casillas, Diane E. Heck, Donald R. Gerecke, Patrick J. Sinko, Debra L. Laskin, Jeffrey D. Laskin

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide, on EpiDerm-FT™, a commercially available full-thickness human skin equivalent. CEES (100-1000μM) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300-1000μM), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5-lipoxygenase, microsomal PGE 2 synthases, leukotriene (LT) A 4 hydrolase and LTC 4 synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1-2 (GSTA1-2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics.

Original languageEnglish (US)
Pages (from-to)178-187
Number of pages10
JournalToxicology and Applied Pharmacology
Volume249
Issue number2
DOIs
StatePublished - Dec 1 2010

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Keywords

  • Apoptosis
  • Eicosanoids
  • Skin
  • Sulfur mustard
  • Vesicant

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