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Mustard vesicants alter expression of the endocannabinoid system in mouse skin.

Authors
  • Wohlman, Irene M1
  • Composto, Gabriella M1
  • Heck, Diane E2
  • Heindel, Ned D3
  • Lacey, C Jeffrey3
  • Guillon, Christophe D3
  • Casillas, Robert P4
  • Croutch, Claire R4
  • Gerecke, Donald R1
  • Laskin, Debra L1
  • Joseph, Laurie B1
  • Laskin, Jeffrey D5
  • 1 Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
  • 2 Environmental Health Science, New York Medical College, Valhalla, NY, United States.
  • 3 Department of Chemistry, Lehigh University, Bethlehem, PA, United States.
  • 4 MRIGlobal, Kansas City, MO, United States.
  • 5 Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ, United States. Electronic address: jla[email protected]
Type
Published Article
Journal
Toxicology and Applied Pharmacology
Publisher
Elsevier
Publication Date
Jul 15, 2016
Volume
303
Pages
30–44
Identifiers
DOI: 10.1016/j.taap.2016.04.014
PMID: 27125198
Source
Medline
Keywords
License
Unknown

Abstract

Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants.

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