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Title: Mustard vesicants alter expression of the endocannabinoid system in mouse skin

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. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid systemmore » regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.« less

Authors:
;  [1]
  1. Departm
Publication Date:
OSTI Identifier:
22689198
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 303; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMIDES; BLISTERS; BRASSICA; CARBAMATES; CARBOXYLIC ACIDS; CONCENTRATION RATIO; EDEMA; EPIDERMIS; GLYCEROL; HEALING; HOMEOSTASIS; HYDROLASES; INFLAMMATION; MICE; NITROGEN MUSTARD; RECEPTORS; SULFUR; WOUNDS

Citation Formats

Wohlman, Irene M., and Composto, Gabriella M.. Mustard vesicants alter expression of the endocannabinoid system in mouse skin. United States: N. p., 2016. Web. doi:10.1016/J.TAAP.2016.04.014.
Wohlman, Irene M., & Composto, Gabriella M.. Mustard vesicants alter expression of the endocannabinoid system in mouse skin. United States. doi:10.1016/J.TAAP.2016.04.014.
Wohlman, Irene M., and Composto, Gabriella M.. Fri . "Mustard vesicants alter expression of the endocannabinoid system in mouse skin". United States. doi:10.1016/J.TAAP.2016.04.014.
@article{osti_22689198,
title = {Mustard vesicants alter expression of the endocannabinoid system in mouse skin},
author = {Wohlman, Irene M. and Composto, Gabriella M.},
abstractNote = {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. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.},
doi = {10.1016/J.TAAP.2016.04.014},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 303,
place = {United States},
year = {2016},
month = {7}
}