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Mustard vesicants alter expression of the endocannabinoid system in mouse skin

TitleMustard vesicants alter expression of the endocannabinoid system in mouse skin
Publication TypeJournal Article
Year of Publication2016
AuthorsWohlman I.M, Composto G.M, Heck D.E, Heindel N.D, Lacey C.J, Guillon C.D, Casillas R.P, Croutch C.R, Gerecke D.R, Laskin D.L, Joseph L.B, Laskin J.D
JournalToxicol Appl Pharmacol
Date PublishedJul 15
ISBN Number0041-008X (Linking)
Accession Number27125198
Keywords*Endocannabinoids, *Epidermis, *Faah, *inflammation, *sulfur mustard, *Vesicants, Alkylating Agents/*toxicity, Amidohydrolases/antagonists & inhibitors/metabolism, Animals, Chemical Warfare Agents/*toxicity, Female, Irritants/*toxicity, Male, Mechlorethamine/*toxicity, Mice, Mice, Hairless, Mustard Gas/*toxicity, PPAR alpha/metabolism, Receptor, Cannabinoid, CB1/metabolism, Receptor, Cannabinoid, CB2/metabolism, Skin/*drug effects/metabolism

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 (PPARalpha). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARalpha 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 PPARalpha, 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.

Short TitleMustard vesicants alter expression of the endocannabinoid system in mouse skin

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