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.
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Wohlman
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: Composto
authors.affiliation: Environmental Health Science, New York Medical College, Valhalla, NY, United States.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, PA, United States.
authors.forename: Ned D
authors.initials: ND
authors.lastname: Heindel
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, PA, United States.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Lacey
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, PA, United States.
authors.forename: Christophe D
authors.initials: CD
authors.lastname: Guillon
authors.affiliation: MRIGlobal, Kansas City, MO, United States.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Casillas
authors.affiliation: MRIGlobal, Kansas City, MO, United States.
authors.forename: Claire R
authors.initials: CR
authors.lastname: Croutch
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gerecke
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Joseph
authors.affiliation: Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ, United States. Electronic address: jlaskin@eohsi.rutgers.edu.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D005260:Female; D007509:Irritants / Q000633:toxicity*; D008297:Male; D008466:Mechlorethamine / Q000633:toxicity*; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000633:toxicity*; D047493:PPAR alpha / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000477:Alkylating Agents; D000581:Amidohydrolases; D002619:Chemical Warfare Agents; D007509:Irritants; D008466:Mechlorethamine; D009151:Mustard Gas; D047493:PPAR alpha; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases
keywords: Endocannabinoids; Epidermis; FAAH; Inflammation; Sulfur mustard; Vesicants