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theses

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) and 2-arachidonoyl glycerol, are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to classical cannabinoid receptors, CB1 and CB2, as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH); inhibitors of this enzyme are known to suppress inflammation. Each of the endocannabinoid proteins was found to be expressed in epidermis and epidermal appendages in mouse skin. Treatment of the skin with SM or NM, at concentrations that induce tissue injury, was found to markedly upregulate FAAH, CB1, CB2 and PPARα; increased expression of these proteins persisted in the tissue during the wound healing process. To determine if the endocannabinoid system regulated the action of vesicants, mouse skin was treated with a novel class of vanilloid carbamates that are potent inhibitors of FAAH. These compounds were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. These data demonstrate that markers of the endocannabinoid system are expressed in mouse skin. Our findings that NM and SM cause changes in the endocannabinoid system and that FAAH inhibitors have the capacity to reduce skin injury support the idea the endocannabinoids contribute to the pathogenic responses to vesicants.

ETD_7121

Ph.D.

Includes bibliographical references

by Irene M. Wohlman

doi:10.7282/T3X350PC

ETD doctoral

The author owns the copyright to this work.