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

Jeffrey D. Laskin, Ph.D. - Mon, 05/29/2017 - 14:00

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

Toxicol Appl Pharmacol. 2016 Jul 15;303:30-44

Authors: Wohlman IM, Composto GM, Heck DE, Heindel ND, Lacey CJ, Guillon CD, Casillas RP, Croutch CR, Gerecke DR, Laskin DL, Joseph LB, Laskin JD

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.

PMID: 27125198 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung.

Paul J. Lioy, Ph.D. - Mon, 05/29/2017 - 14:00

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World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung.

Exp Mol Pathol. 2016 Dec 13;:

Authors: Sunil VR, Vayas KN, Fang M, Zarbl H, Massa C, Gow AJ, Cervelli JA, Kipen H, Laumbach R, Lioy PJ, Laskin JD, Laskin DL

Abstract
Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20μg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3days, a response which persisted for at least 21days. Whereas matrix metalloproteinase was upregulated 7days post-WTC dust exposure, IL6RA-1 was increased at 21days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3days, lysine K27 at 7days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies.

PMID: 27986442 [PubMed - as supplied by publisher]

Categories: Publications from UCDPER Members

Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor.

Jeffrey D. Laskin, Ph.D. - Wed, 05/24/2017 - 02:00

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Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor.

Toxicol Sci. 2017 Feb 10;:

Authors: Venosa A, Gow JG, Hall L, Malaviya R, Gow AJ, Laskin JD, Laskin DL

PMID: 28184907 [PubMed - as supplied by publisher]

Categories: Publications from UCDPER Members