Localization of substance P gene expression for evaluating protective countermeasures against sulfur mustard

Casbohm, Stacy L.; Rogers, James V.; Stonerock, Mindy K.; Martin, Jamie L.; Ricketts-Kaminsky, Karen M.; Babin, Michael C.; Casillas, Robert P.; Sabourin, Carol L.

doi:10.1016/j.tox.2004.07.008

Cited by 17 publications

(6 citation statements)

References 28 publications

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“…SM-induced skin injury appears to be mediated in part through neurogenic inflammatory processes [7,8]; therefore, it is possible that NPY Y 1 could also contribute to dermal inflammation following exposure to SM. Recently, we have demonstrated the potential role of substance P in SMinduced skin injury, which is reduced by pretreatment with olvanil [80].…”

Section: Discussionmentioning

confidence: 99%

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

Sabourin

Rogers

Choi

et al. 2005

J. Biochem. Mol. Toxicol.

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The chemical warfare agent sulfur mustard (SM) produces blister formation with a severe inflammatory reaction in skin of exposed individuals. The development of efficacious countermeasures against SM vesication requires an understanding of the cellular and molecular mechanism of SM-induced tissue injury. This study examined SM-induced alterations in gene expression using Atlas Mouse 5K DNA microarrays (5002 genes) to identify transcriptional events associated with SM skin injury. Mice (N=3) were exposed topically to SM (0.04, 0.08, and 0.16 mg; 48.8, 97.5, and 195 mM) on the inner surface of the right ear and skin tissues were harvested at 1.5, 3, 6, and 12 h. Genes were selected based on the three mice in the same dose group demonstrating a > or =2-fold increase or decrease in gene expression for the SM-exposed tissue when compared to the dichloromethane vehicle control ear at all three doses and four time points. At the 0.04 mg SM dose, the genes observed were primarily involved in inflammation, apoptosis, and cell cycle regulation. Exposure to 0.08 mg SM increased the expression of genes related to inflammation and cell cycle regulation. Exposure to 0.16 mg SM led to a total of six genes that were changed at all observed time periods; however, these genes do not appear to be directly influential in biological mechanisms such as inflammation, apoptosis, and cell cycle regulation as was observed at the lower SM doses of 0.04 and 0.08 mg. These functional categories have been observed in previous studies utilizing both in vivo and in vitro model systems of SM-induced dermal injury, suggesting that molecular mechanisms associated with inflammation, apoptosis, and cell cycle regulation may be appropriate targets for developing prophylactic/therapeutic treatments for SM skin injury.

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Section: Discussionmentioning

confidence: 99%

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

Sabourin

Rogers

Choi

et al. 2005

J. Biochem. Mol. Toxicol.

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“…CGRP and Substance P activate immune cells and induce inflammatory tissue responses such as swelling, vasodilation, increase in blood flow and edema (Beard and Beard, 1989). In a mouse model of SM skin injury, pre-exposure treatment with olvanil, a TRPV1 ligand causing depletion of inflammatory neuropeptides, attenuated skin inflammation and edema and reduced Substance P immunoreactivity in the skin, suggesting that neurogenic inflammation contributes to the cutaneous toxicological effects of SM (Babin et al, 2000; Casbohm et al, 2004; Sabourin et al, 2003). Neurogenic inflammation mediated by CGRP has been implicated in trigeminal pain and migraine, leading to the development of CGRP receptor inhibitors that showed promising preclinical and clinical efficacy (Bell et al, 2012; Romero-Reyes et al, 2015; Voss et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation

et al. 2018

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The skin is highly sensitive to the chemical warfare agent in mustard gas, sulfur mustard (SM) that initiates a delayed injury response characterized by erythema, inflammation and severe vesication (blistering). Although SM poses a continuing threat, used as recently as in the Syrian conflict, no mechanism-based antidotes against SM are available. Recent studies demonstrated that Transient Receptor Potential Ankyrin 1 (TRPA1), a chemosensory cation channel in sensory nerves innervating the skin, is activated by SM and 2-chloroethyl ethyl sulfide (CEES), an SM analog, in vitro, suggesting it may promote vesicant injury. Here, we investigated the effects of TRPA1 inhibitors, and an inhibitor of Calcitonin Gene Related Peptide (CGRP), a neurogenic inflammatory peptide released upon TRPA1 activation, in a CEES-induced mouse ear vesicant model (CEES-MEVM). TRPA1 inhibitors (HC-030031 and A-967079) and a CGRP inhibitor (MK-8825) reduced skin edema, pro-inflammatory cytokines (IL-1β, CXCL1/KC), MMP-9, a protease implicated in skin damage, and improved histopathological outcomes. These findings suggest that TRPA1 and neurogenic inflammation contribute to the deleterious effects of vesicants in vivo, activated either directly by alkylation, or indirectly, by reactive intermediates or pro-inflammatory mediators. TRPA1 and CGRP inhibitors represent new leads that could be considered for validation and further development in other vesicant injury models.

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“…Edema can be quantified by measuring 8-mm-diameter ear punch biopsy weights. This model has been used to screen many compounds and remains the most cost-effective live animal screen available (Casillas et al, 2000a,b;Dachir et al, 2002Dachir et al, , 2004aBabin et al, 2003;Casbohm et al, 2004;Sabourin et al, 2004;Wormser et al, 2004aWormser et al, ,b, 2005Kiser et al, 2005;Amitai et al, 2006;Dillman et al, 2006). These effects occur in a dose-dependent manner (Figure 39.4).…”

Section: Model Systems For Screening Smmentioning

confidence: 99%

“…Capsaicin and its structural analogs, known collectively as vanilloids, have been shown to have anti-inflammatory activity, as demonstrated by inhibition of edema, mast cell degranulation, and leukocyte migration (Brand et al, 1990;Bunker et al, 1991). Analogs octyl homovanillamide and heptyl isovanillamide were shown to display similar protective activities against SM (Casbohm et al, 2004). One such vanilloid, olvanil, is a highly lipophilic analog of capsaicin and has been shown to reduce SM-induced histological damage and edema as well as cytokine and chemokine mRNA induction (Casillas et al, 2000a,b;Sabourin et al, 2003).…”

Section: Trpv1 Ligandsmentioning

confidence: 99%

Dermal Toxicity of Sulfur Mustard

Gray

Shakarjian

Gerecke

et al. 2015

Handbook of Toxicology of Chemical Warfare Agents

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Localization of substance P gene expression for evaluating protective countermeasures against sulfur mustard

Cited by 17 publications

References 28 publications

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation

Dermal Toxicity of Sulfur Mustard

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