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

Abstract

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.

• Authors: Satyanarayana Achanta, Narendranath Reddy Chintagari, Marian Brackmann, Shrilatha Balakrishna, Sven-Eric Jordt
• Journal: Toxicology letters (Toxicol Lett) Vol. 293 Pg. 140-148 (Sep 01 2018) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 29535050 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide
• Acetanilides
• Biomarkers
• Chemical Warfare Agents
• Cytokines
• MK-8825
• Purines
• Pyridines
• Spiro Compounds
• TRPA1 Cation Channel
• Trpa1 protein, mouse
• 2-chloroethyl ethyl sulfide
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Calcitonin Gene-Related Peptide
• Mustard Gas

Topics

• Acetanilides (pharmacology)
• Animals
• Biomarkers (analysis)
• Blister (pathology)
• Calcitonin Gene-Related Peptide (antagonists & inhibitors)
• Chemical Warfare Agents (toxicity)
• Cytokines (biosynthesis)
• Ear, External (pathology)
• Keratinocytes (drug effects)
• Male
• Matrix Metalloproteinase 9 (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Mustard Gas (analogs & derivatives, toxicity)
• Purines (pharmacology)
• Pyridines (pharmacology)
• Skin (pathology)
• Skin Diseases (chemically induced, pathology, prevention & control)
• Spiro Compounds (pharmacology)
• TRPA1 Cation Channel (antagonists & inhibitors)