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

Publication ,  Journal Article
Achanta, S; Chintagari, NR; Brackmann, M; Balakrishna, S; Jordt, S-E
Published in: Toxicol Lett
September 1, 2018

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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Published In

Toxicol Lett

DOI

EISSN

1879-3169

Publication Date

September 1, 2018

Volume

293

Start / End Page

140 / 148

Location

Netherlands

Related Subject Headings

  • Toxicology
  • TRPA1 Cation Channel
  • Spiro Compounds
  • Skin Diseases
  • Skin
  • Pyridines
  • Purines
  • Mustard Gas
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Achanta, S., Chintagari, N. R., Brackmann, M., Balakrishna, S., & Jordt, S.-E. (2018). TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation. Toxicol Lett, 293, 140–148. https://doi.org/10.1016/j.toxlet.2018.03.007
Achanta, Satyanarayana, Narendranath Reddy Chintagari, Marian Brackmann, Shrilatha Balakrishna, and Sven-Eric Jordt. “TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation.Toxicol Lett 293 (September 1, 2018): 140–48. https://doi.org/10.1016/j.toxlet.2018.03.007.
Achanta S, Chintagari NR, Brackmann M, Balakrishna S, Jordt S-E. TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation. Toxicol Lett. 2018 Sep 1;293:140–8.
Achanta, Satyanarayana, et al. “TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation.Toxicol Lett, vol. 293, Sept. 2018, pp. 140–48. Pubmed, doi:10.1016/j.toxlet.2018.03.007.
Achanta S, Chintagari NR, Brackmann M, Balakrishna S, Jordt S-E. TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation. Toxicol Lett. 2018 Sep 1;293:140–148.
Journal cover image

Published In

Toxicol Lett

DOI

EISSN

1879-3169

Publication Date

September 1, 2018

Volume

293

Start / End Page

140 / 148

Location

Netherlands

Related Subject Headings

  • Toxicology
  • TRPA1 Cation Channel
  • Spiro Compounds
  • Skin Diseases
  • Skin
  • Pyridines
  • Purines
  • Mustard Gas
  • Mice, Inbred C57BL
  • Mice