Sensory nerve endings in the skin, airways, eyes and mucous membranes are activated by a wide range of hazardous chemicals. These include pulmonary chemical agents as well as vesicants and noxious industrial chemicals. Activation of sensory nerve endings in the nasal passages and airways induces pain, irritation and apnea. Extended chemical exposure promotes injury by causing the release of inflammatory neuropeptides that contribute to edema formation in the lung and skin, ocular damage, mucus hypersecretion, pulmonary obstruction, and blister formation. In animal models these effects can be strongly reduced by prior neural desensitization or denervation. Thus, pharmacological blockade of neural activation, as well as block of neuropeptide receptors in target tissues, could represent effective measures to prevent and alleviate the deleterious effects of pulmonary agents and vesicants. The molecular targets for pulmonary agents and vesicants on sensory neurons are largely unknown. Recently, a new class of sensory chemoreceptors, the TRP ion channels, was discovered. The founding member, TRPV1, is the receptor for capsaicin, the pungent and inflammatory ingredient in chili peppers that is used as an incapacitating agent. TRPA1, a novel TRP ion channel, is activated by mustard oil (allyl isothiocyanate), a potent irritant and neuroinflammatory agent. We found that TRPA1 is exclusively expressed in sensory fibers that are also sensitive to capsaicin. Mustard oil and other plant-derived activators of TRPA1 show intriguing structural similarities with sulfur mustard. In addition, we found that TRPA1 is strongly activated by hazardous industrial chemicals. These include a,p-unsaturated aldehydes such as acrolein, a pulmonary agent used in the First World War. Our functional and behavioral analysis of mice deficient in TRPA1 showed that TRPA1 is essential for sensory neural responses to mustard oil, acrolein and other chemical hazards. Thus TRPA1, and potentially other TRP channels, may represent effective targets to prevent and treat the toxic effects of pulmonary agents and vesicants.
Our specific aims are to investigate the role of TRP channels in the response to pulmonary agents and vesicants in vitro and in vivo and to analyze the efficacy of TRP channel blockers and neuropeptide antagonists in the reduction of warfare agent toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES015674-05
Application #
7858028
Study Section
Special Emphasis Panel (ZNS1-SRB-R (22))
Program Officer
Shaughnessy, Daniel
Project Start
2006-09-29
Project End
2011-08-21
Budget Start
2010-06-01
Budget End
2011-08-21
Support Year
5
Fiscal Year
2010
Total Cost
$480,761
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Achanta, Satyanarayana; Jordt, Sven-Eric (2017) TRPA1: Acrolein meets its target. Toxicol Appl Pharmacol 324:45-50
Summerhill, Eleanor M; Hoyle, Gary W; Jordt, Sven-Eric et al. (2017) An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness. Ann Am Thorac Soc 14:1060-1072
Tai, Yan; Wang, Chuan; Wang, Zhihua et al. (2017) Involvement of Transient Receptor Potential Cation Channel Member A1 activation in the irritation and pain response elicited by skin-lightening reagent hydroquinone. Sci Rep 7:7532
Rothenberg, Craig; Achanta, Satyanarayana; Svendsen, Erik R et al. (2016) Tear gas: an epidemiological and mechanistic reassessment. Ann N Y Acad Sci 1378:96-107
Liu, Boyi; Tai, Yan; Achanta, Satyanarayana et al. (2016) IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy. Proc Natl Acad Sci U S A 113:E7572-E7579
Liu, Boyi; Tai, Yan; Caceres, Ana I et al. (2016) Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice. PLoS One 11:e0165200
Balakrishna, Shrilatha; Song, Weifeng; Achanta, Satyanarayana et al. (2014) TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 307:L158-72
Gui, Junhong; Liu, Boyi; Cao, Guan et al. (2014) A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1-S4 gating domain. Curr Biol 24:473-83
Liu, Boyi; Escalera, Jasmine; Balakrishna, Shrilatha et al. (2013) TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J 27:3549-63
Jordt, Sven-Eric (2011) Trigeminal TRPs and the scent of pain. Pain 152:4-5

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