Chlorine (CI2), phosgene, vesicants and electrophilic reactive chemicals (industrial and riot control agents) are considered among the most imminent chemical threats to be diverted for terrorism attacks, or released during accidents. In the last four years research in the Jordt laboratory has identified TRPA1, a Transient Receptor Potential ion channel expressed in sensory neurons, as the major neuronal target of chlorine, riot control agents and Industrial chemicals such as acrolein and isocyanates. Post-exposure treatment of chlorine-exposed mice with a TRPA1 antagonist strongly reduced lung inflammation and injury parameters. The same TRPA1 antagonist increased survival rates of phosgene-exposed mice, and also inhibited vesicant injury induced by the sulfur mustard analog, CEES. In our recent work we identified TRPV4, an ion channel expressed in the lung epithelium and vasculature, as an additional mediator of oxidant-induced pulmonary injury. Activation of TRPV4 leads to severe lung injury and cardiovascular depression, and we show that a TRPV4 antagonist inhibits ozone induced oxidative lung edema. TRPV3, a TRP ion channel in keratinocytes, is a candidate mediator of cutaneous injury by vesicants and corrosive electrophiles. TRP channel, through influx of calcium, activate p38 MAP kinase, a major transducer and activator of inflammation and cell death in injured tissue. In summary, we hypothesize that TRP channels are major targets of chemical warfare agents, mediating local and systemic injury and inflammation through neuronal and local cellular signaling. In this proposal we aim to 1: Develop advanced intramuscular formulations of TRPA1 antagonists for immediate and sustained release to counteract chlorine and vesicant injury, 2: Examine the role of pulmonary and cutaneous TRP ion channels in chemical injury, and 3: Investigate the effects of a p38 kinase antagonist in pulmonary and cutaneous chemical injury. Public Health Relevance: Our research is aimed to further develop treatments for lung and skin injury by chemical warfare agents and industrial chemicals that can be diverted for terrorism attacks. We identified a new group of drugs that we found to effectively diminish injury by chlorine gas and skin blistering agents. The goal of this proposal is to improve these drugs and investigate how they counteract injury.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-MDCN-J (50))
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Nadadur, Srikanth
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Yale University
Schools of Medicine
New Haven
United States
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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
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
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
Bessac, Bret F; Jordt, Sven-Eric (2010) Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. Proc Am Thorac Soc 7:269-77
Lanosa, Michael J; Willis, Daniel N; Jordt, Sven et al. (2010) Role of metabolic activation and the TRPA1 receptor in the sensory irritation response to styrene and naphthalene. Toxicol Sci 115:589-95
Bessac, Bret F; Sivula, Michael; von Hehn, Christian A et al. (2009) Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J 23:1102-14
Bessac, Bret F; Jordt, Sven-Eric (2008) Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology (Bethesda) 23:360-70
Bessac, Bret F; Sivula, Michael; von Hehn, Christian A et al. (2008) TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest 118:1899-910