Environmental Factor, July 2009, National Institute of Environmental Health Sciences
Jordt Extends ONES Research on TRPA1 in Study on Asthma
By Eddy Ball
Leading a 15-person team of researchers, NIEHS Outstanding New Environmental Scientist (ONES) awardee Sven-Eric Jordt, Ph.D., reported new findings on the role of sensory neuronal ion channel activation in producing airway inflammation and hyperactivity in asthma. It is the latest report from Jordt's lab on experiments with two sensory transient receptor potential channels, TRPA1 and TRPV1, showing the potential for developing new interventions for the prevention and treatment of human disease and trauma. Funded in part by NIEHS, the study (http://www.pnas.org/content/106/22/9099.long) appears in the June issue of the Proceedings of the National Academy of Sciences (PNAS).
Through a process of elimination, Jordt (http://info.med.yale.edu/pharm/faculty/index.php?bioID=39) , first author Anabel Caceres, Ph.D. (http://info.med.yale.edu/pharm/jordt/people.htm) , and colleagues from the Department of Pharmacology, Department of Pathology and the Section of Pulmonary and Critical Care Medicine at Yale University School of Medicine established the critical role of TRPA1 - the mustard oil and acrolein receptor - in asthma and the efficacy of treatment with a TRPA1 antagonist known as HC-030031. The researchers also clearly showed that TRPV1, the capsaicin receptor, is not required for allergic airway inflammation in the OVA mouse model of asthma, despite its clear involvement in other symptomatic consequences of airway inflammation, such as chronic cough.
In their experiments, the team treated wild type, Trpa1-deficient and Trpv1-deficient mice with ovalbumin (OVA), which induces a Th2-directed allergic response, and HC-030031 - progressively establishing three lines of support for their hypothesis:
- Trpa1-/- mice showed a marked reduction in mucus production and Th2 cytokine levels in broncoalveolar lavage fluid (BALF) following OVA challenge, as opposed to the robust induction in wild type and Trpv1-/- mice with intact TRPA1 function.
- TRPA1 antagonist reduced airway inflammation and hyperreactivity when administered to wild-type mice during OVA airway challenge, resulting in diminished levels of Th2 cytokines in BALF and much lower densities of inflammatory cells in histological sections of airways.
- A strong TRPA1 agonist, 2-chloroacetophenone (CN), produced marked increases in levels of neuropeptides in wild-type mice, but not in Trpa1-/- mice, while pre-treatment with HC-030031 suppressed acute CN-induced neuropeptide release in airways.
In their discussion, the authors wrote, "The data in our present study support the idea that TRPA1 may function as an integrator of chemical and immunological stimuli modulating inflammation in the airways." Moreover, they concluded, "Our study opens an avenue for asthma pharmacology, revealing TRPA1 as potential target for anti-asthmatic drugs," and called for studies in additional animal models of asthma and other allergic inflammatory conditions.
Citation: Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D, D'Amours M, Witek JS, Fanger CM, Chong JA, Hayward NJ, Homer RJ, Cohn L, Huang X, Moran MM, Jordt SE (http://www.pnas.org/content/106/22/9099.long) . 2009. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci U S A. 106(22):9099-9104. Epub 2009 May 19.
From Basic Research to Public Health Applications
When Jordt visited NIEHS in 2006 to present his ONES research, he had already established that TRP channel receptors are part of an early warning system of sensory neurons during injury and chronic painful conditions triggering tears, sneezing, neurogenic inflammation, pain and respiratory constriction in the upper airways. He had also sufficiently characterized the basic thermo- and chemo-sensory mechanisms of TRPA1 and TRPV1 to hypothesize that blocking one or both of them might benefit people with asthma and people exposed to noxious agents, temperature extremes and environmental toxicants with irritant activities.
That basic research culminated in a May 2008 Journal of Clinical Investigation study (http://www.ncbi.nlm.nih.gov/pubmed/18398506) using a mouse knockout strategy to demonstrate a crucial role of TRPA1 in detection of airway irritants, including chlorine and hydrogen peroxide. In their tests of respiratory function, Trpa1(-/-) mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior - demonstrating in vivo that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses.
The study led to a paper (http://www.ncbi.nlm.nih.gov/pubmed/19036859?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) published in the April 2009 issue of FASEB linking the earlier findings to potential clinical applications. In those experiments, Jordt and colleagues in the Yale University Department of Pharmacology and Section of Pulmonary and Critical Care Medicine established a role for TRPA1 in the noxious effects of tear gases and toxic industrial isocyanates - the best known of which is the chemical released during the environmental disaster in Bhopal, India. The researchers also demonstrated that TRPA1 antagonists reduce the adverse health effects of exposures to a wide range of toxic noxious chemicals.
Because many of the environmental irritants activating TRPA1 are suspected of causing or exacerbating asthma, such as chlorine, aldehydes and cigarette smoke constituents, these studies, both featuring Postdoctoral Fellow Bret Bessac, Ph.D. (http://info.med.yale.edu/pharm/jordt/people.htm) , as first author, helped lay the foundation for their latest findings about airway inflammation and hyperreactivity in knockout mice.Citations:
Bessac BF, Sivula M, von Hehn CA, Caceres AI, Escalera J, Jordt SE (http://www.ncbi.nlm.nih.gov/pubmed/19036859?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) . 2009. Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J 23(4):1102-1114.
Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE (http://www.ncbi.nlm.nih.gov/pubmed/18398506) . 2008. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest 118(5):1899-1910.