A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2009; 106(22):9099-9104. DOI: 10.1073/pnas.0900591106


Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune,
smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited
efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation.
TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette
smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including
reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma.
Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1
inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely
abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with
HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration
and prevented the development of airway hyperreactivity. Trpa1−/− mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential
explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between
the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge.
TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.

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Available from: Donato del Camino, Oct 10, 2015
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