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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    • "Reduced OVA-induced allergic airway inflammation in TRPA1- KO mice (Caceres et al., 2009) and following TRPV1-small interfering RNA (siRNA) knockdown (Mabalirajan et al., 2013; Rehman et al., 2013) indicates activation of these channels by endogenous ligands during allergic inflammation, providing the opportunity to target QX-314 into nociceptors in inflamed lungs without the need for administration of an exogenous TRP channel agonist. When QX-314 was administered 60 min prior to a capsaicin challenge to OVA-challenged mice on day 18, at the height of inflammation, capsaicin-evoked neuropeptide release was, unlike the situation in naive mice, markedly decreased (Figure 3D), showing that QX-314 treatment by itself in OVAexposed mice locally blocked nociceptors. "
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    ABSTRACT: Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Neuron
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    • "The agonist actions of NDGA on a key detector of a subset of noxious sensory information suggests that its usefulness in animal studies of sensory function is limited, as it seems to inhibit the activity of enzymes producing pronociceptive compounds (Gregus et al. 2012, 2013), but at the same time be directly activating their potential target. Hitherto unexplained effects of NDGA have been reported in airway smooth muscle (Henry 1994), a tissue where TRPA1 may be expressed on both neuronal and non-neuronal cells (Caceres et al. 2009; Nassini et al. 2012). NDGA and its derivative terameprocol are potential chemotherapeutic agents. "
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    ABSTRACT: Nordihydroguaiaretic acid (NDGA) is a major biologically active component of the creosote bush, Larrea tridentate, widely used in unregulated therapies. NDGA is a lipoxygenase inhibitor while a derivative, terameprocol, has been trialed as a chemotherapeutic agent. When investigating fatty acid activation of the human transient receptor potential cation channel subfamily A, member 1 (hTRPA1), we found that NDGA activated the channel. Here we investigate the actions of NDGA and terameprocol at hTRPA1 and the consequences of this for noxious cold sensitivity in mice. hTRPA1 was stably expressed in HEK 293 cells (HEK 293-TRPA1) and channel activity examined by measuring changes in intracellular calcium ([Ca]i) using a fluorescent dye and activation of membrane currents using patch clamp electrophysiology. The effects of local NDGA and terameprocol application on acetone-induced paw flinching were examined in mice. NDGA (pEC50 of 5.4 ± 0.1, maximum change in fluorescence of 385 ± 30%) and terameprocol (pEC50 4.5 ± 0.2, maximum 550 ± 75%) increased [Ca]i in HEK 293-hTRPA1 cells. NDGA also induced an increase in membrane conductance in HEK 293-hTRPA1 cells. These effects were prevented by the TRPA1 antagonist HC-030031, and were dependent on the presence of Cys621, Cys 641, and Cys 665 in hTRPA1. Neither NDGA nor terameprocol alone produced spontaneous pain behaviors in mice after hind paw injection, but both enhanced responses to acetone. NDGA and terameprocol are efficacious activators of TRPA1. NDGA should be used with care to probe lipoxygenase involvement in nociception while TRPA1 activity should be considered when considering use of these drugs in humans.
    Full-text · Article · Dec 2014
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    • "It is also notable that endogenous lipoxygenase products such as hydroperoxyeicosatetraenoic acids and leukotriene B4 were potent agonists for TRPV1 channel [43]. In animal models, TRPA1 channels have been associated with ovalbumin-induced allergic asthma [44], hypochlorite-induced nonallergic AHR [45], or formaldehyde-promoted asthma [46]. As these channels are also expressed in nonneuronal cells like airway epithelium or bronchial smooth muscle cells [47, 48], their clinical relevance should be further explored. "
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    ABSTRACT: Chronic cough is a common reason for patients to seek medication attention. Over the last few decades, we have experienced significant clinical success by applying the paradigm of 'evaluating and treating the causes for chronic cough'. However, we still ask ourselves 'what underlies chronic cough. Indeed in a considerable proportion of patients cough is idiopathic, or unexplained despite vigorous evaluation. Commonly associated conditions such as rhinitis, eosinophilic bronchitis, asthma, or gastroesophageal acidic reflux may not be fundamental to cough, and thus may be triggers rather than causes. The cardinal feature of chronic cough is persistent upregulation the cough reflex, which may be driven by complex interactions between biologic, neurologic, immunologic, genetic, comorbid, and environmental factors. We suggest the new paradigm 'cough hypersensitivity syndrome' should finally bring us further advances in understanding and management of chronic cough.
    Full-text · Article · Jan 2014
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