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: 9.81). 06/2009; 106(22):9099-9104. DOI: 10.1073/pnas.0900591106

ABSTRACT 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.

Download full-text


Available from: Donato del Camino, Jul 04, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    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.
    12/2014; 2(6). DOI:10.1002/prp2.79
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The role of the Nlrp3 inflammasome in nonallergic airway hyperresponsiveness (AHR) has not previously been reported. Recent evidence supports both interleukin (IL) 1β and short fragments of hyaluronan (HA) as contributors to the biological response to inhaled ozone. Objective: Because extracellular secretion of IL-1β requires activation of the inflammasome, we investigated the role of the inflammasome proteins ASC, caspase1, and Nlrp3 in the biological response to ozone and HA. Methods: C57BL/6J wild-type mice and mice deficient in ASC, caspase1, or Nlrp3 were exposed to ozone (1 ppm for 3 hr) or HA followed by analysis of airway resistance, cellular inflammation, and total protein and cytokines in bronchoalveolar lavage fluid (BALF). Transcription levels of IL-1β and IL-18 were determined in two populations of lung macrophages. In addition, we examined levels of cleaved caspase1 and cleaved IL-1β as markers of inflammasome activation in isolated alveolar macrophages harvested from BALF from HA-treated mice. Results: We observed that genes of the Nlrp3 inflammasome were required for development of AHR following exposure to either ozone or HA fragments. These genes are partially required for the cellular inflammatory response to ozone. The expression of IL-1β mRNA in alveolar macrophages was up-regulated after either ozone or HA challenge and was not dependent on the Nlrp3 inflammasome. However, soluble levels of IL-1β protein were dependent on the inflammasome after challenge with either ozone or HA. HA challenge resulted in cleavage of macrophage-derived caspase1 and IL-1β, suggesting a role for alveolar macrophages in Nlrp3-dependent AHR. Conclusions: The Nlrp3 inflammasome is required for the development of ozone-induced reactive airways disease.
    Environmental Health Perspectives 09/2012; 120(12). DOI:10.1289/ehp.1205188 · 7.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An important function of the chemical senses is to warn against dangerous biological and chemical agents in the environment. The discovery in recent years of “taste” receptor cells outside the oral cavity that appear to have protective functions has raised new questions about the nature and scope of the chemical senses in general and of chemesthesis in particular. The present paper briefly reviews these findings within the context of what is currently known about the body's chemically sensitive protective mechanisms, including nonsensory processes that help to expel or neutralize threatening agents once they have been encountered. It is proposed that this array of defense mechanisms constitutes a “chemofensor complex” in which chemesthesis is the most ubiquitous, functionally diverse, and interactive chemosensory component.
    Chemical Senses 12/2011; 37(3):201-6. DOI:10.1093/chemse/bjr119 · 3.28 Impact Factor