Asthma and lower airway disease
Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells

https://doi.org/10.1016/j.jaci.2008.03.026Get rights and content

Background

The mechanisms responsible for the development of airway hyperresponsiveness in asthma are poorly understood. Adenosine levels are high in the lungs of patients with asthma, but a role for adenosine in the development of this cardinal feature of asthma has not been previously reported.

Objective

To determine the capacity of adenosine to induce airway hyperresponsiveness, and to investigate the mechanisms behind these effects of adenosine on airway physiology.

Methods

Wild-type C57BL/6 mice were exposed to aerosolized adenosine analog adenosine-5′ N-ethylcarboxamide (NECA), and subsequent hyperresponsiveness to methacholine was investigated by measuring airway mechanics after anesthesia and tracheostomy. Similar experiments were conducted with A1-deficient, A3-deficient, and mast cell–deficient mice, as well as with mast cell–deficient mice engrafted with wild-type (wt) or A3–/– mast cells. The effect of NECA on methacholine-induced tension development in ex vivo tracheal rings was also examined.

Results

Exposure of wt mice to NECA resulted in the robust induction of airway hyperresponsiveness. NECA failed to induce hyperresponsiveness to methacholine in tracheal ring preps ex vivo, and NECA-induced airway hyperresponsiveness in vivo was not affected by the genetic inactivation of the A1 adenosine receptor. In contrast, NECA-induced airway hyperresponsiveness was abolished in A3 adenosine receptor-deficient mice and in mice deficient in mast cells. Reconstitution of mast cell–deficient mice with wt mast cells restored hyperresponsiveness, whereas reconstitution with A3 receptor–deficient mast cells did not.

Conclusion

Adenosine induces airway hyperresponsiveness indirectly by activating A3 receptors on mast cells.

Section snippets

Animals

All studies were conducted in accordance with the Institutional Animal Care and Use Committee guidelines of the University of North Carolina at Chapel Hill. Female C57BL/6 mice and WBB6F1/J-KitW/W-v mast cell–deficient mice were purchased from the Jackson Laboratory and bred in our animal facility. Female A1–/– and A3–/– mice were generated and genotyped as previously described, and backcrossed 12 generations to the C57BL/6 background.16, 23, 24 Female C57BL/6 KitW-sh/W-sh mast cell–deficient

NECA robustly induces AHR in C57BL/6 mice

C57BL/6 mice were exposed to NECA (3 mg/mL) for 10 minutes by aerosol. Twenty minutes later, RL, Cdyn, Raw, and Gtissue were measured at the basal level and in response to graded methacholine challenge. Control animals were exposed to vehicle rather than NECA. NECA exposure had no effect on basal respiratory mechanics. Methacholine aerosolization at 20, 40, and 80 mg/mL only modestly increased RL in vehicle-pretreated mice (Fig 1, A). However, the same methacholine dosing resulted in much

Discussion

Airway hyperresponsiveness is a cardinal feature of asthma, characterized by bronchoconstriction after exposure to numerous nonantigenic stimuli, including cold air, perfumes, and exercise. In this report, we describe a previously unrecognized role for adenosine as an inducer of AHR. Because it is well established that adenosine levels are elevated in the asthmatic lung,8, 9 there is a strong implication that adenosine may contribute to the development of AHR in patients with asthma.

Modulatory

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    Supported by National Institutes of Health grants HL71802 (S.L.T.) and HL58506 (R.B.P.) and the China Natural Science Foundation (30700933 to X.H.). D. A. Deshpande is supported by the Pathway to Independence Award (K99-HL-087560).

    Disclosure of potential conflict of interest: B. Fredholm has received research support from the National Institutes of Health, the European Commission, and the Heart & Lung Fund. R. Penn has received research support from the National Institutes of Health. S. Tilley has received research support from the National Institutes of Health and the North Carolina Biotechnology Center. The rest of the authors have declared that they have no conflict of interest.

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    Copyright © 2008 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.