Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells.


Journal Article

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 A(1)-deficient, A(3)-deficient, and mast cell-deficient mice, as well as with mast cell-deficient mice engrafted with wild-type (wt) or A(3)(-/-) 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 A(1) adenosine receptor. In contrast, NECA-induced airway hyperresponsiveness was abolished in A(3) 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 A(3) receptor-deficient mast cells did not. CONCLUSION: Adenosine induces airway hyperresponsiveness indirectly by activating A(3) receptors on mast cells.

Full Text

Duke Authors

Cited Authors

  • Hua, X; Chason, KD; Fredholm, BB; Deshpande, DA; Penn, RB; Tilley, SL

Published Date

  • July 2008

Published In

Volume / Issue

  • 122 / 1

Start / End Page

  • 107 - 113.e7

PubMed ID

  • 18472152

Pubmed Central ID

  • 18472152

Electronic International Standard Serial Number (EISSN)

  • 1097-6825

Digital Object Identifier (DOI)

  • 10.1016/j.jaci.2008.03.026


  • eng

Conference Location

  • United States