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


CONCLUSIONS
Adenosine induces airway hyperresponsiveness indirectly by activating A(3) receptors on mast cells.
Hua
Xiaoyang
X
Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Chason
Kelly D
KD
Fredholm
Bertil B
BB
Deshpande
Deepak A
DA
Penn
Raymond B
RB
Tilley
Stephen L
SL
D000241:Adenosine / Q000378:metabolism*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D006596:Hexosaminidases / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D043684:Receptor, Adenosine A3 / Q000172:deficiency / Q000378:metabolism*
D043684:Receptor, Adenosine A3; D019830:Adenosine-5'-(N-ethylcarboxamide); D006596:Hexosaminidases; D000241:Adenosine