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Vol. 298, Issue 2, 433-440, August 2001
Department of Biochemistry and Molecular Biology, The University of
Texas-Houston Medical School, Houston, Texas (H.Z., J.L.C., J.B.V.,
M.R.B.); and Research Department, Novartis Pharma AG, Basel,
Switzerland (J.R.F.)
Adenosine is a signaling nucleoside that has been suggested to play a
role in asthma in part through its ability to influence mediator
release from mast cells. Adenosine levels are elevated in the lungs of
asthmatics, further implicating this molecule in the regulation of lung
inflammation and suggesting that animal models exhibiting endogenous
increases in adenosine will be useful for the analysis of adenosine
function. Adenosine deaminase (ADA) is a purine catabolic enzyme
responsible for regulating the levels of adenosine in tissues and
cells. ADA-deficient mice develop lung inflammation and damage
reminiscent of that seen in asthma in association with elevated
adenosine levels. In the current study, we investigated the status of
mast cells in ADA-deficient lungs. ADA-deficient mice exhibited
extensive lung mast cell degranulation concurrent with elevated
adenosine levels. ADA enzyme therapy prevented the accumulation of lung
adenosine as well as mast cell degranulation, suggesting that this
process was dependent on elevated lung adenosine levels. Consistent
with this, treatment of ADA-deficient mice with broad spectrum
adenosine receptor antagonists attenuated degranulation by 30 to 40%,
supporting the involvement of adenosine receptor signaling. Moreover,
these studies demonstrate the ability of endogenously generated
adenosine to influence lung mast cell degranulation in a
receptor-mediated manner and establish ADA-deficient mice as a model
system to investigate the specific adenosine receptor responses
involved in the degranulation of lung mast cells.
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