School of Medicine, Respiratory Cell and Molecular Biology Division, Southampton General Hospital, Southampton SO16 6YD, United Kingdom
ADENOSINE IS A PURINE NUCLEOSIDE with
wide ranging intracellular functions linked to intermediary and nucleic
acid metabolism. It is released from cells when under oxidative or
metabolic stress and has a range of extracellular functions mediated
through purinoceptors A1, A2A, A2B,
and A3. In 1983, we first showed that inhaled adenosine, but notably not inosine (the adenosine deaminase metabolite) or guanosine, was a powerful bronchoconstrictor in asthmatic but not
normal subjects (6). An almost identical response was also observed with inhaled adenosine, a 5'-monophosphate that is rapidly converted to adenosine by the ubiquitous ectoenzyme 5'-nucleotidase (16). Despite this evidence, the action of adenosine on
airway smooth muscle in vitro has been conflicting, varying between
species and, in the same species, with the type of preparation, the
initial level of tone, and the concentration of adenosine used. In
isolated human airway preparations, the predominant effect of the
nucleoside is contraction, although its effect is weak
(11). Airway preparations from allergic asthmatic subjects
were more sensitive to the contractile responses of adenosine and
related analogs, but the response could be almost entirely abolished by
inhibition of contractile cysteinyl leukotriene, histamine
H1, and prostanoid effects (3). Together with
cumulative evidence showing that adenosine-induced bronchoconstriction in asthma could be effectively blocked by inhibition of mast cell mediator release (23), antagonism of cysteinyl
LT1 and H1 receptors (20, 24), and
evidence showing that following exposure to AMP, increased levels of
mast cell mediators could be detected in asthmatic airways
(22), this provided the essential link to
incriminate the mast cell as an effector of the acute asthmatic response to this nucleoside (21).
Studies on human lung mast cells established that adenosine could
enhance IgE-dependent mediator release in vitro by interacting with
cell surface purinoceptors of the A2 subtype (15,
18). Such a mechanism helped explain the preferential protective
effect exerted by xanthines such as theophylline against
adenosine-induced bronchoconstriction (7), which may be
relevant to the therapeutic efficacy of this drug class in asthma
(9). Subsequently, two subtypes of A2 receptor
have been uncovered, A2A (linked to Gs coupling) and A2B (linked to Gs and
Gq coupling), the latter being responsible for the
augmenting properties of adenosine on human mast cells
(8). In rats, this effect is also said to be served by the
A2B receptor (13), whereas, in mice, the
A3 receptor subsumes this function (17). The
ability of adenosine released in inflamed airways to enhance mast cell
mediator release via the A2B receptor has led to this
receptor being identified as a novel therapeutic target in asthma.
Enprofylline, which is a weak but selective A2B antagonist,
has been shown to be highly effective in asthma (5), but,
unfortunately, the further development of this drug had to be
discontinued due to toxicity unrelated to its primary pharmacology.
The recent discovery by Blackburn and colleagues
(4) that adenosine deaminase-deficient mice exhibit a lung
phenotype with features of asthma including bronchial
hyperresponsiveness, enhanced mucus section, airway eosinophilia,
increased IgE synthesis, and elevated interleukin-5 levels in
bronchoalveolar lavage that could be reversed with exogenous adenosine
deaminase (6) has further strengthened the causal
association between adenosine and an asthma phenotype. To further
pursue mechanisms, Banerjee et al., report, in one of this issue's
articles in focus (Ref. 2, see p. L169), that in adenosine-deficient
mice, a large number of genes are dysregulated in the lungs, many of
which can be linked to the "asthmatic" changes reported in their
earlier study. Of particular interest is their finding that vascular
endothelial growth factor and monocyte chemotactic peptide-3 in the
lung are also increased at the protein level. However, their elegant
use of nucleic acid arrays also highlighted many other genes that
could be relevant to asthma pathophysiology, including
osteopontin, insulin-like growth factor-I, and fibronectin, with
increases in the adenosine-deficient mice of 28-, 15-, and 6-fold,
respectively. Along with the cathepsin family of proteases (increased
2- to 8-fold), these adenosine-regulated molecules are more closely
linked to the aberrant tissue injury and repair response, a recently
recognized important component of chronic asthma (14). The
use of cDNA gene array technology, followed by quantification of
dysregulated genes and measurement of their protein products, as
illustrated in this study, is a good example of how modern
molecular-based methodology can be used to rapidly identify potential
disease-related targets. However, in the final analysis, it is only
when such methods are applied to human asthma that the significance of
these fascinating findings in mice can be fully appreciated in relation
to the disease in humans (19). The increased occurrence of
eosinophilia and disordered lung function in adenosine
deaminase-deficient humans (26) may lend itself to study
in this way.
The recent discovery that adenosine also causes bronchoconstriction in
chronic obstructive pulmonary disease, but only in those who exhibit
evidence of eosinophilic inflammation in their airways
(25), widens interest in this purine nucleoside as a mediator of lung disease. Even in asthma, it seems that the airway response to adenosine correlates more closely with disease activity than other more conventional forms of bronchial provocation (1, 12). Adenosine may also be linked to bronchoconstriction with exercise (10), a characteristic feature of asthma in
children and young adults. Whether the proasthmatic effects of
adenosine are mediated through the A2B receptor or not will
have to await the introduction of selective antagonists for clinical
trial. Until then, there is still much to be learned about the
ubiquitous effect of this nucleoside on target cells in both normal and
diseased airways.
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REFERENCES
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. T. Holgate, School of Medicine, Respiratory Cell and Molecular Biology Division, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
10.1152/ajplung.00386.2001
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