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San Diego, CA
Dr. Ramsdell is Professor of Clinical Medicine, University of California, San Diego.
Correspondence to: Joe W. Ramsdell, MD, FCCP, University of California, San Diego, 200 W Arbor Dr, No. 8415, San Diego, CA 92103-8415; e-mail: jramsdell{at}ucsd.edu
The role of adenosine in mediating airway hyperreactivity is an interesting and emerging area of study. Subjects with asthma were noted to have airway hyperresponsiveness to inhaled adenosine in 1983.1 This observation led to a series of clinical and basic investigations that have resulted in our current paradigm for the role of adenosine and adenosine receptors in airways allergic inflammation. This topic has been recently reviewed in detail by Meade et al2 and Polosa et al.3
Bronchial hyperreactivity to adenosine may be found in atopic and nonatopic asthmatic patients,1 patients with COPD,4 and patients with allergic rhinitis without asthma.5 In general, patients with COPD tend to be less responsive than asthmatic patients (but they are still responsive compared to healthy individuals).4 Adenosine hyperreactivity does not correlate with methacholine reactivity in these various populations,4 suggesting different mechanisms and clinical significance.
It has been shown that adenosine hyperreactivity in asthmatic patients is more closely associated with sputum eosinophilia compared to methacholine hyperactivity and is less closely associated with baseline FEV1.6 Bronchial constriction in response to adenosine in patients with COPD is also closely linked to airway eosinophilia.7 There are differences, however, in the response to adenosine between patients with asthma and those with COPD in that adenosine airways hyperactivity improves after effective treatment of asthma, whereas there seems to be no significant change in the responsiveness of COPD patients to adenosine following effective treatment (ie, the overall sensitivity follows that of methacholine).8 This has led to the assumption that adenosine hyperreactivity indicates an allergic inflammatory state.
In contrast to methacholine and other agents that act directly on airway smooth muscle (eg, cold air, hyperventilation, exercise, and kinins), adenosine is believed to act predominantly in an indirect manner by way of the activation of mast cells with the subsequent release of mediators or by stimulating the release of neurotransmitters. These mediators act on airways smooth muscle and other cells to cause bronchospasm. As with most things, this probably represents an oversimplification.
The identification of the adenosine receptor subtypes and a better understanding of their activity with different cell populations have helped us to understand the action of adenosine in the lung.2 3 There appear to be four separate adenosine receptors in lung tissue.2 3 The classic adenosine receptor, A1, is found primarily in smooth muscle and nerve tissue, and it causes a reduction in cyclic adenosine monophosphate (cAMP), leading to direct or neurogenic mediated bronchospasm. The A2a receptor, which is found in the mast cell and in the bronchial epithelium, causes an increase in cAMP, thereby inhibiting the release of the mediators of inflammation from mast cells. The A2b receptor, which is closely related to the A2a receptor, is also found in the bronchial epithelium and mast cells. This receptor utilizes different signal-transducing systems than does the A2a receptor. As a result, the A2b receptor stimulates the release of mediators from the mast cell, thereby increasing bronchial reactivity. Among the mast cell mediators that have been shown to be released by the A2b adenosine receptor are tryptase, histamine, interleukins, lypoxygenase products, and other cytokines. The A2a receptor activity predominates at low adenosine concentrations, while the A2b effect predominates at high adenosine concentrations. Finally, the A3 receptor, which is less well-characterized but is known to be present in lung tissue, acts very much like the A1 receptor, reducing cAMP levels. The net result is that the stimulation of the A1 receptor, the A2b receptor, or the A3 receptor leads to bronchoconstriction by both direct and indirect methods. The stimulation of the A2a receptor, on the other hand, would lead to a bronchodilation by inhibiting the mast cell release of mediators of the immune response.
Adenosine is released in the lung in response to both specific and nonspecific mechanisms. Adenosine is released from mast cells as a result of IgE activation.9 Adenosine that is released in this way has an amplifier effect on the mast cell via the A2b receptor and has a direct effect on target organs in allergic inflammation. Nonspecific tissue damage also results in the hydrolysis of adenosine nucleotides and the release of free adenosine. No matter how it is released, adenosine is rapidly metabolized in the lung. It can, however, accumulate to very high levels in the lung tissue of asthma patients.10 Therefore, adenosine can be increased in the airways by allergic and nonallergic airway injury and, acting through adenosine receptors, has the potential to be an important modulator of both nonspecific and IgE-mediated inflammation and bronchospasm in the airways.
How do we reconcile the clinical observations with the biology of adenosine release and its subsequent effects on airway reactivity in different disease states? The relationship with asthma and allergic airway inflammation is straightforward. The relationship with COPD and other airway diseases is less clear. The release of adenosine in response to the nonspecific trauma of cigarette smoking may explain the hyperresponsiveness to adenosine in patients with COPD.4 On the other hand, mast cells have also been demonstrated in smokers11 and in patients with chronic bronchitis.12 The exact role of adenosine bronchial responsiveness in human disease, therefore, remains an area of speculation and investigation.13
The article by Prieto et al in this issue of CHEST (see page 993) illustrates this issue. They found an incremental increase in adenosine bronchial reactivity when the nonspecific stimulus of airways inflammation/damage (ie, smoking) was superimposed on allergic airways inflammation that was associated with allergic rhinitis in the absence of overt airways disease. The fact that these subjects did not have asthma must be accepted at face value. That patients with allergic rhinitis would demonstrate bronchial hyperreactivity to adenosine (or to methacholine for that matter) is not surprising. Likewise, it is expected that smoking might increase bronchial reactivity to either adenosine or methacholine. The fact that the provocative concentration of a substance causing a 20% fall in FEV1 (PC20) for both adenosine and methacholine was lower in patients with allergic rhinitis who also smoked suggests that nonmast cell-mediated adenosine mechanisms may be important for this incremental hyperresponsiveness in smokers.
Finally, what is the clinical significance of tests of adenosine responsiveness? Bronchial hyperactivity in general is not specific for asthma and neither is adenosine hyperreactivity. Like methacholine hypersensitivity, adenosine hyperreactivity may be found in smokers with COPD and in patients with other diseases of the airways.4 The current model for the action of adenosine and airways hyperresponsiveness suggests that it may correlate better than direct stimuli (ie, histamine and methacholine) with airway inflammation, and it has been suggested3 that adenosine hyperresponsiveness may be a way to discriminate between asthma and COPD. However, the observations of Oosterhoff et al4 make this problematic. The distribution and varied effects of adenosine receptors and the specific and nonspecific sources of adenosine in the airways provide a rationale for adenosine responsiveness being a marker for airway mucosal injury but make it difficult to know how much of the effect is specific for allergic inflammation vs other mechanisms. It is clear that patients with atopic asthma respond to much lower doses of adenosine than do patients with COPD, smokers, or healthy individuals. The problem is that clear dose-response criteria with standardized, population-based cutoff points for the PC20 of adenosine are not available. This suggests that, while the adenosine challenge may have an important role in research that is aimed at understanding disease mechanisms and treatment response, its role in the clinical arena is very limited.
References
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