© 2007 American Thoracic Society doi: 10.1164/rccm.200704-525ED
Can a Deep Breath Blow Away the Fog Surrounding Airway Hyperresponsiveness?Woolcock Institute of Medical Research and University of Sydney, Camperdown, Australia The most consistent diagnostic feature of asthma is the presence of airway hyperresponsiveness (AHR). Therefore, understanding the mechanisms underlying AHR seems essential for the development of interventions to control or cure asthma. Despite enormous research effort, we still do not fully understand why the asthmatic airways respond to much lower concentrations of provoking agents than do normal airways. We do know, however, that the lung volume at which we breathe and the presence of deep inspirations (DIs) have the capacity to markedly modulate these airway responses and exhibit different effects on individuals with and without asthma. Therefore, it seems reasonable to propose that an understanding of mechanisms underpinning the DI responses may shed light on the nature of AHR itself. During bronchial challenge, DI causes bronchodilatation in individuals without asthma (1), whereas this effect is less marked or absent in patients with asthma (2). In spontaneous asthma attacks, a DI may result in bronchoconstriction (3). There are a number of possible explanations for the inability of patients with asthma to overcome airway narrowing with a DI. These include stiffer airways resulting from airway remodeling (4), greater heterogeneity of airway closure and narrowing (5), stiffer airway smooth muscle (ASM) due to a frozen or latch state of the cross-bridges (6), and a reduction in interdependence due to adventitial edema or loss of elastic recoil. The magnitude of the individual contributions of these factors is unknown, but the degree of airway inflammation appears to be important in modulating the DI response and may act through a number of these mechanisms. The DI response is inversely proportional to the clinical severity of asthma and to airway inflammation measured by bronchoalveolar lavage (BAL) (7). Furthermore, the constrictor response to a DI during spontaneous acute asthma improves with corticosteroid treatment and resolution of the exacerbation (3). Clearly, it is now important to characterize the nature of the airway inflammation associated with these DI responses, if we are to understand the underlying mechanisms and find interventions to "normalize" the asthmatic airway. The study by Slats and colleagues (8) in this issue of the Journal (pp. 121–128) makes an important contribution to understanding the role of specific inflammatory cells on DI bronchodilator responses. The authors studied the bronchodilatation associated with one or five DIs after methacholine-induced bronchoconstriction in groups of subjects with mild persistent asthma and mild to moderate COPD. They used the forced oscillation technique to measure respiratory system resistance, thereby obviating the confounding effect of a DI associated with the test of airway function (9). They then performed bronchoscopy and obtained airway biopsies and quantified the number of T lymphocytes, eosinophils, mast cells, macrophages, and neutrophils in the airway wall. Consistent with other studies, there was a reduction in DI bronchodilatation in patients with asthma compared with subjects without asthma. Importantly, this was related to the numbers of mast cells within the ASM bundles and to CD4+ lymphocytes in the lamina propria. The relationship of the DI to mast cells in the ASM is of interest in light of the demonstration of a relationship between mast cells within the ASM and AHR by Brightling and coworkers (10). Mast cells contain mediators such as histamine, prostaglandin D2, and cysteinyl leukotrienes, which could affect the contractile state of the ASM, resulting in the ASM being less able to be stretched by the DI. The implication of the relationship to T lymphocytes is less clear. These cells are drivers of eosinophilic inflammation. Eosinophilic inflammation could affect DI bronchodilatation by increasing microvascular leakage, which might reduce interdependence, and by effects on other aspects of remodeling, such as airway wall fibrosis. However, in this study, there was no relationship between DI response and eosinophils, but the numbers of eosinophils, although higher than in the subjects with chronic obstructive pulmonary disease (COPD), were low compared with other studies (11, 12). This is curious since these patients were not receiving inhaled corticosteroids. In previous studies, DI bronchodilatation was related to BAL eosinophils (7) and sputum eosinophils (13), although the latter explained only a small amount of the variance. It might be expected that inflammatory cells in the airway wall would be more closely related than luminal cells to airway behavior. However, with relatively few eosinophils in the airway wall, any relationship with DI bronchodilatation would be difficult to detect and further studies will be needed to confirm a lack of relationship. It seems that the role of eosinophils in DI bronchodilatation is as elusive as their role in AHR (12) since AHR is also present in neutrophilic asthma (14). The relationship of DI effects to lymphocytes and ASM bundle mast cells may be specific to asthma. The patients with COPD demonstrated reduced DI bronchodilatation as well but this was not related to any specific cell type. It is more likely that, in COPD, structural changes in the lungs resulting in loss of elastic recoil are responsible for the reduction of DI bronchodilatation (15). So where does this leave us in the interpretation of DI responses? Clearly, there are a range of potential mechanisms. The study by Slats and coworkers (8) suggests that, in asthma, airway wall inflammation involving CD4+ lymphocytes and mast cells are important determinants of DI bronchodilatation. We will have to await confirmatory studies to ensure that these associations are more consistent than those seen with eosinophils. An interesting point is the variable effect of inhaled corticosteroids on DI bronchodilatation after induced bronchoconstriction (2), in contrast to the more consistent effect of corticosteroids on the constrictor response of a DI in "natural" bronchoconstriction (3). Since corticosteroids can reduce airway wall eosinophils (11) and BAL mast cells (16), this might suggest that DI bronchodilatation is not related to cellular inflammation, whereas steroid-sensitive inflammatory cells might modulate the DI effects in natural bronchoconstriction. While eagerly awaiting data on the effects of corticosteroids on ASM bundle mast cells, the way is open for other mechanisms, such as increased airway wall stiffness or thickness related to airway remodeling, to be responsible for the lack of DI bronchodilatation after induced bronchoconstriction. The various mechanisms contributing to DI bronchodilatation can only be sorted out by a study in which all these factors are measured using a combination of appropriate physiological techniques, including a measure of DI bronchodilatation using a non–deep breath test, assessment of cellular inflammation using airway biopsy, BAL, or induced sputum, and imaging to measure airway wall thickness. Such a study represents a significant challenge but might blow away the fog surrounding the nature of the DI responses and their relationship to airway inflammation, remodeling, and AHR. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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