© 2003 American Thoracic Society
Airway Hyperresponsiveness in AsthmaGeometry Is Not Everything!University of British Columbia McDonald Research Laboratories Vancouver, British Columbia, Canada In this issue of the Journal (pp. 983–988), Niimi and associates (1) used HRCT to measure the dimensions of the right apical segmental bronchus for comparison with indices of airway responsiveness in asthmatic subjects. Perhaps surprisingly, they found that the thickening of this airway was inversely related to airway reactivity; the thicker the bronchus the less reactive were the airways. To the extent that thickening of this airway is a measure of "airway remodeling" in the remainder of the bronchial tree, this result is apparently counter-intuitive because remodeling is usually associated with asthma severity and asthma severity is associated with increased airway responsiveness. Two issues are worthy of comment: the usefulness of assessing the dimensions of a single large airway as a measure of airway remodeling; and the relationship of airway dimensions to measures of airway responsiveness. There is accumulating evidence that careful measurement of the dimensions of large airways is a useful surrogate for the dimensions of smaller airways in asthma and COPD. Nakano and associates (2) have shown that the wall area of the apical segmental bronchus correlates with the severity of COPD, independently of the degree of emphysema. Because the major site of airway obstruction in COPD is the membranous bronchioles (3), this observation suggests that central airway remodeling can be used as an indicator of small airway disease. Similarly, Niimi and coworkers (4) have shown that the dimensions of the apical segmental bronchus correlate with asthma severity and chronicity. Despite their complexity, in vivo inhalation dose–response curves to pharmacologic agonists have been analyzed as would in vitro dose–response curves. Thus, sensitivity, reactivity, and maximal responsiveness can be separately derived from these curves and, as in the organ bath, these measures of response can be influenced by separate factors. Sensitivity is an indicator of the position of the dose–response curve relative to the x-axis; increased sensitivity represents an initiation of the response at a lower concentration of agonist. Reactivity is commonly defined as the relationship between the incremental dose and the response, i.e., the slope of the dose–response curve in its linear portion. Finally, the maximal response, or plateau, represents an estimate of the maximal capacity to respond. Extrapolation of the pharmacologic model to in vivo dose–response curves has yielded important insights but also is fraught with pitfalls if too rigorously applied (5, 6). Niimi and coworkers used a continuous measurement of respiratory resistance during inhalation of progressively increasing concentrations of methacholine to estimate two parameters derived from the dose–response curve, sensitivity, and reactivity. For sensitivity, they used the minimum dose of methacholine that caused a significant increase in resistance; for reactivity, they used the slope of the dose–response curve beyond that dose. Methacholine inhalation was continued until the respiratory resistance had about doubled, but a plateau on the dose–response curve was not achieved and thus this measure of responsiveness could not be assessed in these patients. As has been discussed by Moreno and coworkers (5) and Sterk and Bel (6) different factors may determine the sensitivity of the airways to a contractile agonist and the slope and maximal responsiveness. Indeed, Niimi and coworkers (1) found no correlation between their measure of sensitivity and reactivity. Increased sensitivity correlated with a marker of airway inflammation (sputum esosinophilia), whereas reactivity correlated negatively with airway wall dimensions of the apical segmental bronchus on computed tomography. The mechanism of airway hyper-responsiveness in asthma remains unclear. Computational modeling of the tracheobronchial tree (7) has suggested that increased airway wall thickness has the potential to cause increased reactivity and maximal narrowing without changing sensitivity. In the models, the increase in reactivity and maximal response caused by airway wall thickening is related to one or a combination of three mechanisms. Increase in the airway wall thickness internal to the smooth muscle layer can amplify the airway narrowing for a given degree of airway smooth muscle shortening. Increase in the thickness of the adventitial layer has the potential to uncouple the airway muscle layer from the surrounding parenchyma allowing the smooth muscle to shorten more before being balanced by parenchyma tethering. Increase in the smooth muscle layer could result in greater force development and therefore shortening against the loads that normally attenuate airway muscle shortening. If modeling predicts that airway wall thickening exaggerates airway responsiveness, what can be the explanation for the exactly opposite result in this study? The modeling studies were primarily based on altered geometry and did not fully take into account the potential effect of airway wall thickening on the mechanical properties of the airway, e.g., stiffness of the airway. Deposition of connective tissue in the adventitia could uncouple the smooth muscle from the surrounding parenchyma, but if the material deposited in this layer was stiff and resulted in a rigid airway, the thickening could also attenuate the ability of the smooth muscle to narrow the lumen. In a similar way, thickening of the airway wall between the smooth muscle layer and the epithelium, although it has the potential to amplify the effect of the smooth muscle shortening, could stiffen the airway. Lambert and coworkers (7) suggested that the thickening of the airway smooth muscle layer had the greatest potential to contribute to airway hyperresponsivenss, if the smooth muscle phenotype maintained its contractile capacity. There is increasing evidence that proliferating smooth muscle can change from a contractile to a synthetic phenotype (8); increased amount of muscle may not mean greater contractile capacity. In addition, thickening of the airway smooth muscle layer in asthma is not only due to an increase in amount of muscle but is also due to accumulation of matrix between smooth muscle cells and bundles (9). Constraint of the muscle by connective tissue has been proposed as a mechanism by which airway smooth muscle shortening is attenuated (10, 11). During smooth muscle shortening there is a distortion of the airway tissue internal and external to the smooth muscle layer. The airway does not narrow concentrically; rather the mucosal membrane buckles and is thrown into folds. To the extent that the tissue resists this distortion, this structural reorganization provides a series elastic load that could attenuate smooth muscle shortening (12). Because the bending stiffness of a layer is directly related to its thickness cubed, airway wall thickening alone, without a change in the mechanical properties of the tissue, could be protective. To the extent that the added tissue is stiffer than the normal components of the wall, this effect could be even greater. Wiggs and colleagues (13) attempted to model the potential importance of mucosal folding by using finite element analysis in a computer model of the process. By doubling of the thickness of the subepithelial collagen layer, mimicking the increased thickness observed in asthmatic airways, they found that a substantially greater force would be required to induce an equivalent degree of folding and narrowing. In summary, the apparently paradoxical relationship between airway geometry and airway responsiveness shown by Niimi and coworkers (1) may be a function of the mechanical properties of the material deposited within the airway wall. These results suggest that our thinking about the relationship between airway remodeling and responsiveness may be simplistic; it is not only the amount but the mechanical properties of the material that thickens the airway that will influence the ultimate response. Geometry is important but it is not everything! REFERENCES
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