A Few Bad Airways Can Wreak Havoc: Recognizing Asthma as a Local Disorder

Stimulating airway smooth muscle (ASM) in an individual with asthma can cause some airways to hyperconstrict in ways healthy airways would not. Although several reasons could contribute to this, there is unequivocal experimental evidence that the ASM surrounding many asthmatic airways is thicker, and more so with severe asthma (1). Starting with Lambert and colleagues (2) and continued with increasing more morphometrically and three-dimensionally consistent airway trees (3–5), computational models consistently show that if one assumes maximum ASM force generation scales proportionately with its thickness, the thickened ASM found in asthmatic airways can lead to hyperresponsiveness. The above, however, is inadequate to fully understand how lung function degrades during an asthma attack in a specific patient or to guide optimal treatment strategies in a patient-specific fashion. The percentage of ASM thickening is not the same everywhere, either in large versus small airways or across airways of similar original diameter throughout the lung or across subjects with a similar clinical classification of asthma severity (6, 7).

Surely all airways do not constrict identically during an asthma attack; ergo, heterogeneous constriction is a fundamental feature of asthma (8, 9). In fact, this feature is the most important contributor to the degradation of lung function that occurs during an attack (3–5). Models predict that ASM thickening enhances the heterogeneity of the resulting constriction (4). Hence, it would seem useful to identify the precise locations of abnormal ASM thickening. Stated another way, understanding the average constriction across all airways is of limited value when conceptualizing more effective future treatment methods. Rather, it is all about the anatomic origins of heterogeneity. This last statement speaks to the heart of insights from the new study by James and colleagues (pp. 452–460) in this issue of the Journal (10).

James and colleagues (10) meticulously measured the thickness of the ASM for nine consecutive airway generations along three distinct airway pathways in the lungs of subjects without asthma, subjects with nonfatal asthma (NFA), and subjects with fatal asthma. Each pathway progresses from larger (∼9 mm diameter) to smaller (∼1 mm diameter) airways. The data allowed them to assess two forms of heterogeneity in ASM thickening: longitudinal (e.g., large vs. small) and spatially distributed heterogeneity (airways of similar generations but distinctly different lung areas). They classified any airway as having abnormal ASM thickness if the thickness was 2 Standard Deviation above the mean from a corresponding normal airway. They found that subjects without asthma had little evidence of thickening of their ASM on average or even in any individual airway along any of the pathways. In contrast, subjects with NFA were far more likely to possess at least one airway, and in many cases a few airways, with highly thickened ASM along one or more pathways, even though the mean ASM across all airways was often within the normal range. Interestingly, they also found that about 20% of subjects with NFA had abnormal thickening only in their small airways. Most of the subjects with fatal asthma showed abnormal thickening in the ASM of both one or more large and one or more small airways and across all three pathways in almost all such subjects. But, even here, averaging across all airways often dampened evidence that there were always at least some individual airways along a pathway with highly abnormal ASM thickness. They conclude that using mean data to compare cases of asthma underestimates the potential severity of disease due to ASM remodeling. This conclusion inherently appreciates that it is the capacity to create heterogeneous constriction that drives asthma severity for subjects with NFA and that only a few airways along a pathway need to possess abnormally thick ASM to accomplish this (i.e., many airways can be within the normal range).

They also report that although there was no correlation of abnormal ASM across airways of the same generation, along different pathways there was some degree of correlation along adjacent airways, suggesting that if an airway in each path had abnormal ASM thickening it was more likely to find another airway close by with the same.

James and colleagues did not report any functional data to support their notion that assessing mean data only might depress one’s sense of asthma clinical severity. But there are ample studies that are consistent with this notion. Computational models have shown that when a few airways hyperconstrict heterogeneously the result is a dramatic degradation of lung mechanical function and ventilation distribution in ways that may not at all be evident by simply measuring the overall increase in airway resistance, which reflects mean diameter reduction (3–5). To match measured degradation in mechanics and ventilation distribution simultaneously, Tgavalekos and colleagues (5) only had to hyperconstrict a small percentage of small airways heterogeneously. Constriction of only large airways could not replicate these measurements. Imaging studies (9, 11) have shown that many ventilation defects occur in similar anatomic locations in the same subjects with asthma when imaged longitudinally in time, suggesting elevated ASM thickness might be a local pathology.

Taken together, the study by James and colleagues convincingly supports that asthma is more likely a consequence of local airway abnormalities. James and colleagues showed that more often than not subjects with moderate asthma have abnormal thickening in only a few airways, even while the mean change in ASM thickness is not abnormal. Moreover, the most abnormal airways were in different places from subject to subject.

Regarding the origins of the abnormal ASM thickness, James and colleagues note that many individuals with asthma may already have abnormal ASM thickening at birth. But other factors throughout life can locally elevate ASM around an airway. Inflammatory mediators can upregulate both ASM and extracellular matrix (ECM) remodeling (12), and it seems reasonable that inflammation would not be identical throughout all airways. Similarly, elevated and repeated ASM and airway tension can induce remodeling because of mechanobiological factors upregulating growth factors (12). There is no reason to believe these factors will impact all airways identically. Finally, recent studies show that the ASM and ECM do not operate independently and that stiffening of the ECM can actually amplify the ability of the ASM to create an elevated and sustained force (13). Thickening of the ASM and ECM remodeling could work in tandem then to further create localized abnormalities causing heterogeneity and asthma.

The study by James and colleagues continues the recent trend of raising awareness that the pathological airway conditions in asthma are likely local rather than evenly spread. Consequently, optimal treatments might best target these local abnormalities. In principle, bronchial thermoplasty (BT) could address this, if the clinician knew in advance precisely which airways to target. But BT cannot yet get to all the small airways that are important. Nevertheless, we should focus on creative, perhaps hybrid (imaging plus delivery) methods to treat individuals with asthma on a personalized basis, targeting the specific locations in each individual subject that can create heterogeneity of constriction pattern (14, 15). In sum, preventing or minimizing the heterogeneity should be an explicit goal.