Bridging the Gap: Small Airways, Mechanical Stress, and the Evolution of Emphysema

The clinical relationship between airway disease and emphysema has been recognized for quite some time, as the earliest descriptions of what would ultimately be termed chronic obstructive pulmonary disease (COPD) recognized the presence of both chronic bronchitis and emphysema. Despite this, many questions have surrounded the pathogenesis of emphysema and the relationship between airway pathology and alveolar destruction. On the basis of work from Jim Hogg and others, a prevailing thought has been that small airway disease plays a crucial role as being the primary site of airflow obstruction before the development of emphysema (1). Histologic studies also led by Hogg have shown that even before air space enlargement, loss of terminal bronchioles can be detected (2). This concept is also supported by the fact that emphysematous destruction typically emanates from the center of the lobule, where the respiratory bronchioles reside.

Yet at the same time, this clearly is not the entire story. One missing piece of the puzzle has been a solid explanation for why lung function decline and emphysematous destruction continue even after noxious triggers associated with disease development, such as cigarette smoke exposure, are discontinued. The thought has been that this must be due to ongoing smoldering “inflammation,” which, once incited, becomes self-propagating.

In this issue of the Journal, Bhatt and colleagues (pp. 1409–1417) present their work “Mechanically Affected Lung and Progression of Emphysema” (3). In this study, they build on their prior work (4) demonstrating that new emphysema arises in at-risk regions of the lung that have high mechanical impact of existing emphysema. The authors hypothesize that mechanical stress caused by the weakening of lung structure introduced by emphysema leads to further perpetuation of emphysema. In other words, emphysema begets emphysema.

This is an important concept and gets at the idea that for some patients, there may be a point of no return for certain areas of the lung where mechanical stress and emphysema will continue, even if the source of the initial stress, such as cigarette smoke exposure, has stopped. Bhatt and colleagues (3) state that large coalesced superclusters really become evident when quantitatively measured emphysema is about 15% of total lung volume and become well established when quantitatively measured emphysema is about 30% of lung volume.

However, Bhatt and colleagues (3) also argue that small airway disease contributes minimally to disease progression, once emphysema is established. This explanation, however, may not tell the whole story. Going back to Jim Hogg’s work, he established that small airways become progressively thickened as lung function declines and that inflammation and wall thickening are seen even in early disease (5). He also demonstrated that the total number of small airways 2–2.5 mm in diameter is reduced in patients with COPD, even in the absence of emphysema (2). Subsequent studies, in part led by Dr. Bhatt, have also demonstrated that computed tomography (CT)–detected small airway abnormality helps identify individuals at risk for more rapid FEV₁ decline and development of emphysema, particularly in early disease (6).

When we look at the patients included in this present analysis, patients had to have at least 5% emphysema to be included. This threshold is not insignificant and has previously been shown to be associated with increased symptoms, exacerbations, and mortality (7). Thus, the present analysis does not really examine the contribution of small airway disease to early emphysema or preemphysematous lung. In Dr. Bhatt’s prior work, CT-defined small airway disease (using parametric response mapping functional small airway disease [fSAD]) identified patients at risk for disease progression, particularly among individuals in Global Initiative for Chronic Obstructive Lung Disease stages 0–2. Additional work, also done in COPDGene (Genetic Epidemiology of COPD), has shown that when followed longitudinally, tissue defined as small airway disease on CT becomes emphysema when identical sections of lung are examined (8).

In this paper, the authors report 60.5% of high and 37.1% of intermediate mechanically affected lung (MAL) at baseline transitions to emphysema at follow-up. This is presented in contrast to the 4.8% of fSAD transitioning to emphysema at follow-up. Although this shows that a significant portion of fSAD-affected lung does not transition to emphysema, it does not disprove that new emphysema does not originally arise from fSAD, which is an important distinction.

There is also likely significant overlap between areas of lung labeled as MAL and fSAD. This is illustrated in an example case from the COPDGene study showing the relationship between the spatial distribution of quantitatively defined fSAD, MAL, and emphysema at baseline and new emphysema at 5-year follow-up (Figure 1). On the lefthand side, parametric response mapping fSAD is depicted in yellow, and in the middle, MAL is depicted in blue for the same subject at baseline. As can be seen, areas of the lung labeled MAL (in blue) appear to identify a subset of tissue labeled fSAD (in yellow). fSAD encompasses a broader region, whereas the areas identified as MAL are those closest to existing emphysema (in red). For context, the righthand figure shows areas of new emphysema that developed after baseline but were detected at 5-year follow-up. Hence, MAL may be identifying the area of fSAD at highest risk for transition.

Figure 1.

An example case from COPDGene (Genetic Epidemiology of COPD) showing emphysema progression as a result of functional small airway disease (fSAD) and mechanically affected lung (MAL) distribution. (Left) fSAD (yellow) and emphysema (red) distribution. (Middle) MAL (cyan) and emphysema (red) distribution. (Right) New emphysema at 5-year follow-up. Notice that the distributions of fSAD and MAL are both well aligned with the distribution of new emphysema at follow-up. In this example, 15% of fSAD at baseline converted to emphysema, while 38% of MAL converted to emphysema. However, 37% of new emphysema at follow-up was fSAD at baseline, while a similar amount of new emphysema (35%) was originally MAL. Hence, there is significant overlap between tissue labeled MAL and fSAD.

Overall, the concepts that small airway disease may be precede the earliest kernels of emphysema and that more severe emphysema, once established, fuels further progression are not mutually exclusive. In fact, they are highly complementary, as we know that the loss of alveolar attachments caused by stress-mediated structural remodeling is a primary cause of small airway collapse, resulting in increased airflow obstruction (9). Importantly, this analysis does not directly measure local tissue stress (force being applied). What is does show is that that local strain (how much tissue deforms with force) is actually reduced in areas surrounding emphysema. In other words, the tissue just adjacent to emphysema is less compliant, which may contribute to alveolar breakage and emphysema development. One way to think about this is that tissue characterized as small airway abnormality is a pool of “at risk” tissue from which emphysema may form. Once emphysema becomes established, due at least in part to mechanical forces, more emphysema is likely to develop within that adjacent region.

What is perhaps even more interesting are the potential implications for this body of work on treatment. There is a growing body of evidence that interventions targeting SAD, such as antiinflammatory treatments and bronchodilators, may be most effective in early COPD and may slow emphysema progression (10). If small airway disease is important very early on in the process, then this is when targeted interventions such as antiinflammatory therapies and bronchodilators might be most useful in potentially halting disease progression. However, once significant emphysema forms, are there other interventions that would reduce mechanical stress on the lung and potentially reduce the further propagation of emphysema?

In summary, this analysis really helps make clear that later stage emphysema predominantly progresses from regions where there was existing emphysema. These regions were determined to be less compliant. From a mechanical perspective, we know that stress accumulates at interfaces between compliant (normal) and noncompliant (stiff) regions, which creates localized high mechanical stress. This could promote further emphysema development through a positive feedback loop. However, these same surrounding regions are also high in fSAD. This study did not examine early-stage disease and does not disprove the hypothesis that early-stage emphysema arises primarily from small airway disease. This distinction is crucial because it properly situates small airway disease as an initiating factor, but it is not the only driver of emphysema once it has already developed.