American Journal of Respiratory and Critical Care Medicine

The boundary between purely conducting airways and gas exchanging tissue is formed by the terminal bronchioles as they divide into transitional bronchioles where alveolar openings first appear (1). The numbers of alveolar openings increase with each successive generation of branching until they take up the entire luminal surface in the alveolar ducts and the ducts branch for several more generations before ending blindly in alveolar sacs (2). McDonough and colleagues recently used a combination of multidetector computed tomography (MDCT) and micro-CT to show that there are about 44,510 ± 15,574 (± SD) terminal bronchioles/lung pair (3), a number that compares favorably to a mean of 44,500 ± 18,574 (± SD) obtained in four separate studies of individual lung casts (1, 46). Each terminal bronchiole supplies a unit of lung termed the acinus, and a secondary lobule refers to a group of acini that are either surrounded by a connective tissue septum (Figure 1A) when examined by histology (2), or where bronchioles cluster only millimeters apart (Figure 1B) when examined in a bronchogram (7).

Rohrer calculated that the small conducting airways were the major site of increased resistance in the lower airways in the 1920s, and this paradigm lasted until the 1960s (8), when Green repeated Rohrer’s calculations using new anatomic data from Weibel’s classic monograph and found that small airway resistance was much lower than Rohrer had reported (1, 9). Macklem and Mead completed this paradigm shift by making the first direct measurements that showed that airways <2 mm in diameter offer <20% of the total resistance below the larynx in both anesthetized animal and post mortem human lungs (10). Subsequent studies confirmed these observation in human post mortem lungs and extended them by showing that the resistance of the small airways <2 mm in diameter increased 4- to 40-fold in lungs from patients with chronic obstructive pulmonary disease (COPD) (11). Although Macklem and Mead’s conclusions about control lungs were challenged by a Belgian group (12), subsequent studies in living persons with normal lung function confirmed their finding that the resistance to flow is low in the smaller airways (1315); and everyone, including the Belgian group, agreed that the small airways became the major site of increased resistance in persons with COPD (11, 12, 14). However, whether this increase was due to primary narrowing of the small airways by disease or secondary narrowing caused by either emphysematous destruction of the elastic recoil force and/or physical disruption of the alveolar supporting structure remained an open question.

The almost simultaneous description of centrilobular emphysema by McLean in Australia and Leopold and Gough in Great Britain provided the first indication that there were different emphysematous phenotypes of COPD (16, 17). Both these reports showed that these lesions favored the upper regions of the lung, that the primary lesion was destruction of the respiratory bronchioles within a single acinus (Figure 1D), and that coalescence of the primary lesions first destroyed the center of the lobule (Figure 1E) and then spread to the edge of the lobule (Figure 1F) before the coalescence of many destroyed lobules produced bullous lesions. In contrast, the panacinar phenotype of emphysema described a few years later by Wyatt and associates and subsequently linked to α1-antitrypsin deficiency by Laurell and Eriksson (18, 19) produced uniform dilatation and destruction of all the acini within a lobule that is difficult to recognize in its early stages without making measurement but becomes obvious in the mid and lower regions of the lung as the disease progresses. Although α1-antitrypsin deficiency was initially thought to be a pure form of emphysema without airway obstruction, micro-CT studies have shown that the terminal bronchioles are narrowed and destroyed in both centrilobular and panlobular phenotypes of COPD (3). The third phenotype, paraseptal emphysema, begins at the periphery of the lobule and then spreads to its center (20). Although it is relatively rare in comparison to the centrilobular and panlobular phenotypes in this pathologist’s experience, a recent workshop in which chest physicians and radiologists examined large numbers of CT scans in the COPD gene study suggests that paraseptal emphysema is more common than most pathologists expected (21).

On theoretical grounds, the 4- to 40-fold increase in peripheral airway resistance measured in lungs from subjects with severe COPD is easier to explain by generalized narrowing than by a reduction in numbers of small airways, because narrowing increases the resistance of tubes in proportion to the reduction in the lumen radius raised to the fourth power, whereas removal of half of the airways is required to simply double the resistance of tubes arranged in parallel, because it adds according to the formula 1/RT = 1/R1 + 1/R2 + 1/R3 +…1/Rn. For example, starting from a peripheral airway resistance of 0.70 ± 0.26 cm H2O/L/second measured in living humans with normal lung function (14). Removal of half the small airways would only increase this resistance to 1.4 cm H2O/L/second (14), a value well below the 2.78 and 4.59 cm H2O/L/second actually measured in living persons with COPD in that study (14). Furthermore, removal of half the remaining airways (i.e., a reduction to 25% of their starting numbers) would only increase small airway resistance to 2.8 cm H2O/L/second, which is barely within the lower range of the resistance measured in the same study. And a reduction in terminal bronchioles to 12.5% of their starting number is required to reach the upper limits of resistance measured in that study of COPD (14). As most thought this degree of small airway destruction improbable, gradual generalized narrowing of the smaller conducting airways was assumed to explain the decline in FEV1 associated with progression of COPD. Bignon and colleagues provided data in support of this hypothesis by showing an increase in the proportion of bronchioles <400 μm in diameter in lungs from patients that died from respiratory failure in severe COPD (22). Matsuba and Thurlbeck also reported a similar trend that did not reach statistical significance, but added the caveat that complete destruction of the smallest bronchioles might have buffered the downward shift in small airway diameters measured in their study (23). Unfortunately, neither the study by Bignon and colleagues nor the Matsuba and Thurlbeck study was conducted following a protocol that allowed the total numbers of bronchioles in the lungs to be computed (2224).

The introduction of micro-CT and its combination with MDCT made it possible to compute the total number of terminal bronchioles following a protocol endorsed by both the American Thoracic Society and European Respiratory Society (3, 24). This protocol requires micro-CT identification of each terminal bronchiole within a known volume of lung tissue and computation of the total number per lung as the product of the number per milliliter of sample and total lung volume computed from the MDCT scan. Importantly, the numbers of terminal bronchioles observed in control lungs were in good agreement with previous data reported from casts. Somewhat surprisingly, these new data also showed a reduction in terminal bronchioles to 10% of control values in persons with the severe centrilobular emphysematous phenotype of COPD and to 25% of the control values in the panlobular emphysematous phenotype of COPD in patients treated by lung transplantation. Furthermore, the observation that this reduction in the number of terminal bronchioles occurred prior to the onset of emphysematous destruction provides compelling evidence that the narrowing and destruction of the terminal bronchioles precedes the appearance of emphysematous destruction in both these phenotypes of COPD (3).

These new data support the hypothesis that the decline in FEV1 that occurs in everyone as they age can be explained by a gradual subtraction of multiple airways in parallel as the person ages. Moreover, it suggests that the rapid decline in FEV1 that characterizes the development of severe COPD is caused by a more rapid rate of subtraction of diseased airways, by a process that destroys terminal bronchioles before spreading along the walls of surviving terminal bronchioles to initiate emphysematous destruction of alveolar tissue over a time course measured in weeks to months for individual airways. It also suggests that the rate at which these subtractions occur determines the rate of decline in FEV1 over the natural history of COPD. The advantage of this hypothesis is that it can explain why progression often occurs in fits and starts rather than on a smooth curve. It also explains intermediate phenotypes such as the airway-dominant phenotype of COPD, in which the disease is primarily restricted to the small conducting airways with little or no emphysematous destruction, as well as the emphysema-dominant phenotype, in which the destructive process rapidly extends along surviving distal conducting airways to initiate emphysematous destruction of the alveolar surface. Moreover, it can also account for the appearance of emphysema before a sufficient number of small airways have been destroyed to cause a reduction in FEV1 and for the recent observations that mild overinflation and early appearance of emphysematous destruction on CT scans predicts the rapid decline in FEV1 (2528).

Finally, the observations that COPD is associated with hyperinflated lungs and a reduced vital capacity (VC) were established by the midpoint of the 20th century. The introduction of MDCT scanning toward the end of the 20th century made it possible to identify where the gas was trapped in the lung by comparing MDCT scans performed at total lung capacity and residual volume (RV). The comparison of micro-CT examinations of regions that trap excess gas to those that do not trap excess gas at RV in lung specimens that have been surgically removed from patients with mild to moderate COPD as treatment for lung cancer should make it possible to determine if the lung regions that lower the VC by trapping excess gas at RV have reduced numbers of terminal bronchioles with surviving bronchioles that have thickened walls and narrowed lumens.

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