© 2006 American Thoracic Society doi: 10.1164/rccm.200607-960ED
Looking at the Acinus with Function TestsCan You Believe It?McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada Physiology-based lung function tests have developed over time in an attempt to mirror the underlying anatomy and pathology of the lung. In 1846, Hutchinson reasoned that the lung destruction associated with tuberculosis (TB) ought to be accompanied by a decrease in measurable gas in the lungs. He then proceeded to develop a sophisticated machine to measure this gas—the spirometer—for screening and diagnosis of TB (1). With the spirometer, in 1939 Cournand and colleagues (2) noted the expiratory slowing that occurred in emphysema. Subsequently, Dayman described that bronchi, bronchioles, and emphysema could obstruct flow (3). At about the same time, the seminal descriptions of emphysema and involvement of the small airways in this disease were provided by Gough (4) who laid the foundation of the modern knowledge of pulmonary emphysema. The next step in the understanding of chronic obstructive pulmonary disease (COPD) were the studies by Hogg and colleagues (5) describing how the "small airways" of the lung contribute most of the resistance to flow in emphysema (COPD). Function tests to mirror the abnormalities of the small airways were developed—among them, the widely used single-breath nitrogen washout. A good correlation between tests of small airway function with pathology was shown (6). From these studies, we have learned how in smokers the small airways become inflamed, constricted, narrow, and then remodel; how small airway alterations become worse as the disease progresses; how the abnormalities of the airways are unevenly distributed; and how, in the acinus, the respiratory bronchioles are inflamed, and become the first structures to break down and become emphysematous. A new, better test to examine the periphery of the lung has been recently developed by Paiva and Engel (7), Crawford and coworkers (8), and Paiva and Verbanck (9). Using an elegant theoretical approach, which consisted of applying classic physical laws in a branching lung structure, they were able to adapt the modified multiple-breath washout (MBW) test to the recognition and quantitation of asymmetry of distal lung structures. The principle for this test evolves from the different ways gas is transported in the lung: convection and diffusion. Convective flow refers to the movement of a gas at the mean velocity of the airstream, requires the presence of a pressure gradient, and is the mechanism of gas transport in the conducting airways. The increase in cross-sectional area of the conducting airways as they approach the alveoli results in a progressive fall of convective velocity to zero in the alveolar sacs. For these reasons, the transport of gas in the very peripheral structures is by molecular diffusion driven by a concentration gradient. Between zones of convective and diffusive transport, an intermediate zone, the diffusion front (10), exists and corresponds anatomically to the terminal respiratory bronchioles just at the entrance of the acinus. It is then possible, by utilizing the modified MBW, to quantitate the asymmetry of lung structures distal to the diffusion front (Sacin, acinar structures), or proximal to the diffusion front, where convective gas transport takes place (Scond, in the conductive airways). This remarkable piece of research has provided us with an insightful, sound, and useful tool to explore the lung and its response to injury in all of its compartments. In this issue of the Journal, Verbanck and coworkers (pages 853–857), in an elegant example of "translational" research, have used the MBW to investigate where the lung gets injured after cigarette smoke exposure and what is the outcome after smoking cessation (11). Not only the acinar part of the lung (respiratory bronchioles, alveolar ducts, and alveoli) sustains injury at a stage when FEV1 is normal; furthermore, this injury, as portrayed by the Sacin, does not revert to normal after 1 year of smoking cessation. In contrast, Scond (small airways) does return to normal, most likely because a decrease in inflammation relaxes the airway, the integrity of the epithelium with all its important consequences is restored, and the minimal remodeling in the small airways present with this degree of smoke exposure improves. However, Sacin does not improve in this setting, suggesting that the inflammation in the acinus has produced tissue breakdown, most likely a consequence of "respiratory bronchiolitis," an inflammatory infiltrate already present in young smokers that is found around the respiratory bronchioles and beyond (12). Destruction of alveolar structures in the respiratory bronchioles and alveolar ducts, with consequent enlargement and repair (fibrosis), is evident under the microscope in areas of "respiratory bronchiolitis" (13) and probably explains the lack of improvement in Sacin after smoking cessation. Respiratory bronchiolitis can be found in 50% of ex-smokers even after 2 years or more of lack of exposure (14). Verbanck and colleagues' data also show, in Figure 2 of their article, that Sacin does become normal after 1 year in some of the ex-smokers. This population might represent the "healthy smokers" in whom lung abnormalities never progress in spite of constant smoking. In contrast, the persistence of abnormal Sacin could indicate smokers who would go to progressive damage of the acinus, emphysema, and COPD with further deterioration of Sacin, as these authors have previously shown (15). There might be more to be learned from the combination of Scond and Sacin even in established COPD. In a previous article (15), these authors showed that patients with COPD (abnormal FEV1) can have significant abnormalities of Sacin, with no alterations in Scond, whereas in others, both Sacin and Scond are abnormal. This finding is intriguing and could be important since it might describe different COPD phenotypes. We have shown that smokers can develop either centrilobular emphysema with prominent abnormalities in the small airways or panlobular emphysema (PLE) in which the small airways are much less abnormal and decreases in flow are mainly due to losses of recoil (16). Abnormal flows with normal Scond and abnormal Sacin might define PLE and would help in the proper clinical phenotyping of COPD, a badly needed exercise. FOOTNOTES Conflict of Interest Statement: M.G.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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