Reply to Janssen and Wouters: Loss of Alveolar Attachments as a Pathomechanistic Link between Small Airway Disease and Emphysema

remaining small airways have thickened walls and narrowed lumens (3).However, it remains to be determined how small airway disease leads to emphysema.Based on Vascilescu and colleagues' study in combination with decades-old research (1, 6), we propose that loss of bronchiolar-alveolar attachments is the most plausible link between small airway disease and emphysema.Lungs from smokers and lifelong nonsmokers who died suddenly of nonrespiratory causes outside of a hospital, as well as lungs/lobes from smokers who had undergone resection for localized pulmonary lesions, were examined by Saetta and colleagues (6).The internal diameter of the small airways and the alveolar size-as histological measures of small airway disease and emphysema, respectively-did not significantly differ between groups.However, reduced numbers of normal bronchiolar-alveolar attachments were found in smokers compared with never-smokers.Furthermore, the quantity and quality of the bronchiolar-alveolar attachments was related to the level of inflammation in the small airways.Figure 1 of Saetta and colleagues' article, which shows a cross-section of a nonrespiratory bronchiole surrounded by alveoli, probably says more than a thousand words.Inflammation has progressed through the entire airway wall into adjacent alveolar septa, which are relatively thin compared with the much thicker bronchiolar wall and would be the first to succumb to inflammation-induced proteolytic activity.In a microcomputed tomography analysis, Vascilescu and colleagues showed that PRM SAD was related to an increased number of obstructed terminal bronchioles, decreased terminal bronchial cross-sectional lumen area, and decreased circularity of the terminal bronchioles, whereas PRM Emph was associated with airspace size, alveolar surface area, and the number of alveolar attachments (1).Previously, Labaki and colleagues demonstrated that over a 5-year period, PRM SAD often evolves into PRM Emph (5).Together, these PRM studies suggest that lung areas with small airway disease only transform into emphysema if bronchiolar-alveolar attachments are destroyed (1, 5).Based on the above findings, we propose the following sequence of pathological steps leading from smoking to emphysema formation: deposition of cigarette smoke particles in small airways→inflammation of small airways→propagation of inflammation through the entire bronchiolar wall into adjacent alveolar septa→destruction of bronchiolar-alveolar attachments→lung parenchyma degradation proceeding from the centers of the secondary pulmonary lobules toward the surrounding interlobular septa.Disease-modifying therapies should be established to prevent destruction of bronchiolar-alveolar attachments and thus the progression from small airway disease to emphysema.

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