Loss of Alveolar Attachments as a Pathomechanistic Link between Small Airway Disease and Emphysema.

To the Editor:

Vasilescu and colleagues are the first to provide confirmation that an imaging biomarker, parametric response mapping (PRM), has the ability to differentiate small airway disease (PRMSAD) from emphysema (PRMEmph) in patients with established chronic obstructive pulmonary disease (COPD) (1). This is of utmost importance given the urgent clinical and scientific need to noninvasively detect terminal bronchial pathology.

COPD is characterized by the presence of persistent airflow limitation and respiratory symptoms. Airways smaller than 2 mm in internal diameter are the dominant site of airflow obstruction in patients with COPD. This obstruction is caused by a mixture of pathogenic events (with)in and around the small airways, namely, loss of airways (2, 3), thickening of remaining airway walls (3), luminal obstruction by endobronchial mucus, and loss of bronchiolar–alveolar attachments leading to reduced radial traction.

Emphysema is a key pathological condition in COPD that is defined by an abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls and without obvious fibrosis. Whereas in an editorial addressing the landmark study of McDonough and colleagues (2), Mitzner (4) questioned whether emphysema formation starts in the small airways or lung parenchyma, accumulating evidence now strongly suggests that small airway disease precedes emphysema formation (2, 3, 5). It has been demonstrated that a significant proportion of terminal and transitional bronchioles are lost in lung samples from patients with COPD without signs of emphysema (2, 3), and that the 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 PRMSAD 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 PRMEmph 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, PRMSAD often evolves into PRMEmph (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.