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

From the Authors:

We thank Dr. Janssen and Dr. Wouters for highlighting the importance of our study (1) to validate parametric response mapping (PRM) as an imaging biomarker to identify small airway disease in patients with chronic obstructive pulmonary disease (COPD). We agree with them that our data provide further support for the notion, as previously stated (2), that small airway disease is an important target for COPD therapies. The unique data set and tissues available from our work clearly demonstrate that the number of terminal bronchioles is significantly reduced in lung regions where the airspace size (a surrogate for emphysema) remains below the detectible level of clinical computed tomography, and that these regions are predominantly classified as PRM functional small airway disease. In contrast, the data show that the number of terminal bronchioles is further reduced in regions where PRM emphysema is dominant. However, our data were obtained from patients with severe COPD and cannot unambiguously define whether this pathological process is the same for all patients with COPD. Nonetheless, when these results are combined with the longitudinal imaging data of Labaki and colleagues (3), which demonstrated that in patients with COPD of different degrees of severity, PRM functional small airway disease regions progress to PRM emphysema regions, it becomes evident that initial small airway disease may disseminate into the surrounding tissues, leading to extensive emphysema, as shown by Saetta and colleagues (4). Supporting this mechanism, we previously demonstrated in a cross-sectional study that small airways are lost before loss of alveolar surface area occurs in mild and moderate COPD (5).

Importantly, as the authors point out, a next step is to identify the mechanism by which small airways are lost. The proposed sequential pathological steps, which were first suggested by Saetta and colleagues in 1985 (4) and later revised by Mitzner (6), of “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” are highly plausible. Support comes from other cross-sectional studies in advanced COPD (7–9). However, we should emphasize that this postulate must be confirmed via rigorous quantitative analyses in earlier COPD stages (10).

Other investigators and we have previously reported that volumetric microcomputed tomography imaging of tissue samples provides a unique opportunity to target specific lesions for histological examination, and therefore to assess the unique properties of the cellular composition within and around a lesion. Tanabe and colleagues demonstrated that the destruction of the alveolar attachments in the preterminal bronchioles could be driven by a B cell–mediated immune response (11). Assessment of the terminal and transitional bronchioles poses greater challenges with regard to analytic imaging techniques, but it is not impossible.

An additional crucial issue is the exact process behind the tissue destruction. What causes the alveolar attachments to “snap”? We believe the most plausible explanation is that the extracellular matrix is remodeled by infiltrating cells, leading collagen and elastin fibers to become deranged to such a degree that they cannot withstand the continual stretching and contraction during breathing. Novel methods, including nonlinear optical microscopy, which was previously applied to study airway remodeling in patients with asthma (12), may shed light on this process.

Hence, performing a targeted analysis of the remodeling, cellular infiltration, and gene expression of the terminal bronchioles, and assessing their association with PRM classifications at earlier disease stages are high research priorities for our group. We are confident that this multipronged approach will shed more light on the mystery of how destruction of the small airways and surrounding tissues occurs.