The study results suggest that AWC is lower in COPD patients with mild-to-moderate airflow obstruction than in healthy controls both at middle lung volume involving large intrathoracic airways and at low lung volume, likely involving both large and small intrathoracic airways. The unremitting remodeling process affecting the structure of the central and mostly peripheral airways wall in COPD patients with prevalent chronic bronchiolitis may explain these functional features (14, 15). However, these findings were opposite to what has been shown in other studies where AWC in COPD patients was found normal or increased compared with healthy control subjects (16, 17). We have no clear explanation for these conflicting results. Heterogeneity of AWC measurements between COPD patients, according to the prevalent underlying disease of airflow obstruction (i.e. emphysematous vs bronchiolitic COPD patients) and small sample size could play a role, as well as the site of AWC measuring, central vs peripheral airways.
Looking at histopathological changes described in central and peripheral airways of COPD patients with prevalent chronic bronchiolitis and no or mild centrilobular emphysema typically showing an extensive sub-epithelial and particularly peri-adventitial fibrosis, it is hard to believe AWC can be increased, causing a greater distensibility of their bronchial and bronchiolar wall. In contrast, the chronic remodeling process that damages the structure of the central and mostly peripheral airways in COPD patients leading to progressive thickening and scarring of their wall, may better fit with our data and explain these findings.
Conversely, a lower AWC conferring a greater airway stiffness may allow higher maximal expiratory flows for the same degree of airway obstruction according to the tube wave-speed theory described in the following equation (V,max = A x [A/ρ x Ptm/A]0.5), where V,max = maximal flow rate, A = cross-sectional surface area, Ptm = transmural pressure, ρ = gas density (18). In addition, a lower AWC may offer an increased elastic load to the airway smooth muscle to limit an excessive reduction of airways lumen during bronchoconstriction (19).
On the other hand, using different approaches, several studies have shown a reduced airway distensibility in asthma likely due to the modifications of intrinsic mechanical properties of airway wall following the remodeling process occurring in both central and peripheral airways in asthma where lung elastic recoil and integrity of alveolar attachments are usually preserved, as is the case in COPD patients with chronic bronchiolitis (20–26).
In both our groups, baseline AWC was less at lower lung volumes during forced maximal expiration when the downstream segment was more enlarged, likely including smaller airways. This result appears at odds with what was found in asthmatics who showed a slightly increased AWC (also when corrected for airway area, i.e., specific AWC) during forced vital capacity moving from the trachea to lower lobar bronchus (20). In contrast, using anatomic optical coherence tomography, in patients with asthma, COPD and bronchiectasis, AWC significantly decreased progressively as airway generation increased from 0 to 5, although specific AWC did not differ appreciably across airway generations (17). Therefore, the relationship between the central airway compliance to that of more peripheral airways in patients with airflow obstruction is not clear and needs to be further investigated.
After acute inhalation of bronchodilator, the airways wall became more compliant not only in healthy subjects but also in these COPD patients, potentially increasing the collapsibility of the airway and so limiting the maximal expiratory flow at each lung volume, in the presence of high negative transmural pressure, as it happens at different choke points along the intrathoracic airways during forced expiratory maneuver. This contrasting effect induced by broncho-dilating drugs should be considered when bronchial responsiveness is assessed looking at the change of maximal flows and time-related volumes (i.e., FEV1) during a forced expiratory maneuver in patients with obstructive ventilatory defect, like those who suffer from COPD. In fact, the possible bronchodilator-induced increase of small airway caliber due to greater cross-sectional internal surface area could be partly masked by increased airway wall compliance that becomes relevant during expiratory efforts in terms of final maximal expiratory flows obtained at any given lung volume.
Direct measurements before and after bronchodilator of either airway flow resistance by plethysmography at functional residual capacity or respiratory system flow resistance at different frequencies during tidal volume by forced oscillation technique (FOT) could easily avoid this problem, showing the real beneficial effect of bronchodilators, if any in COPD patients.
We cannot assume that similar AWC changes may occur with short-acting muscarinic receptor antagonists with rapid onset of action in COPD patients because we did not test this class of bronchodilator drugs, although such an effect is highly plausible in the presence of an elevated cholinergic tone, as previously suggested in COPD (27).
The small number of patients can be a limit of this study because of possible type 1 error, as well as the inherent limitations of the method due to the impossibility of determining the exact location of the choke point that might be different between COPD patients and healthy subjects at relative iso-volumes.