Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are distinct respiratory diseases that share features such as the obstruction of small airways and disease flare-ups that are called exacerbations and are often caused by infections. Along the airway epithelium, immunoglobulin (Ig) A contributes to first line mucosal protection against inhaled particles and pathogens. Dimeric IgA produced by mucosal plasma cells is transported towards the apical pole of airway epithelial cells by the polymeric Ig receptor (pIgR), where it is released as secretory IgA. Secretory IgA mediates immune exclusion and promotes the clearance of pathogens from the airway surface by inhibiting their adherence to the epithelium. In this review, we summarize the current knowledge regarding alterations of the IgA/pIgR system observed in those major obstructive airway diseases and discuss their implication for disease pathogenesis.

Small airways (<2 mm diameter) are major sites of airflow obstruction in chronic obstructive pulmonary disease (COPD). This study aimed to quantify the impact of small airway disease, characterized by narrowing, occlusion, and obliteration, on airflow parameters in smokers and end-stage patients with COPDs. We performed computational fluid dynamics (CFD) simulations of inspiratory airflow in three lung groups: control non-used donor lungs (no smoking/emphysema history), non-used donor lungs with a smoking history and emphysema, and explanted end-stage COPD lungs. Each group included four lungs, with two tissue cylinders. Micro-CT-scanned small airways were segmented into 3D models for CFD simulations to quantify pressure, resistance, and shear stress. CFD results were benchmarked against simplified linear and Weibel models. CFD simulations showed higher pressures in COPD vs. controls (p = 0.0091) and smokers (p = 0.015), along with increased resistance (p = 0.0057 vs. controls; p = 0.0083 vs. smokers) and up to a tenfold rise in shear stress (p = 0.010 vs. controls). Narrowing and occlusion were shown to independently increase pressure, resistance, and shear stress, which were validated through segmentation corrections. Pressures and resistance assessed with simplified models were up to seven-fold higher for smokers and even 72 higher for COPD compared with CFD values. These findings show that increased airflow parameters can explain the association between small airway disease and airflow limitation in COPD, underscoring small airway vulnerability. Additionally, they highlight the limitations of theoretical models in accurately capturing small airway disease. Supported by the KU Leuven (C16/19/005).

Goblet cell (GC) metaplasia is a paramount feature of small airway (SA) disease in COPD, often considered as present at all generations of SA. We aim to localize which generations of SA are affected by this process in a spectrum ranging from healthy and early-emphysematous to end-stage COPD lungs. Donor lungs unused for extra pulmonary reasons (n=10), donor lungs radiologically and histologically characterized by emphysema (n=10) and COPD explants (n=10) were frozen at TLC and processed in cores (1.4 cm diameter cylinders). From each lung, up to 4 cores (27 donors, 20 emphysema, 15 COPD cores) were randomly selected and microCT-scanned (10μm resolution), and paraffin sections were stained for GC marker MUC5AC. SA were segmented on microCT and labelled as TB (terminal bronchioles)/TB-1, TB-2/TB-3 or TB-4/TB-5 according to the generation, upwards from TB (figure 1a). At the level of TB/TB-1, MUC5AC stained area were low in all 3 groups. In TB-2/TB-3 airways, stained area was also low although more scattered in the emphysema group. At the level of TB-4/TB-5, MUC5AC was increased in emphysema (p= 0.019) and COPD (p=0.05) vs donors (figure 1b). The data show that GC metaplasia occurs in the distal part of the SA from an early stage of the disease. However, the absence of GC metaplasia in the very distal airways needs to be taken into account when studying this vulnerable zone of the lung.