Determinants of Airflow Limitation in Chronic Obstructive Pulmonary Disease

Abstract

Background: Although a variety of pathological changes have been described in small airways of patients with COPD, the critical determinants of airflow limitation remain incompletely characterized. Aims and Objectives: To perform comprehensive histopathological analysis of lung tissue samples obtained from patients with COPD and non-diseased controls and to determine critical factors driving airflow limitation. Methods: Lung tissue specimens were obtained from 18 non-smokers without chronic lung disease and 55 former smokers with COPD. Small airways (<1 mm in diameter) were examined for alveolar attachments, epithelial and subepithelial tissue thickness, collagen and elastin content, luminal mucus, and immune-inflammatory cell infiltration. Results: Small airways from COPD patients showed loss of alveolar attachments, epithelial and subepithelial tissue thickening, mucus plugging, and reduced collagen density. Although all parameters significantly correlated with Forced Expiratory Volume exhaled in one second (FEV1), multivariable regression analysis indicated that loss of alveolar attachments was the major determinant of airflow limitation. Alveolar attachment loss in patients with COPD was associated with degradation of collagen and elastin in the outer adventitia, but not with the severity of emphysema assessed on CT scanning. At the same time, their loss was strongly associated with neutrophilic infiltration of the airway wall. Conclusions: Loss of radial alveolar attachments in small resistance airways, likely mediated by neutrophilic inflammation, is the primary determinant of airflow limitation in COPD.