AUTHOR=Zhou Ruoyi , Wang Haojie , Zhang Yulu , Mai Jieming , Yang Liuliu 

TITLE=Small airway disease as a key factor in COPD: new perspectives and insights

JOURNAL=Frontiers in Medicine

VOLUME=Volume 12 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1648612

DOI=10.3389/fmed.2025.1648612

ISSN=2296-858X

ABSTRACT=Small airways–defined as bronchioles <2 mm in internal diameter that lack cartilaginous support–are frequently involved in the earliest stages of chronic obstructive pulmonary disease (COPD). While COPD is defined per GOLD by persistent post-bronchodilator airflow limitation, small-airway dysfunction can precede spirometric abnormality, motivating earlier, imaging- and physiology-based detection (Agustí et al., 2023). Pathological progression typically begins with loss and stenosis of terminal bronchioles, followed by mucus retention/plugging, fibrotic remodeling, chronic inflammation, microvascular abnormalities, and cellular senescence, ultimately resulting in irreversible impairment of gas exchange. Early diagnosis remains difficult, but a suite of advanced non-invasive modalities–including impulse oscillometry system/forced oscillation techniques (IOS/FOT), single- and multiple-breath washout tests, high-resolution CT with parametric response mapping (PRM), nuclear medicine approaches (e.g., SPECT), dynamic measurements of lung compliance, and Fluorine-19 (19F) MRI–combined with artificial intelligence markedly improve the sensitivity and specificity for detecting small-airway disease. Therapeutic strategies that target cellular senescence and fibrotic pathways–such as senolytics and antifibrotic interventions–are showing promise, particularly approaches that clear senescent cells or block pro-fibrotic signaling. The integration of single-cell omics, high-resolution microvascular imaging, and molecularly targeted therapies is expected to accelerate precision diagnostics and enable personalized early interventions. This review summarizes recent insights into small-airway physiology, key pathophysiological and molecular mechanisms, and current pharmacological strategies, and emphasizes the clinical principle of “early detection, early diagnosis, early intervention” for managing COPD-related small-airway disease.