Direct visualisation and measurement of lung microstructure reveal insights into extracellular matrix dysregulation in COPD

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BACKGROUND: Extracellular matrix (ECM) dysregulation is a key process in the pathology of COPD. However, an inability to characterise ECM remodelling in vivo has limited our understanding of its relationship with functional decline and disease mechanisms. We aimed to quantify in vivo ECM remodelling using probe-based confocal laser endomicroscopy (pCLE) and determine associations with physiological, radiological, histological, and serological markers of COPD. METHODS: 16 patients with COPD and 20 controls underwent pulmonary function testing, CT imaging, bronchoscopy, and pCLE. Alveolar morphometrics and elastin linearity scores (ELS) were quantified using a novel automated algorithm. Bronchial biopsies were analysed for elastin and collagen content. Serum biomarkers of elastin and collagen turnover were measured in a combined cohort of 54 COPD patients and 61 controls. RESULTS: Compared with never-smoking controls, current smokers without airflow obstruction demonstrated larger alveolar dimensions including increased alveolar opening area (AOA) (46,282 ± 16,805 vs. 33,549 ± 2,595 μm², p = 0.003). Alveolar dimensions were further increased in COPD, with larger AOA (56,468 ± 11,079 vs. 46,282 ± 16,805 μm², p < 0.001) compared with all controls. COPD was also associated with greater elastin fibre disorganisation (ELS 54.9 ± 6.0 vs. 47.5 ± 10.7, p = 0.032). Across the cohort, ELS correlated with airflow obstruction and surrogate markers of small airway disease. Airway collagen content was increased in COPD and correlated with ELS (r = 0.665, p = 0.005). COPD was associated with higher circulating elastin and collagen degradation biomarkers, including ELP-3, C1M, C6M, and EL-CG (all p < 0.05), which correlated with pCLE morphometrics. CONCLUSION: Using an innovative lung imaging technique, we provide the first objective quantification of in vivo airway elastic fibre disorganisation and demonstrate quantifiable lung microstructural changes that may precede abnormalities detected by established techniques. These quantifiable signals relate to biomarkers of lung ECM turnover, offering a new platform for early disease detection and mechanistic understanding of COPD.

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