In vivo imaging of the human pulmonary tract identifies extracellular matrix remodelling in COPD

Abstract

Elastin and collagen are fundamental proteins in the pulmonary extracellular matrix (ECM), providing vital structural and functional stability. In COPD, disruptions in ECM homeostasis result in abnormal tissue destruction, small airway fibrosis, and impaired lung function. ECM remodelling in the small airways often occurs before airflow obstruction is detectable, making it a critical focus for disease identification and monitoring. However, detecting these early disease changes remains challenging. To address this, novel biomarkers are needed to identify individuals at high risk of developing COPD and to monitor disease
activity effectively. In this regard, probe-based confocal laser endomicroscopy (pCLE) is an innovative imaging technique that allows direct visualisation of the ECM structure in the airways and lungs, offering potential insights for better disease management. This study aims to assess the potential of pCLE in detecting and quantifying ECM remodelling in COPD. It also seeks to explore the relationship between pCLE airway parameters, conventional lung function, and
CT imaging findings to establish pCLE as a potential biomarker for COPD. Additionally, the study investigates the role of ECM composition and remodelling using serological biomarkers and advanced microscopy and image analysis techniques. To achieve these aims, the study utilised pCLE to objectively quantify the structural disorder caused by ECM remodelling. Elastin and collagen fibres in bronchial biopsies were analysed using immunostaining, and the structural properties of collagen fibrils were examined using transmission electron microscopy (TEM). The expression of lysyl oxidases (LOX(L)), enzymes involved in elastin and collagen cross-linking, was assessed in COPD patients compared to healthy controls. RNA-sequence transcriptomic analysis of bronchial brushings was conducted to investigate key ECM genes associated with COPD pathogenesis.
The study revealed increased deposition of airway collagen fibres and greater disorder of airway elastic fibres in COPD, as indicated by a higher elastin linearity score (ELS). The ELS correlated with physiological and CT parameters of airway disease, as well as serological biomarkers of elastin and collagen turnover.
RNA-sequence analysis identified upregulation of key collagen-related genes, including matrix metalloproteinases and LOX(L), confirming accelerated collagen turnover in COPD. Elevated levels of lysyl oxidase-like 2 (LOXL2) were observed in COPD lung sections. The data in this thesis underscore the importance of ECM dysregulation in COPD and hold promising implications for diagnosis and treatment. pCLE demonstrates potential to detect and quantify ECM remodelling in COPD. Moreover, targeting ECM pathology opens new possibilities for addressing airway remodelling and advancing the development of future COPD treatments.

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ORCID for Chia Wei Kong: orcid.org/0000-0002-8260-6967

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