Abstract Rationale Chronic Obstructive Pulmonary Disease (COPD) involves distinct pathological changes in small versus medium and large airways, with small airways (2 mm diameter) being the primary site of airflow obstruction and disease progression. Histologically, small airways undergo severe remodeling characterized by wall thickening, fibrosis, goblet cell metaplasia, and mucus plugging, leading to luminal obliteration and alveolar damage. In contrast, large and medium airways exhibit goblet cell hyperplasia, and wall inflammation, contributing mainly to chronic bronchitis symptoms. Chronic inflammation occurs across all airway sizes, but the type and degree of inflammation, as well as molecular changes, differ in small vs medium and large airways. To investigate different mechanisms contributing to disease progression a systematic sampling of small, medium and large airways from COPD patients and healthy controls was conducted. Methods Biopsies were freshly frozen for proteomics analysis and adjacent samples were paraffin embedded for histology. Using a nano liquid chromatography coupled to mass spectrometry (nLC-MS/MS) platform, a comprehensive protein profile was obtained. Additionally, Differentially Expressed Proteins (DEPs) were analyzed with the Ingenuity Knowledge Base database to perform canonical pathways analysis. Results DEPs both down- and up-regulated, were identified comparing the two general populations: COPD vs Healthy controls and comparing the three different regions of the bronchial tree: COPD Small vs Healthy Small, COPD Medium vs Healthy Medium and COPD Large vs Healthy Large. Among the differentially expressed proteins, several biomarkers were identified, alpha 1 antitrypsin, soluble RAGE were found to be significantly downregulated in COPD samples across all comparisons considered. Several cathepsins (CTS), including CTSS, were found to be significantly upregulated in COPD compared to Healthy samples across all comparisons. As a direct consequence, collagen levels were increased across all COPD vs Healthy comparisons, and most importantly in the COPD Small vs Healthy Small one, contributing to fibrosis, airway narrowing, and airflow. Conclusion These results contribute to a deeper understanding of the molecular mechanisms underlying COPD and may provide potential targets for future investigation. This abstract is funded by: Chiesi Farmaceutici S.p.A.
Sgroi et al. (Fri,) studied this question.