Pulmonary arterial remodelling in smokers and patients with early COPD: potential drivers of EndMT

Introduction/Aim: We previously reported pulmonary arterial remodelling and active endothelial to mesenchymal transition (EndMT) in smokers and patients with early COPD. In this study, we aimed to evaluate the role of different drivers of EndMT.

Methods: Immunohistochemical staining for EndMT drivers, TGF-β1, pSMAD-2/3, SMAD-7, and β-catenin was performed on surgically resected lung tissue from 46 subjects. Twelve were non-smoker controls (NCs), six were normal lung function smokers (NLFS), nine were patients with small-airway diseases (SADs), nine were mild-moderate COPD-current smokers (COPD-CSs), and ten were COPD-ex-smokers (COPD-ESs). Histopathological measurements were taken using Image ProPlus software V7.0.

Results: We observed lower levels of total TGF-β1 (p<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher pSMAD-2/3 and SMAD-7 expression (p <0.05) in total and individual layers than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared to NC patients. Total β-catenin expression was significantly higher in smoking groups across arterial sizes (p <0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total β-catenin was positively correlated with total S100A4 in small and medium arteries (r= 0.35, 0.50; p=0.02, 0.01, respectively), with vimentin in medium arteries (r=0.42, p=0.07), and with arterial thickness of medium and large arteries (r= 0.34, 0.41, p=0.02, 0.01, respectively).

Conclusion: This is the first study uncovering an active endothelial SMAD pathway independent of TGF-β1 in smokers, SAD, and COPD patients. Increased expression of β-catenin indicates its potential interaction with the SMAD pathway, warranting further research to identify the deviation from this classical pathway.