TGFβ1, SMAD and β-catenin in pulmonary arteries of smokers, patients with small airway disease and COPD: potential drivers of EndMT

• Published in: Clinical science (1979) Vol. 138; no. 17; p. 1055
• Main Authors: Bhattarai, Prem, Lu, Wenying, Hardikar, Ashutosh, Gaikwad, Archana Vijay, Dey, Surajit, Shahzad, Affan Mahmood, Myers, Stephen, Williams, Andrew, Sutherland, Darren, Singhera, Gurpreet Kaur, Hackett, Tillie-Louise, Eapen, Mathew S, Sohal, Sukhwinder Singh
• Format: Journal Article
• Language: English
• Published: England 04.09.2024
• Subjects: Adult; Aged; beta Catenin - metabolism; Case-Control Studies; Endothelial-Mesenchymal Transition; Epithelial-Mesenchymal Transition; Female; Humans; Male; Middle Aged; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Pulmonary Disease, Chronic Obstructive - physiopathology; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Smad7 Protein - metabolism; Smokers; Smoking - adverse effects; Transforming Growth Factor beta1 - metabolism; Endothelial to mesenchymal transition; Vascular remodelling; Small airway disease; TGF-β1/SMAD pathway; Smoking; chronic obstructive pulmonary disease
• ISSN: 1470-8736
• DOI: 10.1042/CS20240721

We previously reported pulmonary arterial remodelling and active endothelial-to-mesenchymal transition (EndMT) in smokers and patients with early chronic obstructive pulmonary disease (COPD). In the present study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-β1, pSMAD-2/3, SMAD-7, and β-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. 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 (P<0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared with NC. 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). This is the first study uncovering active endothelial SMAD pathway independent of TGF-β1 in smokers, SAD, and COPD patients. Increased expression of β-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway.