Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology

Prem Bhattarai; Wenying Lu; Ashutosh Hardikar; Surajit Dey; Archana Vijay Gaikwad; Affan Mahmood Shahzad; Collin Chia; Andrew Williams; Gurpreet Kaur Singhera; Tillie-Louise Hackett; Mathew Suji Eapen; Sukhwinder Singh Sohal

doi:10.1183/23120541.00767-2023

Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology

ERJ Open Res. 2024 Feb 12;10(1):00767-2023. doi: 10.1183/23120541.00767-2023. eCollection 2024 Jan.

Authors

Prem Bhattarai^{1

2}, Wenying Lu^{1

2}, Ashutosh Hardikar^{3

4}, Surajit Dey¹, Archana Vijay Gaikwad¹, Affan Mahmood Shahzad¹, Collin Chia^{1

2

5}, Andrew Williams¹, Gurpreet Kaur Singhera^{6

7}, Tillie-Louise Hackett^{6

7}, Mathew Suji Eapen¹, Sukhwinder Singh Sohal^{1

2}

Affiliations

¹ Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia.
² Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia.
³ Department of Cardiothoracic Surgery, Royal Hobart Hospital, Hobart, TAS, Australia.
⁴ Department of Cardiothoracic Surgery, The Royal Adelaide Hospital, Adelaide, SA, Australia.
⁵ Department of Respiratory Medicine, Launceston General Hospital, Launceston, TAS, Australia.
⁶ Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
⁷ Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.

Abstract

Background: We have previously reported pulmonary arterial remodelling in smokers and patients with early COPD, which can be attributed to endothelial to mesenchymal transition (EndMT). In this study, we aimed to evaluate if EndMT is an active mechanism in smokers and COPD.

Methods: Immunohistochemical staining for the EndMT biomarkers CD31, N-cadherin, vimentin and S100A4 was done on lung resection tissue from 49 subjects. These comprised 15 nonsmoker controls (NC), six normal lung function smokers (NLFS), nine patients with small airway disease (SAD), nine current smokers with mild-moderate COPD (COPD-CS) and 10 ex-smokers with COPD (COPD-ES). Pulmonary arteries were analysed using Image ProPlus software v7.0.

Results: We noted reduced junctional CD31⁺ endothelial cells (p<0.05) in the intimal layer of all smoking groups compared to NC. We also observed increased abundance of the mesenchymal markers N-cadherin (p<0.05) and vimentin (p<0.001) in all smoking groups and across all arterial sizes versus NC, except for N-cadherin in large arteries in COPD-CS. The abundance of S100A4 correlated with arterial thickness (small: r=0.29, p=0.05; medium: r=0.33, p=0.03; large: r=0.35, p=0.02). Vimentin in the small arterial wall negatively correlated with forced expiratory volume in 1 s/forced vital capacity (r= -0.35, p=0.02) and forced expiratory flow rate at 25-75% of forced vital capacity (r= -0.34, p=0.03), while increased cytoplasmic CD31 abundance in the intimal layer of medium and large arteries negatively correlated with predicted diffusing capacity of the lung for carbon monoxide (medium: r= -0.35, p=0.04; large: r= -0.39, p=0.03).

Conclusion: This is the first study showing the acquisition of mesenchymal traits by pulmonary endothelial cells from NLFS, SAD and mild-moderate COPD patients through EndMT. This informs on the potential early origins of pulmonary hypertension in smokers and patients with early COPD.