Endothelial-to-mesenchymal transition: a precursor to pulmonary arterial remodelling in patients with idiopathic pulmonary fibrosis

Archana Vijay Gaikwad; Wenying Lu; Surajit Dey; Prem Bhattarai; Greg Haug; Josie Larby; Collin Chia; Jade Jaffar; Glen Westall; Gurpreet Kaur Singhera; Tillie-Louise Hackett; Mathew Suji Eapen; Sukhwinder Singh Sohal

doi:10.1183/23120541.00487-2022

Endothelial-to-mesenchymal transition: a precursor to pulmonary arterial remodelling in patients with idiopathic pulmonary fibrosis

ERJ Open Res. 2023 Apr 17;9(2):00487-2022. doi: 10.1183/23120541.00487-2022. eCollection 2023 Mar.

Authors

Archana Vijay Gaikwad^{1

2}, Wenying Lu^{1

2

3}, Surajit Dey¹, Prem Bhattarai¹, Greg Haug^{1

4}, Josie Larby^{1

4}, Collin Chia^{1

3

4}, Jade Jaffar^{5

6}, Glen Westall^{5

6}, Gurpreet Kaur Singhera^{7

8}, Tillie-Louise Hackett^{7

8}, Mathew Suji Eapen^{1

2

9}, Sukhwinder Singh Sohal^{1

3

9}

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 National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, Respiratory Medicine and Sleep Unit, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
³ Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia.
⁴ Department of Respiratory Medicine, Launceston General Hospital, Launceston, TAS, Australia.
⁵ Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, VIC, Australia.
⁶ Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia.
⁷ Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
⁸ Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
⁹ These authors contributed equally to this work.

Abstract

Background: We have previously reported arterial remodelling in patients with idiopathic pulmonary fibrosis (IPF) and suggested that endothelial-to-mesenchymal transition (EndMT) might be central to these changes. This study aims to provide evidence for active EndMT in IPF patients.

Methods: Lung resections from 13 patients with IPF and 15 normal controls (NCs) were immunostained for EndMT biomarkers: vascular endothelial cadherin (VE-cadherin), neural cadherin (N-cadherin), S100A4 and vimentin. Pulmonary arteries were analysed for EndMT markers by using computer- and microscope-assisted image analysis software Image ProPlus7.0. All the analysis was done with observer blinded to subject and diagnosis.

Results: Increased expression of mesenchymal markers N-cadherin (p<0.0001), vimentin (p<0.0001) and S100A4 (p<0.05) was noted with downregulation of junctional endothelial VE-cadherin (p<0.01) in the intimal layer of the arteries from patients with IPF compared to NCs. Cadherin switch was observed in IPF patients, showing increase in endothelial N-cadherin and decrease in VE-cadherin (p<0.01). There was also VE-cadherin shift from junctions to cytoplasm (p<0.01), effecting endothelial cell integrity in patients with IPF. In IPF, individual mesenchymal markers vimentin and N-cadherin negatively correlated with diffusing capacity of the lungs for carbon monoxide (r'= -0.63, p=0.03 and r'= -0.66, p=0.01). Further, N-cadherin positively correlated with arterial thickness (r'=0.58, p=0.03).

Conclusion: This is the first study to demonstrate active EndMT in size-based classified pulmonary arteries from IPF patients and potential role in driving remodelling changes. The mesenchymal markers had a negative impact on the diffusing capacity of the lungs for carbon monoxide. This work also informs early origins of pulmonary hypertension in patients with IPF.