TGF-β1, pSmad-2/3, Smad-7, and β-Catenin Are Augmented in the Pulmonary Arteries from Patients with Idiopathic Pulmonary Fibrosis (IPF): Role in Driving Endothelial-to-Mesenchymal Transition (EndMT)

Archana Vijay Gaikwad; Mathew Suji Eapen; Surajit Dey; Prem Bhattarai; Affan Mahmood Shahzad; Collin Chia; Jade Jaffar; Glen Westall; Darren Sutherland; Gurpreet Kaur Singhera; Tillie-Louise Hackett; Wenying Lu; Sukhwinder Singh Sohal

doi:10.3390/jcm13041160

TGF-β1, pSmad-2/3, Smad-7, and β-Catenin Are Augmented in the Pulmonary Arteries from Patients with Idiopathic Pulmonary Fibrosis (IPF): Role in Driving Endothelial-to-Mesenchymal Transition (EndMT)

J Clin Med. 2024 Feb 19;13(4):1160. doi: 10.3390/jcm13041160.

Authors

Archana Vijay Gaikwad^{1

2}, Mathew Suji Eapen^{1

2}, Surajit Dey¹, Prem Bhattarai¹, Affan Mahmood Shahzad¹, Collin Chia^{1

3

4}, Jade Jaffar^{5

6}, Glen Westall^{5

6}, Darren Sutherland^{7

8}, Gurpreet Kaur Singhera^{7

8}, Tillie-Louise Hackett^{7

8}, Wenying Lu^{1

2

3}, Sukhwinder Singh Sohal^{1

2

3}

Affiliations

¹ Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS 7248, Australia.
² National Health and Medical Research Council (NHMRC) Centre of Research Excellence (CRE) in Pulmonary Fibrosis, Respiratory Medicine and Sleep Unit, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
³ Launceston Respiratory and Sleep Centre, Launceston, TAS 7250, Australia.
⁴ Department of Respiratory Medicine, Launceston General Hospital, Launceston, TAS 7250, Australia.
⁵ Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, VIC 3004, Australia.
⁶ Department of Immunology and Pathology, Monash University, Melbourne, VIC 3004, Australia.
⁷ Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
⁸ Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada.

Abstract

Background: We have previously reported that endothelial-to-mesenchymal transition (EndMT) is an active process in patients with idiopathic pulmonary fibrosis (IPF) contributing to arterial remodelling. Here, we aim to quantify drivers of EndMT in IPF patients compared to normal controls (NCs). Methods: Lung resections from thirteen IPF patients and eleven NCs were immunohistochemically stained for EndMT drivers, including TGF-β1, pSmad-2/3, Smad-7, and β-catenin. Intima, media, and adventitia were analysed for expression of each EndMT driver in pulmonary arteries. Computer- and microscope-assisted Image ProPlus7.0 image analysis software was used for quantifications. Results: Significant TGF-β1, pSmad-2/3, Smad-7, and β-catenin expression was apparent across all arterial sizes in IPF (p < 0.05). Intimal TGF-β1, pSmad-2/3, Smad-7, and β-catenin were augmented in the arterial range of 100-1000 μm (p < 0.001) compared to NC. Intimal TGF-β1 and β-catenin percentage expression showed a strong correlation with the percentage expression of intimal vimentin (r' = 0.54, p = 0.05 and r' = 0.61, p = 0.02, respectively) and intimal N-cadherin (r' = 0.62, p = 0.03 and r' = 0.70, p = 0.001, respectively). Intimal TGF-β1 and β-catenin expression were significantly correlated with increased intimal thickness as well (r' = 0.52, p = 0.04; r' = 0.052, p = 0.04, respectively). Moreover, intimal TGF-β1 expression was also significantly associated with increased intimal elastin deposition (r' = 0.79, p = 0.002). Furthermore, total TGF-β1 expression significantly impacted the percentage of DLCO (r' = -0.61, p = 0.03). Conclusions: This is the first study to illustrate the involvement of active TGF-β/Smad-2/3-dependent and β-catenin-dependent Wnt signalling pathways in driving EndMT and resultant pulmonary arterial remodelling in patients with IPF. EndMT is a potential therapeutic target for vascular remodelling and fibrosis in general in patients with IPF.

Keywords: endothelial-to-mesenchymal transition; idiopathic pulmonary fibrosis; pulmonary artery; pulmonary hypertension; vascular remodelling.

Abstract

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