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)

• Published in: Journal of clinical medicine Vol. 13; no. 4; p. 1160
• Main Authors: Gaikwad, Archana Vijay, Eapen, Mathew Suji, Dey, Surajit, Bhattarai, Prem, Shahzad, Affan Mahmood, Chia, Collin, Jaffar, Jade, Westall, Glen, Sutherland, Darren, Singhera, Gurpreet Kaur, Hackett, Tillie-Louise, Lu, Wenying, Sohal, Sukhwinder Singh
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.02.2024
• Subjects: Biobanks; endothelial-to-mesenchymal transition; Extracellular matrix; Fibroblasts; Growth factors; idiopathic pulmonary fibrosis; Lung diseases; Morphology; Pulmonary arteries; pulmonary artery; Pulmonary fibrosis; pulmonary hypertension; Software; vascular remodelling; Veins & arteries; Australia; United States > US; endothelial-to-mesenchymal transition; vascular remodelling; pulmonary artery; idiopathic pulmonary fibrosis; pulmonary hypertension
• ISSN: 2077-0383; 2077-0383
• DOI: 10.3390/jcm13041160

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). 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. Significant TGF-β1, pSmad-2/3, Smad-7, and β-catenin expression was apparent across all arterial sizes in IPF ( < 0.05). Intimal TGF-β1, pSmad-2/3, Smad-7, and β-catenin were augmented in the arterial range of 100-1000 μm ( < 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, = 0.05 and r' = 0.61, = 0.02, respectively) and intimal N-cadherin (r' = 0.62, = 0.03 and r' = 0.70, = 0.001, respectively). Intimal TGF-β1 and β-catenin expression were significantly correlated with increased intimal thickness as well (r' = 0.52, = 0.04; r' = 0.052, = 0.04, respectively). Moreover, intimal TGF-β1 expression was also significantly associated with increased intimal elastin deposition (r' = 0.79, = 0.002). Furthermore, total TGF-β1 expression significantly impacted the percentage of DLCO (r' = -0.61, = 0.03). 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.