Darren Sutherland

Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung fibrotic disorder of unknown cause. It has been reported that bacterial and viral co-infections exacerbate disease pathogenesis. These pathogens use adhesion molecules such as platelet activating factor receptor (PAFR) and intercellular adhesion molecule-1 (ICAM–1) to gain cellular entry, causing infections. Methods: Immunohistochemical staining was carried out for lung resections from IPF patients (n = 11) and normal controls (n = 12). The quantification of PAFR and ICAM–1 expression is presented as a percentage in the small airway epithelium. Also, type 2 pneumocytes and alveolar macrophages were counted as cells per mm² of the parenchymal area and presented as a percentage. All image analysis was done using Image Pro Plus 7.0 software. Results: PAFR expression significantly increased in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Similar trend was observed for ICAM–1 expression in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Furthermore, the proportion of positively expressed type 2 pneumocytes and alveolar macrophages was higher in IPF than in normal control. Conclusions: This is the first study to show PAFR and ICAM–1 expression in small airway epithelium, type 2 pneumocytes and alveolar macrophages in IPF. These findings could help intervene microbial impact and facilitate management of disease pathogenesis.

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.