Sebastian Kölmel1, Lukas Hobohm1,2, Anja Käberich1,2, Valentin J Krieg1, Magdalena L Bochenek1,2,3, Philip Wenzel1,2,3, Christoph B Wiedenroth4, Christoph Liebetrau3,5,6, Gerd Hasenfuß7,8, Eckhard Mayer4, Stavros V Konstantinides1,9, Katrin Schäfer2,3, Stefan Guth4, Mareike Lankeit1,7,10,11. 1. Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 2. Cardiology I, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 3. DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Germany. 4. Department of Thoracic Surgery, Kerckhoff Heart and Lung Center, Bad Nauheim, Germany. 5. Department of Cardiology, Kerckhoff Heart and Lung Center, Bad Nauheim, Germany. 6. Division of Cardiology, Department of Internal Medicine I, University of Giessen, Giessen, Germany. 7. Clinic of Cardiology and Pneumology, Heart Centre, University Medicine Göttingen, Göttingen, Germany. 8. DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany. 9. Department of Cardiology, Democritus University of Thrace, Alexandroupoli, Greece. 10. Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité-University Medicine, Berlin, Germany. 11. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
Abstract
BACKGROUND: Inflammation and incomplete thrombus resolution leading to obstructive fibrotic remodelling are considered critical mechanisms for the development of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Osteopontin (OPN) is involved in a variety of biological processes including inflammation and tissue fibrosis. METHODS: OPN plasma concentrations were measured in 70 CTEPH and 119 PE patients. Tissue material from 6 CTEPH patients removed during pulmonary endarterectomy and murine venous thrombi induced by subtotal ligation of the inferior vena cava in C57BL/6 mice were analysed by (immuno)histochemistry. RESULTS: CTEPH patients had higher OPN plasma concentrations (median, 106.9 [interquartile range, 75.6-155.9]) compared to PE patients (90.4 [53.3-123.9] ng/mL, p = 0.001). OPN- and matrix metalloproteinase (MMP)-9-positive cells were predominantly present in myofibroblast-rich and profibrotic areas of CTEPH tissue material. Early stages of murine thrombus resolution were characterised by high numbers of OPN- and MMP-2-positive cells while OPN was almost absent in fresh thrombi of CTEPH tissue material. PE patients with OPN plasma concentrations of < 55 ng/mL had a 15.2-fold (95% confidence interval, 1.7-135.5, p = 0.015) increased risk for a diagnosis of CTEPH during follow-up. CONCLUSION: The results of the present observational translational study point to a possible involvement of OPN in the pathogenesis of CTEPH by affecting early inflammatory and late fibrotic processes. Georg Thieme Verlag KG Stuttgart · New York.
BACKGROUND:Inflammation and incomplete thrombus resolution leading to obstructive fibrotic remodelling are considered critical mechanisms for the development of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Osteopontin (OPN) is involved in a variety of biological processes including inflammation and tissue fibrosis. METHODS:OPN plasma concentrations were measured in 70 CTEPH and 119 PE patients. Tissue material from 6 CTEPHpatients removed during pulmonary endarterectomy and murinevenous thrombi induced by subtotal ligation of the inferior vena cava in C57BL/6 mice were analysed by (immuno)histochemistry. RESULTS:CTEPHpatients had higher OPN plasma concentrations (median, 106.9 [interquartile range, 75.6-155.9]) compared to PE patients (90.4 [53.3-123.9] ng/mL, p = 0.001). OPN- and matrix metalloproteinase (MMP)-9-positive cells were predominantly present in myofibroblast-rich and profibrotic areas of CTEPH tissue material. Early stages of murine thrombus resolution were characterised by high numbers of OPN- and MMP-2-positive cells while OPN was almost absent in fresh thrombi of CTEPH tissue material. PE patients with OPN plasma concentrations of < 55 ng/mL had a 15.2-fold (95% confidence interval, 1.7-135.5, p = 0.015) increased risk for a diagnosis of CTEPH during follow-up. CONCLUSION: The results of the present observational translational study point to a possible involvement of OPN in the pathogenesis of CTEPH by affecting early inflammatory and late fibrotic processes. Georg Thieme Verlag KG Stuttgart · New York.
Authors: Andrei A Karpov; Nikita A Anikin; Aleksandra M Mihailova; Sergey S Smirnov; Dariya D Vaulina; Leonid A Shilenko; Dmitry Yu Ivkin; Alexei Y Bagrov; Olga M Moiseeva; Michael M Galagudza Journal: Int J Mol Sci Date: 2021-01-24 Impact factor: 5.923