Epidermal growth factor receptor inhibition by erlotinib prevents vascular smooth muscle cell and monocyte–macrophage function in vitro |
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| Institution: | 1. Transplantation and Liver Surgery Unit, Helsinki University Central Hospital Helsinki, Haartmaninkatu 4, PO Box 340, 00029 HUS, Finland;2. Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3 (PO Box 21), 00014 Helsinki, Finland;3. Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 372, 00029 HUS, Finland;1. Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;2. Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;3. Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;4. Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland |
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| Abstract: | IntroductionVascular smooth muscle cells (VSMCs) and monocyte–macrophages play a central role during the development of chronic allograft injury, which still remains an important challenge in organ transplantation. Inflammation, fibrosis and accelerated arteriosclerosis are typical features for chronic allograft injury. Growth factors participate in cell proliferation, differentiation and migration in this pathological process.ObjectiveHere we studied the role of epidermal growth factor receptor (EGFR) in VSMC and monocyte–macrophage function in vitro. EGFR inhibition by erlotinib, a selective EGF tyrosine kinase inhibitor, was studied in VSMC proliferation and migration as well as monocyte–macrophage proliferation and differentiation.Materials and methodsRat coronary artery SMCs were used for VSMC studies. As a model for monocyte–macrophage proliferation and differentiation human monocytic cell line U937 was used. Phorbol ester TPA was used to induce these cells to differentiate into macrophages.ResultsPlatelet-derived growth factor (PDGF)-B, a known VSMC inducer, caused 2.1-fold stimulation in VSMC proliferation compared to non-stimulated VSMC. Erlotinib prevented this VSMC proliferation in a dose-dependent manner, p < 0.001 in all groups compared to controls. PDGF-B stimulation increased VSMC migration to 2.5-fold when compared with non-stimulated cells. Erlotinib decreased VSMC migration dose-dependently and this effect was significant with all doses, p < 0.05. Erlotinib inhibited dose-dependently the proliferation of U937 monocytic cells, p < 0.001. Erlotinib prevented also TPA-induced macrophage differentiation in a dose-dependent way, p < 0.05.DiscussionErlotinib significantly prevents VSMC proliferation and migration in vitro. Erlotinib inhibited also significantly both monocyte proliferation and differentiation. Our data suggest that EGFR inhibition in VSMC and monocyte function has beneficial effects on chronic allograft injury. |
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