title: Epidermal growth factor receptor inhibition by erlotinib prevents vascular smooth muscle cell and monocyte-macrophage function in vitro.
abstract: BACKGROUND
  Vascular 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.
  
  
  OBJECTIVE
  Here 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.
  
  
  METHODS
  Rat 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.
  
  
  RESULTS
  Platelet-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.
  
  
  CONCLUSIONS
  Erlotinib 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.
authors: Transplantation and Liver Surgery Unit, Helsinki University Central Hospital Helsinki, Haartmaninkatu 4, PO Box 340, 00029 HUS, Finland; Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3 (PO Box 21), 00014 Helsinki, Finland. Electronic address: johanna.savikko@helsinki.fi.
authors: Johanna
authors: J
authors: Savikko
authors: Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3 (PO Box 21), 00014 Helsinki, Finland.
authors: Jukka M
authors: JM
authors: Rintala
authors: Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3 (PO Box 21), 00014 Helsinki, Finland.
authors: Sini
authors: S
authors: Rintala
authors: Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3 (PO Box 21), 00014 Helsinki, Finland; Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 372, 00029 HUS, Finland.
authors: Petri
authors: P
authors: Koskinen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D003331:Coronary Vessels / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D006084:Graft Rejection / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D000069347:Erlotinib Hydrochloride; C483803:Egfr protein, rat; D066246:ErbB Receptors
keywords: Chronic allograft injury; EGFR; Erlotinib; Macrophage; Monocyte; Smooth muscle cell