title: Intimal fibrosis in human cardiac allograft vasculopathy.
abstract: Human Cardiac Allograft Vasculopathy (CAV) is one of the major complications for patients after heart transplantation. It is characterized by a concentric luminal narrowing due to (neo) intimal expansion in the coronary arteries of donor hearts after heart transplantation. In this process fibrosis plays an important role. Aim of this study is to analyze the factors and cells involved in this fibrotic process. Coronary arteries from five heart transplantation patients and three controls were obtained at autopsy. Quantitative real-time PCR was performed on mRNA obtained from various arterial layers isolated by laser micro dissection. Positive gene expression was confirmed by immunohistochemistry and/or in situ hybridisation. The strongest mRNA expression of fibrotic factors (predominantly pro-fibrotic) was found in the neo-intima. Especially, connective tissue growth factor expression was higher in the CAV vessels than in the controls. The lymphocyte activity of interferon gamma was only detected in CAV vessels. Furthermore as shown by in situ hybridisation, the lymphocytes producing interferon gamma also expressed transforming growth factor beta. Anti-fibrotic factors, such as bone morphogenic protein 4, were only expressed in CD3(-)/CD68(-) stromal cells. Macrophages present in the CAV and control vessels showed to be of the M2 type and did not produce any fibrotic factor(s). In conclusion, T-cells producing both interferon gamma and transforming growth factor beta, may play an important role in the fibrotic process in CAV vessels by upregulation of connective tissue growth factor production.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. m.m.h.huibers@umcutrecht.nl
authors.forename: Manon
authors.initials: M
authors.lastname: Huibers
authors.forename: Nicolaas
authors.initials: N
authors.lastname: De Jonge
authors.forename: Joyce
authors.initials: J
authors.lastname: Van Kuik
authors.forename: Erica Siera-De
authors.initials: ES
authors.lastname: Koning
authors.forename: Dick
authors.initials: D
authors.lastname: Van Wichen
authors.forename: Hub
authors.initials: H
authors.lastname: Dullens
authors.forename: Marguérite
authors.initials: M
authors.lastname: Schipper
authors.forename: Roel
authors.initials: R
authors.lastname: De Weger
mesh_terms: D000293:Adolescent; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis; D005260:Female; D005355:Fibrosis; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008264:Macrophages; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger; D017154:Stromal Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014184:Transplantation, Homologous / Q000009:adverse effects; D017539:Tunica Intima / Q000473:pathology*; D014652:Vascular Diseases / Q000473:pathology*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma