title: Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.
abstract: Chronic inflammation, a hallmark of obliterative bronchiolitis, is known to induce lymphangiogenesis. We therefore studied the role of lymphangiogenic vascular endothelial growth factor C (VEGF-C), its receptor VEGFR-3, and lymphangiogenesis during development of experimental obliterative bronchiolitis [ie, obliterative airway disease (OAD)] in rat tracheal allografts. The functional importance of VEGF-C was investigated by adenovirus-mediated overexpression of VEGF-C (AdVEGF-C), and by inhibition of VEGF-C activity with VEGFR-3-Ig (AdVEGFR-3-Ig). Analyses included histology, immunohistochemistry, and real-time RT-PCR 10 and 30 days after transplantation. In the course of OAD development, lymphangiogenesis was induced in the airway wall during the alloimmune response, which was reversed by cyclosporine A in a dose-dependent fashion. VEGF-C overexpression in tracheal allografts induced epithelial activation, neutrophil chemotaxis, and a shift toward a Th17 adaptive immune response, followed by enhanced lymphangiogenesis and the development of OAD. In contrast, inhibition of VEGF-C activity with VEGFR-3-Ig inhibited lymphangiogenesis and angiogenesis and reduced infiltration of CD4(+) T cells and the development of OAD. Lymphangiogenesis was linked to T-cell responses during the development of OAD, and VEGF-C/VEGFR-3 signaling modulated innate and adaptive immune responses in the development of OAD in rat tracheal allografts. Our results thus suggest VEGFR-3-signaling as a novel strategy to regulate T-cell responses in the development of obliterative bronchiolitis after lung transplantation.
authors.affiliation: Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Finland. rainer.krebs@helsinki.fi
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Jussi O
authors.initials: JO
authors.lastname: Ropponen
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Janne J
authors.initials: JJ
authors.lastname: Jokinen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology*; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002633:Chemotaxis / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006084:Graft Rejection / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007136:Immunoglobulins / Q000494:pharmacology; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014132:Trachea / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D007136:Immunoglobulins; D042582:Vascular Endothelial Growth Factor C; D016572:Cyclosporine; D040321:Vascular Endothelial Growth Factor Receptor-3