03199nas a2200529 4500008004100000022001400041245013000055210006900185260001300254300001200267490000800279520162800287653002201915653001201937653002901949653001501978653001701993653002002010653003702030653002002067653002102087653001502108653002002123653002102143653002002164653001702184653002202201653001602223653001602239653000902255653002402264653001502288653001202303653003202315653001802347653004102365653005002406100001802456700002302474700002302497700002102520700002202541700002602563700002302589700002302612856003402635 2012 eng d a1525-219100aCritical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.0 aCritical role of VEGFCVEGFR3 signaling in innate and adaptive im c2012 Nov a1607-200 v1813 a
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.
10aAdaptive Immunity10aAnimals10aBronchiolitis Obliterans10aChemotaxis10aCyclosporine10aDendritic Cells10aDose-Response Relationship, Drug10aDown-Regulation10aEpithelial Cells10aEpithelium10aGraft Rejection10aImmunity, Innate10aImmunoglobulins10aInflammation10aLymphangiogenesis10aMacrophages10aNeutrophils10aRats10aSignal Transduction10aTh17 Cells10aTrachea10aTransplantation, Homologous10aUp-Regulation10aVascular Endothelial Growth Factor C10aVascular Endothelial Growth Factor Receptor-31 aKrebs, Rainer1 aTikkanen, Jussi, M1 aRopponen, Jussi, O1 aJeltsch, Michael1 aJokinen, Janne, J1 aYlä-Herttuala, Seppo1 aNykänen, Antti, I1 aLemström, Karl, B uhttps://jeltsch.org/Krebs2012