@article {427,
	title = {Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.},
	journal = {Am J Pathol},
	volume = {181},
	year = {2012},
	month = {2012 Nov},
	pages = {1607-20},
	abstract = {<p>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.</p>},
	keywords = {Adaptive Immunity, Animals, Bronchiolitis Obliterans, Chemotaxis, Cyclosporine, Dendritic Cells, Dose-Response Relationship, Drug, Down-Regulation, Epithelial Cells, Epithelium, Graft Rejection, Immunity, Innate, Immunoglobulins, Inflammation, Lymphangiogenesis, Macrophages, Neutrophils, Rats, Signal Transduction, Th17 Cells, Trachea, Transplantation, Homologous, Up-Regulation, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3},
	issn = {1525-2191},
	doi = {10.1016/j.ajpath.2012.07.021},
	author = {Krebs, Rainer and Tikkanen, Jussi M and Ropponen, Jussi O and Jeltsch, Michael and Jokinen, Janne J and Yl{\"a}-Herttuala, Seppo and Nyk{\"a}nen, Antti I and Lemstr{\"o}m, Karl B}
}
