title: VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury.
abstract: Leakage of fluid from blood vessels, leading to oedema, is a key feature of many diseases including hyperoxic acute lung injury (HALI), which can occur when patients are ventilated with high concentrations of oxygen (hyperoxia). The molecular mechanisms driving vascular leak and oedema in HALI are poorly understood. VEGF-D is a protein that promotes blood vessel leak and oedema when overexpressed in tissues, but the role of endogenous VEGF-D in pathological oedema was unknown. To address these issues, we exposed Vegfd-deficient mice to hyperoxia. The resulting pulmonary oedema in Vegfd-deficient mice was substantially reduced compared to wild-type, as was the protein content of bronchoalveolar lavage fluid, consistent with reduced vascular leak. Vegf-d and its receptor Vegfr-3 were more highly expressed in lungs of hyperoxic, versus normoxic, wild-type mice, indicating that components of the Vegf-d signalling pathway are up-regulated in hyperoxia. Importantly, VEGF-D and its receptors were co-localized on blood vessels in clinical samples of human lungs exposed to hyperoxia; hence, VEGF-D may act directly on blood vessels to promote fluid leak. Our studies show that Vegf-d promotes oedema in response to hyperoxia in mice and support the hypothesis that VEGF-D signalling promotes vascular leak in human HALI. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Sato
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paquet-Fifield
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Harris
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Roufail
authors.affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Nedlands, Australia.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Turner
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: You-Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.|Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
authors.affiliation: Department of Pathology, University of Melbourne, Victoria, Australia.|Department of Anatomical Pathology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Williams
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Nedlands, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
mesh_terms: D055371:Acute Lung Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010100:Oxygen / Q000378:metabolism; D011654:Pulmonary Edema / Q000150:complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D042643:Vascular Endothelial Growth Factor D / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3; D010100:Oxygen
keywords: VEGF-D; VEGFR-2; VEGFR-3; hyperoxia; hyperoxic acute lung injury; pulmonary oedema; vascular leak