PMID- 26924464 OWN - NLM STAT- MEDLINE DCOM- 20170530 LR - 20181113 IS - 1096-9896 (Electronic) IS - 0022-3417 (Print) IS - 0022-3417 (Linking) VI - 239 IP - 2 DP - 2016 Jun TI - VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury. PG - 152-61 LID - 10.1002/path.4708 [doi] AB - 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. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. CI - (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. FAU - Sato, Teruhiko AU - Sato T AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. AD - Ludwig Institute for Cancer Research, Parkville, Victoria, Australia. FAU - Paquet-Fifield, Sophie AU - Paquet-Fifield S AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. FAU - Harris, Nicole C AU - Harris NC AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. AD - Ludwig Institute for Cancer Research, Parkville, Victoria, Australia. FAU - Roufail, Sally AU - Roufail S AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. FAU - Turner, Debra J AU - Turner DJ AD - Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Nedlands, Australia. FAU - Yuan, Yinan AU - Yuan Y AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. FAU - Zhang, You-Fang AU - Zhang YF AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. FAU - Fox, Stephen B AU - Fox SB AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia. FAU - Hibbs, Margaret L AU - Hibbs ML AD - Ludwig Institute for Cancer Research, Parkville, Victoria, Australia. AD - Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia. FAU - Wilkinson-Berka, Jennifer L AU - Wilkinson-Berka JL AD - Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia. FAU - Williams, Richard A AU - Williams RA AD - Department of Pathology, University of Melbourne, Victoria, Australia. AD - Department of Anatomical Pathology, St Vincent's Hospital, Melbourne, Victoria, Australia. FAU - Stacker, Steven A AU - Stacker SA AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. AD - Ludwig Institute for Cancer Research, Parkville, Victoria, Australia. AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia. FAU - Sly, Peter D AU - Sly PD AD - Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Nedlands, Australia. FAU - Achen, Marc G AU - Achen MG AD - Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. AD - Ludwig Institute for Cancer Research, Parkville, Victoria, Australia. AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160330 PL - England TA - J Pathol JT - The Journal of pathology JID - 0204634 RN - 0 (VEGFD protein, human) RN - 0 (Vascular Endothelial Growth Factor D) RN - EC 2.7.10.1 (FLT4 protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-3) RN - S88TT14065 (Oxygen) SB - IM MH - Acute Lung Injury/*complications/metabolism/pathology MH - Animals MH - Bronchoalveolar Lavage Fluid MH - Cell Line, Tumor MH - Female MH - Humans MH - Hyperoxia/*complications/metabolism/pathology MH - Lung/metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - Mice, Knockout MH - Mice, SCID MH - Oxygen/metabolism MH - Pulmonary Edema/complications/*etiology/metabolism/pathology MH - *Signal Transduction MH - Vascular Endothelial Growth Factor D/administration & dosage/genetics/*metabolism MH - Vascular Endothelial Growth Factor Receptor-3/genetics/*metabolism MH - Xenograft Model Antitumor Assays PMC - PMC5071654 OTO - NOTNLM OT - VEGF-D OT - VEGFR-2 OT - VEGFR-3 OT - hyperoxia OT - hyperoxic acute lung injury OT - pulmonary oedema OT - vascular leak EDAT- 2016/03/01 06:00 MHDA- 2017/05/31 06:00 PMCR- 2016/10/20 CRDT- 2016/03/01 06:00 PHST- 2015/12/21 00:00 [received] PHST- 2016/02/07 00:00 [revised] PHST- 2016/02/17 00:00 [accepted] PHST- 2016/03/01 06:00 [entrez] PHST- 2016/03/01 06:00 [pubmed] PHST- 2017/05/31 06:00 [medline] PHST- 2016/10/20 00:00 [pmc-release] AID - PATH4708 [pii] AID - 10.1002/path.4708 [doi] PST - ppublish SO - J Pathol. 2016 Jun;239(2):152-61. doi: 10.1002/path.4708. Epub 2016 Mar 30.