期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 47, 期 1, 页码 55-61出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2009.03.027
关键词
Hypoxia; HIF; VEGF; Pulmonary edema; Reactive oxygen species; Free radicals
资金
- NIH NSRA Training [5-T32-HL07171]
Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS-HIF-1-VEGF pathway in pulmonary vascular leak has not been defined. We hypothesized that the ROS-HIF-1-VEGF pathway has an important role in producing hypoxia-induced pulmonary vascular leak. Human pulmonary artery endothelial cell (HPAEC) monolayers were exposed to either normoxia (21% O-2) or acute hypoxia (3% O-2) for 24 h and monolayer permeability and H2O2, nuclear HIF-1 alpha, and cytosolic VEGF levels were determined. HPAEC were treated with antioxidant cocktail (AO; ascorbate, glutathione, and alpha-tocopherol) HIF-1 siRNA or the VEGF soluble binding protein fins-like tyrosine kinase-1 (sFlt-1) to delineate the role of the ROS-HIF-1-VEGF pathway in hypoxia-induced HPAEC leak. Additionally, mice exposed to hypobaric hypoxia (18,000 ft, 10% O-2) were treated with the same antioxidant to determine if in vitro responses corresponded to in vivo hypoxia stress. Hypoxia increased albumin permeativity, H2O2 production, and nuclear HIF-1 alpha and cytosolic VEGF concentration. Treatment with an AO lowered the hypoxia-induced HPAEC monolayer permeability as well as the elevation of HIF-1 alpha and VEGF. Treatment of hypoxia-induced HPAEC with either an siRNA designed against HIF-1 alpha or the VEGF antagonist sFlt-1 decreased monolayer permeability. Mice treated with AO and exposed to hypobaric hypoxia (18,000 ft, 10% 02) had less pulmonary vascular leak than those that were untreated. Our data suggest that hypoxia-induced permeability is due, in part, to the ROS-HIF-1 alpha VEGF pathway. (C) 2009 Elsevier Inc. All rights reserved.
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