Am. J. Respir. Cell Mol. Biol., Volume 22, Number 3, March, 2000 272-279

Oxygen-Independent Upregulation of Vascular Endothelial Growth Factor and Vascular Barrier Dysfunction during Ventilated Pulmonary Ischemia in Isolated Ferret Lungs

Patrice M. Becker, Armina Alcasabas, Aimee Y. Yu, Gregg L. Semenza, and Tracie E. Bunton

Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Pediatrics and Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Vascular endothelial growth factor (VEGF) is a potent mediator of endothelial barrier dysfunction, and is upregulated during ischemia in many organs. Because ventilated pulmonary ischemia causes a marked increase in pulmonary vascular permeability, we hypothesized that VEGF would increase during ischemic lung injury. To test this hypothesis, we measured VEGF expression by Northern and Western blot analysis in isolated ferret lungs after 45 (n = 12) or 180 (n = 12) min of ventilated (95% or 0% O₂) ischemia. Pulmonary vascular permeability, assessed by measurement of osmotic reflection coefficient for albumin (_alb), was evaluated in the same lungs, as was expression of the transcription factor, hypoxia-inducible factor (HIF)-1. Distribution of VEGF as a function of ischemic time and oxygen tension was also evaluated by immunohistochemical staining in separate groups of lungs (n = 3). VEGF messenger RNA (mRNA) increased 3-fold by 180 min of ventilated ischemia, independent of oxygen tension. VEGF protein increased in parallel to mRNA. Immunohistochemical staining demonstrated the appearance of VEGF protein along alveolar septae after 180 min of hyperoxic ischemia, and after 45 or 180 min of hypoxic ischemia. _alb was not altered by 45 min of hyperoxic ischemia (0.69 ± 0.09 versus 0.50 ± 0.12, respectively), but decreased significantly after 180 min of hyperoxic ischemia and after 45 and 180 min of hypoxic ischemia (0.20 ± 0.03, 0.26 ± 0.08, and 0.23 ± 0.03, respectively; P < 0.05). HIF-1 mRNA increased during both hyperoxic and hypoxic ischemia, but HIF-1 protein increased only during hypoxic ischemia. These results implicate VEGF as a potential mediator of increased pulmonary vascular permeability in this model of acute lung injury.

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