Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema.
We hypothesized that the angiogenic mediator, vascular endothelial growth factor (VEGF), known to be expressed in the lung and to be capable of inducing local edema in skin, might evoke the development of lung edema if expressed in excess amounts. To test this hypothesis, we developed an in vivo model of VEGF overexpression in the lung on the basis of delivery to the respiratory epithelium of the VEGF165 complementary DNA by an E1(-) adenovirus vector (AdVEGF165). Administration of AdVEGF165 by the intratracheal route (10(9) plaque-forming units [pfu]) to C57Bl/6 mice showed increased expression of VEGF messenger RNA in lung tissue by Northern analysis. Overexpression of VEGF protein in the lung at Days 1 to 10 was confirmed by enzyme-linked immunosorbent assay. Intratracheal administration of AdVEGF165 resulted in a dose-dependent increase in lung wet/dry weight ratios over time, lung histology showed widespread intra- alveolar edema, and pulmonary capillary permeability was significantly increased as quantified by the Evans blue dye assay and [(131)I]albumin permeability. To confirm the specificity of these observations, mice were pretreated with intranasal administration of an adenovirus vector expressing a truncated soluble form of the VEGF receptor flt-1 (Adsflt). Adsflt (10(9) pfu) pretreatment completely abrogated the increased lung wet/dry weight ratio caused by AdVEGF165 administration, whereas an identical adenovirus vector with an irrelevant transgene had no effect upon subsequent AdVEGF165-induced pulmonary edema. Together, these data suggest that overexpression of VEGF in the lung may be one mechanism of increased pulmonary vascular permeability in the early stages of acute lung injury.
Kaner
R J
RJ
Division of Pulmonary and Critical Care Medicine and Weill Medical College of Cornell University, New York, New York, USA. geneticmedicine@mail.med.cornell.edu
Ladetto
J V
JV
Singh
R
R
Fukuda
N
N
Matthay
M A
MA
Crystal
R G
RG
D000280:Administration, Inhalation; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D004396:Coloring Agents / Q000493:pharmacokinetics; D018076:DNA, Complementary / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics*; D005070:Evans Blue / Q000493:pharmacokinetics; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011654:Pulmonary Edema / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D014867:Water / Q000378:metabolism
D004396:Coloring Agents; D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014867:Water; D005070:Evans Blue; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1