title: Protective role of vascular endothelial growth factor in endotoxin-induced acute lung injury in mice.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation, is an important survival factor for endothelial cells. Although overexpressed VEGF in the lung induces pulmonary edema with increased lung vascular permeability, the role of VEGF in the development of acute lung injury remains to be determined.
  
  
  METHODS
  To evaluate the role of VEGF in the pathogenesis of acute lung injury, we first evaluated the effects of exogenous VEGF and VEGF blockade using monoclonal antibody on LPS-induced lung injury in mice. Using the lung specimens, we performed TUNEL staining to detect apoptotic cells and immunostaining to evaluate the expression of apoptosis-associated molecules, including caspase-3, Bax, apoptosis inducing factor (AIF), and cytochrome C. As a parameter of endothelial permeability, we measured the albumin transferred across human pulmonary artery endothelial cell (HPAEC) monolayers cultured on porous filters with various concentrations of VEGF. The effect of VEGF on apoptosis HPAECs was also examined by TUNEL staining and active caspase-3 immunoassay.
  
  
  RESULTS
  Exogenous VEGF significantly decreased LPS-induced extravascular albumin leakage and edema formation. Treatment with anti-VEGF antibody significantly enhanced lung edema formation and neutrophil emigration after intratracheal LPS administration, whereas extravascular albumin leakage was not significantly changed by VEGF blockade. In lung pathology, pretreatment with VEGF significantly decreased the numbers of TUNEL positive cells and those with positive immunostaining of the pro-apoptotic molecules examined. VEGF attenuated the increases in the permeability of the HPAEC monolayer and the apoptosis of HPAECs induced by TNF-alpha and LPS. In addition, VEGF significantly reduced the levels of TNF-alpha- and LPS-induced active caspase-3 in HPAEC lysates.
  
  
  CONCLUSIONS
  These results suggest that VEGF suppresses the apoptosis induced by inflammatory stimuli and functions as a protective factor against acute lung injury.
authors: Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan. hidefumi_koh@saimiya.com
authors: Hidefumi
authors: H
authors: Koh
authors: Sadatomo
authors: S
authors: Tasaka
authors: Naoki
authors: N
authors: Hasegawa
authors: Wakako
authors: W
authors: Yamada
authors: Mie
authors: M
authors: Shimizu
authors: Morio
authors: M
authors: Nakamura
authors: Makoto
authors: M
authors: Yonemaru
authors: Eiji
authors: E
authors: Ikeda
authors: Yoshiyuki
authors: Y
authors: Adachi
authors: Seitaro
authors: S
authors: Fujishima
authors: Kazuhiro
authors: K
authors: Yamaguchi
authors: Akitoshi
authors: A
authors: Ishizaka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology; D011651:Pulmonary Artery / Q000166:cytology; D011654:Pulmonary Edema / Q000188:drug therapy / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D053148:Caspase 3
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