Vascular endothelial growth factor antagonist modulates leukocyte trafficking and protects mouse livers against ischemia/reperfusion injury.
Although hypoxia stimulates the expression of vascular endothelial growth factor (VEGF), little is known of the role or mechanism by which VEGF functions after ischemia and reperfusion (I/R) injury. In this report, we first evaluated the expression of VEGF in a mouse model of liver warm ischemia. We found that the expression of VEGF increased after ischemia but peaked between 2 and 6 hours after reperfusion. Mice were treated with a neutralizing anti-mouse VEGF antiserum (anti-VEGF) or control serum daily from day -1 (1 day before the initiation of ischemia). Treatment with anti-VEGF significantly reduced serum glutaminic pyruvic transaminase levels and reduced histological evidence of hepatocellular damage compared with controls. Anti-VEGF also markedly decreased T-cell, macrophage, and neutrophil accumulation within livers and reduced the frequency of intrahepatic apoptotic terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells. Moreover, there was a reduction in the expression of pro-inflammatory cytokines (tumor necrosis factor-alpha and interferon-gamma), chemokines (interferon-inducible protein-10 and monocyte chemoattractant protein-1) and adhesion molecules (E-selectin) in parallel with enhanced expression of anti-apoptotic genes (Bcl-2/Bcl-xl and heme oxygenase-1) in anti-VEGF-treated animals. In conclusion, hypoxia-inducible VEGF expression by hepatocytes modulates leukocyte trafficking and leukocyte-induced injury in a mouse liver model of warm I/R injury, demonstrating the importance of endogenous VEGF production in the pathophysiology of hepatic I/R injury.
Tsuchihashi
Sei-ichiro
S
The Dumont-UCLA Transplant Center, Los Angeles, CA 90095-7054, USA.
Ke
Bibo
B
Kaldas
Fady
F
Flynn
Evelyn
E
Busuttil
Ronald W
RW
Briscoe
David M
DM
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D020287:In Situ Nick-End Labeling; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011817:Rabbits; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*
D018925:Chemokines; D016207:Cytokines; D019040:E-Selectin; D007074:Immunoglobulin G; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D051547:Heme Oxygenase-1