VEGF-A blockade reduces reperfusion edema but favors arterial thromboembolism in a rat model of orthotopic lung transplantation.
BACKGROUND
Ischemia-reperfusion edema is a common early complication after lung transplantation where the hypoxia-induced vascular endothelial growth factor (VEGF)-A plays a pivotal role. It remains unclear whether a VEGF blockade is beneficial in lung transplantation.


METHODS
VEGF-A blockade was investigated in an orthotopic rat model of lung transplantation. VEGF-A antibody was added into the preservation solution alone (α-VEGF D/-), in the preservation solution and systemically to the recipient before reperfusion (α-VEGF D/R), or applied to the recipient alone before reperfusion (α-VEGF -/R). Forty-eight hours after lung transplantation, left lungs were collected and wet-to-dry ratio, Western blotting, RT-PCR, and immunohistology were performed.


RESULTS
VEGF-A blockade in α-VEGF D/-, α-VEGF D/R, and α-VEGF -/R resulted in neutralization of tissue VEGF-A. Reperfusion edema was only reduced in α-VEGF D/R and α-VEGF D/- groups versus Perfadex controls. Some α-VEGF -/R rats showed a hyperinflammation leading to increased pro-inflammatory cytokine expressions as well as increased edema. Whereas generally the α-VEGF D/- group showed decreased inflammation, the combination with anti-VEGF treatment to the recipient resulted in a pro-inflammatory and a pro-apoptotic phenotype. Short-term survival, however, was not significantly different in all groups as compared to the controls. In the α-VEGF (D/R) or (D/-) groups, animals mainly died from arterial thromboembolisms and in the α-VEGF (-/R) group, hyperinflammation was the main cause of death.


CONCLUSIONS
VEGF-A directly contributes to the formation of a reperfusion edema, which might be reduced by its blockade. However, the α-VEGF effect on the endothelial integrity might also favor arterial thrombosis formation.
1 Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany. 2 Clinic of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria. 3 Faculty of Medicine, Philipps-University, Marburg, Germany. 4 Address correspondence to: Patrick Paulus, M.D., Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
Patrick
P
Paulus
Johannes
J
Holfeld
Bertram
B
Scheller
Kai
K
Zacharowski
Christin
C
Reissig
Elisabeth
E
Tybl
Pia Alexandra
PA
Ockelmann
Anja
A
Urbschat
D000818:Animals; D017209:Apoptosis; D001158:Arteries / Q000473:pathology; D004195:Disease Models, Animal; D004487:Edema / Q000378:metabolism*; D000860:Hypoxia; D007249:Inflammation; D016040:Lung Transplantation; D008297:Male; D019188:Organ Preservation Solutions; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D013923:Thromboembolism / Q000473:pathology*; D013927:Thrombosis; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019188:Organ Preservation Solutions; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt