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 (-VEGF D/-), in the preservation solution and systemically to the recipient before reperfusion (-VEGF D/R), or applied to the recipient alone before reperfusion (-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 -VEGF D/-, -VEGF D/R, and -VEGF -/R resulted in neutralization of tissue VEGF-A. Reperfusion edema was only reduced in -VEGF D/R and -VEGF D/- groups versus Perfadex controls. Some -VEGF -/R rats showed a hyperinflammation leading to increased pro-inflammatory cytokine expressions as well as increased edema. Whereas generally the -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 -VEGF (D/R) or (D/-) groups, animals mainly died from arterial thromboembolisms and in the -VEGF (-/R) group, hyperinflammation was the main cause of death. Conclusion VEGF-A directly contributes to the formation of a reperfusion edema, which might be reduced by its blockade. However, the -VEGF effect on the endothelial integrity might also favor arterial thrombosis formation.