Rapid Activation of Pro-Lymphangiogenic Phenotype and Consequent Increase of Lymphatic Density Occurs during the Development of Chronic Lung Allograft Dysfunction

Purpose Lung transplant shows poor long-term survival due to chronic lung allograft dysfunction (CLAD). VEGF-C/VEGFR3 signaling may regulate lymphatic vessel activation and initiate alloimmunity after transplantation. However, its role in CLAD development remains unclear. Methods The CLAD model was established in mouse orthotopic left lung transplantation with a single mismatch (HLA-A2 knock-in C57BL/6 to C57BL/6). The allografts were collected at 14, 28 and 56d after surgery. Syngeneic transplantations were used as control. We analyzed the change of lymphatic density, lymphatic phenotype and the activation of pro-lymphangiogenic genes during CLAD development. Results We found increased expression of PROX-1 7d after transplantation in CLAD model. We further observed a significant increase of lymphatic vessel density 56d after transplantation in CLAD model. The trend of increased lymphatic activation reached no significance (Figure 1). Conclusion Our results show that lung transplantation leads to the rapid activation of pro-lymphangiogenic phenotype with consequent increase of lymphatic vessel density in CLAD model. The early activation of lymphangiogensis during the CLAD development may stimulate chronic alloimmune response. VEGF-C/VEGFR3 inhibition during lung transplant might therefore prevent CLAD.