Rapid Activation of Lymphangiogenesis Causes Increased Lymphatic Density during the Development of Chronic Lung Allograft Dysfunction

Objectives: Lung transplantation displays the worst long-term survival of all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). VEGFR3 signaling can activate lymphatic vessels and regulate interstitial drainage and leukocyte trafficking, and therefore affects alloimmunity. VEGFR3 signaling in heart kidney transplantation has been described, but its role in CLAD development is unclear.

Methods: Mouse orthotopic left lung transplantation with a single mismatch (HLA-A2 knock-in C57BL/6 to C57BL/6) was used as CLAD model. The allografts were collected at 7, 14, 28, and 56 days after surgery. Syngeneic transplantations were used as control. We analyzed the change of lymphatic density, lymphatic phenotype and the activation of prolymphangiogenic genes during CLAD development. To mimic ischemia reperfusion injury (IRI) in vitro, macrophages were treated with lipopolysaccharide to analyze the activation of VEGF-C and VEGFR3 expression.

Result: We observed elevated expression of PROX-1 7 days after transplantation in CLAD model, illustrating early activation of lymphangiogenesis. We further observed an increase of lymphatic vessel activation leading to elevated lymphatic density during a 56-day period after transplantation in CLAD model.

Conclusion: Lung transplantation leads to the rapid activation of prolymphangiogenic phenotype with consequent increase of lymphatic activation and lymphatic density in CLAD model. The early activation of lymphangiogenesis during the CLAD development thus seems to be associated with chronic alloimmune response. Therapeutic targeting of VEGF-C/VEGFR3 signaling in lung transplantation might prevent CLAD.

Publication History

Article published online:
19 February 2021