Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

Lung transplantation is the standard of care for end-stage lung disease, yet acute rejection remains a major barrier to long-term survival. Because surgical procedures for lung transplantation do not reconnect donor lymphatic vessels, the graft suffers from interrupted lymphatic drainage. This study investigates whether this lymphatic impairment contributes to the accumulation of inflammatory extracellular matrix components—specifically hyaluronan (HA)—and whether restoring lymphatic function can mitigate rejection.

The researchers utilized a mouse model of orthotopic lung transplantation to observe the fate of lymphatic vessels during rejection. They quantified lymphatic density using markers such as LYVE-1, VEGFR-3, and PROX-1. To test the therapeutic potential of lymphangiogenesis, they administered VEGF-C156S, a mutant growth factor that selectively stimulates lymphatic vessel growth without inducing blood vessel angiogenesis. They also performed loss-of-function experiments using LYVE-1 blocking antibodies to confirm that the therapeutic benefit was specifically due to lymphatic-mediated HA clearance. Finally, they correlated these findings with longitudinal transbronchial biopsies from human lung transplant patients.

The study found a significant decline in lymphatic vessel density in rejected lung allografts, which correlated with an accumulation of low-molecular-weight HA in the lung tissue. Treatment with VEGF-C156S successfully induced lymphangiogenesis, reduced LEC (lymphatic endothelial cell) apoptosis, and promoted the clearance of HA from the graft. This intervention significantly reduced the severity of acute cellular rejection and decreased the infiltration of inflammatory T cells and macrophages. Blocking the LYVE-1 receptor reversed these benefits, confirming that lymphatic drainage of HA is a critical mechanism for maintaining graft health.