*Purpose: Chronic allograft dysfunction (CLAD) remains a major determinant of the generally poor long-term outcome of lung transplantation compared to that of other solid organ transplants. Much attention has been directed towards analysis of the roles of the immune system in development of bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS), in contrast to the relatively little consideration of the contribution of lung parenchymal cells. With regard to the latter, we now report data concerning an important role of pulmonary lymphatic endothelial cells in determining the development of BOS.

*Methods: Left lung allografts were performed using the murine C57BL/B6->C57BL/10 strain combination in which WT donor lungs or those with various gene knockouts were evaluated (n>10/group), including the deletion (DTR/VEGFR3) or proliferation (VGEFR3cre/PTEN) of pulmonary lymphatics.

*Results: Use of iDTR VEGFR-3Cre^ERT2 donor mice to delete pulmonary lymphatics doubled the incidence of post-lung transplant BOS to almost 100% at 30 days (p<0.01). By contrast, donor lung deletion of PTEN led to tonic VEGF stimulation of lymphangiogenesis, as shown by increased Prox1 mRNA and VEGFR3 staining (both p<0.05), and an absence of BOS in 30-day lung allografts (p<0.01). The latter lung allografts showed well-preserved airspaces and accumulations of leukocytes within dilated lymphatics surrounding bronchovascular bundles.

*Conclusions: These studies show that pulmonary lymphatic endothelial cells contribute to the health of lung allografts and help regulate the development of BOS. Our ongoing molecular, biochemical, and cellular studies are directed towards dissecting the interactions of immune cells and pulmonary lymphatics in efforts to understand these diametrically opposed datasets.

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