Lymphatic Disruption as a Driver of Lung Transplant Fibrosis

The consequence of lymphatic disruption during transplantation of solid organs remains unknown. Long-term survival after thoracic organ transplantation is limited by chronic rejection, a poorly understood process involving fibrotic remodeling and functional decline of the graft. Here, we report that transplanted human lungs and hearts with chronic rejection exhibit fibrosis distributed along dysmorphic lymphatics in areas densely concentrated with hyaluronan, an interstitial glycosaminoglycan which depends on lymphatic drainage for clearance. We illustrate similar findings in mouse lung and heart grafts which are accompanied by lymphographic findings of graft lymphedema. We identify interleukin-1-mediated hyaluronan accumulation as a mechanism driving fibrosis that can occur independent of alloimmunity in the setting of lymphatic disruption after lung transplantation and outline three therapeutic interventions with clinical potential. Overall design: Following syngeneic left lung transplantation of C57BL/6 lungs into C57BL/6 recipients, recipients were treated with an IL-1R1 antagonist versus saline control. Lung grafts were collected at 7 days post-transplant. Two lungs were pooled for submitted samples. Lung tissue was digested, and single-cell suspensions were prepared. Cells were stained using DAPI and CD45. Cells were sorted using a BD FACS Melody cell sorter into CD45+ leukocytes and CD45- stroma. Collected cells were submitted for sequencing.