An experimental approach toward chronic pulmonary allograft rejection: Orthotopic lung versus heterotopic tracheal segment transplantation in rats.

Background: Despite the impact of chronic rejection (CR) on long-term outcomes, clinically relevant experimental models are sparse, often including a design of subcutaneous implantation of tracheal segments. However, this latter site lacks anatomic correlation, adequate perfusion, and ventilatory function. In this study, we compared the spatial and sequential course of CR in models of orthotopic single lung transplantation (LT) versus heterotopically implanted tracheal segments in rats.

Methods: We performed 30 orthotopic left single LTs from Fisher 344 (F344) to Wistar Kyoto (WKY) rats for comparison with the outcomes of 3 tracheal segments implanted subcutaneously in every recipient. As a control group, 3 syngeneic tracheal segments were implanted into 12 WKY rats. For histopathologic examinations, tracheal segments and pulmonary allografts were harvested between days 1 and 112 and between weeks 4 and 18, respectively.

Results: Allogeneic tracheal segments showed rapid fragmentation of the respiratory epithelium, with complete luminal occlusion by week 4, whereas the lumen in isografts remained unobstructed. In contrast, bronchioles from orthotopically transplanted lungs did not show epithelial changes before week 14. However, marked lymphocytic sequestration into bronchioles occurred by week 8 with sequential destruction of all layers of the small airways, with loss of respiratory epithelium by week 16.

Conclusions: Based on the different histomorphologic dynamics of CR, direct comparison between those 2 models is limited. When investigating CR in future studies, initial findings based on tracheal implantation experiments should be expanded in the site of orthotopic pulmonary transplantation.