Background: Secondary extremity lymphedema is a chronic and progressive condition
caused by obstructed lymphatic drainage, commonly following lymphadenectomy, infection,
or trauma. Rodent models are preferred for experimental lymphedema research due to
cost-effectiveness and reproducibility. Currently, rat tail models encounter limitations
due to transient swelling and their inability to fully replicate the comprehensive
pathophysiology of lymphedema, particularly concerning the effects of lymph node removal.
Methods: We developed a series of rat tail lymphedema models incorporating skin resection,
deep lymphatic vessel disruption, and gluteal lymph node (GLN) excision to assess
effects on lymphatic architecture, inflammation, and fibrosis. Indocyanine green (ICG)
lymphography was used to visualize lymphatic function. Tail volume and circumference
were measured weekly, and histological assessments quantified fibrosis and fibroadipose
thickening. Bulk RNA sequencing was performed to characterize the inflammatory processes
triggered by GLN removal.
Results: The combined model (skin removal, deep lymphatic disruption and GLN excision)
resulted in severe and persistent lymphedema marked by progressive swelling and pronounced
fibrosis. ICG lymphography confirmed disruption of superficial lymphatic flow with
partial recanalization of deep channels. Notably, lymphangiogenesis was observed at
the GLN excision site, forming compensatory pathways connecting the tail to popliteal
lymph nodes. Histology revealed extensive collagen deposition and fibroadipose thickening
in groups with lymph node removal, with the combined model showing the most pronounced
changes. Bulk-RNA sequencing confirmed the removal of GLN involving inflammatory and
fibrosis process in tail model.
Conclusion: This lymphosome-based rat tail model successfully replicates key features
of lymphedema, including sustained swelling, lymphatic disruption, inflammation and
fibrosis.
