A lymphadenectomy and irradiation-induced rat lymphedema model exhibits persistent dermal backflow and region-dependent fibrosis-associated remodeling.

BACKGROUND AND AIMS: Secondary lymphedema is characterized by persistent lymphatic dysfunction and tissue remodeling after oncological treatment. Existing rodent models often show spontaneous recovery and are evaluated using limited endpoints. We aimed to establish a persistent rat hindlimb model and characterize its temporal and spatial progression through integrated functional, histological, tissue-level, and circulating assessments.

METHODS

Secondary lymphedema is characterized by persistent lymphatic dysfunction and tissue remodeling after oncological treatment. Existing rodent models often show spontaneous recovery and are evaluated using limited endpoints. We aimed to establish a persistent rat hindlimb model and characterize its temporal and spatial progression through integrated functional, histological, tissue-level, and circulating assessments.

RESULTS

Both groups exhibited severe early dermal backflow. By weeks 4-6, control hindlimbs showed partial restoration of organized linear drainage, whereas lymphedema hindlimbs retained significantly higher dermal backflow scores and persistent unorganized drainage. At week 6, all lymphedema hindlimbs remained within Type IIIa or IIIb categories. Dermal thickness was greater in lymphedema hindlimbs at both anatomical sites. Immunofluorescence showed directionally higher collagen III and α-SMA signals in subsets of paired lymphedema tissues; however, none of the comparisons reached statistical significance, and substantial inter-animal variability was observed. Circulating α-SMA was significantly higher in the lymphedema group at days 1 and 7, whereas PIIINP was numerically higher at days 7 and 15 without significant between-group differences.

CONCLUSION

Radical lymphadenectomy combined with circumferential skin resection and localized irradiation produced persistent lymphatic impairment and sustained regional dermal remodeling. Collagen III and α-SMA immunofluorescence provided additional evidence of heterogeneous fibrosis-associated tissue changes. Circulating α-SMA may provide a complementary systemic readout, whereas PIIINP remains exploratory. This multimodal model offers a preclinical framework for studying secondary lymphedema progression and evaluating therapeutic strategies.