Sex-Related Differences in the Mouse Tail Lymphedema Model
Kevin Kuonqui, Adana-Christine Campbell, Hyeung Ju Park, Stav Brown, Ananta Sarker, Jinyeon Shin, Raghu P. Kataru, Babak Mehrara
Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Background: The mouse tail model is frequently used to study post-surgical lymphedema. We have anecdotally observed that male mice have significantly more inflammation and swelling compared with female mice. Although primary lymphedema is more common in females, the effect of sex on secondary lymphedema remains largely unknown. The purpose of this study was, therefore, to study the effect of sex on tail lymphedema in the mouse tail model
Methods: We performed microsurgical tail lymphatic excision on male and female wildtype (WT) and constitutive iNOS knockout (iNOS-KO) mice. To assess the progression of the lymphedema phenotype, we performed weekly tail diameter measurements over a 6-week period. Each week, we also recorded the number of necrosed tails in each group. Additionally, we assessed fibroadipose deposition using histology and immune cell tissue infiltration using immunofluorescence (IF) and flow cytometry with anti-CD45 antibodies
Results: WT male mice had markedly increased tail swelling shortly after surgery compared with female mice. We found higher rates of tail necrosis in WT males compared to females. Additionally, WT males that did not have tail necrosis tended to have increased swelling at each time point after surgery. We found that iNOS-KO males had reduced necrosis rates compared with WT mice; although tail volumes did not significantly differ in the tails that did survive until 6 wk postop. The loss of iNOS in female mice had no effect on tail necrosis or tail volumes over time. iNOS KO male mice had decreased dermal fibroadipose deposition on histology and reduced numbers of CD45+ (pan-leukocyte marker) cells on IF and flow cytometry at 6 wk compared with WT males
Conclusion: Our preliminary findings suggest that male mice have an increased propensity for developing inflammation and oxidative stress after lymphatic injury. Our findings further suggest that anti-oxidative treatments may have some efficacy for preventing/treating lymphedema. Future studies will determine how oxidative stress injures lymphatics, and how sex-related differences contribute to primary or secondary lymphedema
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