Mouse tail models of secondary lymphedema: fibrosis gradually worsens and is irreversible.

Although the mouse tail model of secondary lymphedema has been widely used in research, our knowledge regarding some of the characteristic changes in this model is lacking. Therefore, in the current study, we aimed to identify pathologic changes after surgery. Tail lymphedema was created in C57BL/6J mice by disconnecting both superficial and deep lymphatic vessels. The surgery resulted in chronic edema formation with the proliferation of subcutaneous adipose tissue, deposition of fibrotic tissue, and gradual increase in CD4 T lymphocyte infiltration. Furthermore, dramatic expansion and an increased number of lymphatic vessels were observed postoperatively. Lymphatic reflux was established at least 8 weeks after surgery, as evidenced by staining of the scar from the surgical excision. In addition, tissue fibrosis was irreversible, although CD4 T cell infiltration, tail swelling, and subcutaneous adipose hyperplasia were alleviated over time. We also show that necrosis could be effectively avoided by paying attention to several details in the modeling process. As animal models play a key role in exploring the pathophysiology of disease, our findings provide strong support for the study of lymphedema. The irreversibility of fibrosis suggests the importance of treating lymphedema by preventing fibrosis development.