SUMMARY

Lymphedema is a devastating disease that predominantly affects breast cancer patients post-surgery, leading to swelling at the extremities and tissue fibrosis. There are currently no pharmacological treatments available for lymphedema. However, LTB4, a metabolite of arachidonic acid, has been implicated in the development of lymphedema and identified as a possible drug target. The objective of this study is to determine if LTB4 drives lymphatic collecting vessel failure. The hypothesis is that LTB4 inhibits lymphatic collecting vessel contraction at high concentrations occurring post-injury, leading to lymphatic failure. We predict that this functional effect of LTB4 occurs through two mechanisms; LTB4 directly acts on lymphatic collecting vessels to inhibit pumping and LTB4 drives macrophage recruitment to the site of injury. First, we will test LTB4’s direct effect on lymphatic collecting vessel contractility. Next, an LTB4 antagonist will be used to treat mice induced with lymphedema to study how LTB4 affects collecting vessel function during disease progression. A genetic macrophage depletion mouse model will be used to examine if there is a macrophage-mediated effect of LTB4 on collecting vessel pump function during lymphedema development. The results of this study will help identify multiple mechanisms by which LTB4 drives lymphatic collecting vessel pump failure.