J. Brandon Dixon, Ph.D. (Georgia Institute of Technology)

Committee:

Krishnendu Roy, Ph.D. (Georgia Institute of Technology)

Rudolph Gleason, Ph.D. (Georgia Institute of Technology)

Fredrik Vannberg, Ph.D. (Georgia Institute of Technology)

Mark Nicolls, M.D. (Stanford University School of Medicine)

The role of leukotriene B₄ in driving lymphatic failure in lymphedema

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.