Mitigation of lymphatic injury by retinoic acid therapy in a large animal model

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Lymphedema is an incurable condition characterized by lymphatic obstruction, tissue swelling, immune dysfunction, and fibrosis after lymphatic injury. Lymphedema affects 5 million Americans and is associated with poor quality of life due to extremity disability, disfigurement, and risk for recurrent limb-threatening infection. In the US, lymphedema is most commonly a consequence of lymph node dissection for the treatment of malignancies such as breast or pelvic tumors. Once established, this disease is progressive and difficult to treat. We have previously demonstrated that administration of 9-cis retinoic acid (9-cis RA) at the time of lymphatic injury can stimulate lymphangiogenesis and mitigate disease progression in mice. A critical step in translating these findings to the clinical setting involves demonstrating efficacy in a second, non-rodent, large animal model. To address this, we have chosen swine due to the fact that it has soft tissue anatomy and physiology that is more similar to human than rodent models. While the central goal of this proposal will be to determine if 9-cis RA can prevent postsurgical lymphedema in swine, the two specific aims of this proposal include Aim 1: To determine the effect of 9-cis RA on limb volume, MRI characteristics, and lymphatic transport after critical lymphatic injury in swine; and Aim 2: To assess the effect of 9-cis RA on the histopathological and molecular changes in tissues at the site of critical lymphatic injury in swine. Completion of this proposal will yield highly relevant and translatable findings that will facilitate development of a 9-cis RA based therapeutic approach to prevention and management of secondary lymphedema in humans.