Prevention of Postsurgical Lymphedema by 9-cis Retinoic Acid.

ABSTRACT: OBJECTIVE:To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema. BACKGROUND:9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema. METHODS:Lymphedema was induced in the right hind limb after a single fraction of 20?Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08?mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis. RESULTS:Using our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle-treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05). CONCLUSIONS:We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.

SUBMITTER: Bramos A 

PROVIDER: S-EPMC7513676 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature