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.

journal_name

Ann Surg

journal_title

Annals of surgery

authors

Bramos A,Perrault D,Yang S,Jung E,Hong YK,Wong AK

doi

10.1097/SLA.0000000000001525

subject

Has Abstract

pub_date

2016-08-01 00:00:00

pages

353-61

issue

2

eissn

0003-4932

issn

1528-1140

journal_volume

264

pub_type

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