A chronic and latent lymphatic insufficiency follows recovery from acute lymphedema in the rat foreleg

Abstract

Secondary lymphedema in humans is a common consequence of axillary lymph node dissection (ALND) to treat breast cancer. Remarkably, secondary lymphedema generally first appears following a delay of over a year and can be triggered suddenly by an inflammatory insult. However, it remains unclear why the apparently functional lymphatic system is unable to accommodate an inflammatory trigger. To provide mechanistic insight into the delayed and rapid secondary lymphedema initiation, we compared the ability of the ALND-recovered rat foreleg lymphatic system to prevent edema during an inflammatory challenge with that of the uninjured lymphatic system. At 73 days postsurgery, the forelegs of ALND−- and ALND+-sensitized rats were exposed to the proinflammatory agent oxazolone, which was found to reduce fluid drainage and increase skin thickness in both ALND− and ALND+ forelegs ( P < 0.05). However, drainage in the ALND-recovered forelegs was more severely impaired than ALND− forelegs, as visualized by indocyanine green lymphography and quantified by interstitial transport of fluid marker ( P < 0.05). Although both ALND+ and ALND− forelegs experienced significant inflammation-induced edema with the oxazolone exposure ( P < 0.05), the peak tissue swelling in the ALND+ group was significantly greater than that of the ALND− forelegs (arm area peaked at ∼13.4 vs. ∼5.7% swelling, respectively, P < 0.005; wrist diameter peaked at 9.7 vs. 2.2% swelling, respectively, P < 0.005). The findings demonstrate that outward recovery from ALND in the rat foreleg masks an ensuing chronic and latent lymphatic insufficiency, which reduces the ability of the foreleg lymphatic system to prevent edema during an acute inflammatory process.