oxazolone and Lymphedema

Lymphatic vessels play an important role in body fluid, as well as immune system homeostasis. Although the role of malfunctioning or missing lymphatics has been studied extensively, less is known on the functional consequences of a chronically expanded lymphatic network or lymphangiogenesis.. To this end, we used K14-VEGF-C (keratin-14 vascular endothelial growth factor-C) transgenic mice overexpressing the vascular endothelial growth factor C in skin and investigated the responses to inflammatory and fluid volume challenges. We also recorded interstitial fluid pressure, a major determinant of lymph flow. Transgenic mice had a strongly enhanced lymph vessel area in skin. Acute inflammation induced by lipopolysaccharide and chronic inflammation by delayed-type hypersensitivity both resulted in increased interstitial fluid pressure and reduced lymph flow, both to the same extent in wild-type and transgenic mice. Hyperplastic lymphatic vessels, however, demonstrated enhanced transport capacity after local fluid overload not induced by inflammation. In this situation, interstitial fluid pressure was increased to a similar extent in the 2 strains, thus, suggesting that the enhanced lymph vessel area facilitated initial lymph formation. The increased lymph vessel area resulted in an enhanced production of the chemoattractant CCL21 that, however, did not result in augmented dendritic cell migration after induction of local skin inflammation by fluorescein isothiocyanate.. An expanded lymphatic network is capable of enhanced chemoattractant production, and lymphangiogenesis will facilitate initial lymph formation favoring increased clearance of fluid in situations of augmented fluid filtration.

Topics: Animals; Chemokine CCL21; Chemotaxis; Dendritic Cells; Dermatitis, Allergic Contact; Disease Models, Animal; Extracellular Fluid; Female; Fluid Shifts; Fluorescein-5-isothiocyanate; Genotype; Keratin-14; Lipopolysaccharides; Lymph; Lymphangiogenesis; Lymphatic Vessels; Lymphedema; Male; Mice, Inbred C3H; Mice, Transgenic; Oxazolone; Phenotype; Pressure; Promoter Regions, Genetic; Signal Transduction; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor C

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.

Topics: Acute Disease; Animals; Female; Forelimb; Inflammation; Lymph Node Excision; Lymphatic System; Lymphedema; Lymphography; Models, Animal; Oxazolone; Rats; Rats, Sprague-Dawley