Although
radiation therapy is a major risk factor for the development of
lymphedema following
lymphadenectomy, the mechanisms responsible for this effect remain unknown. The purpose of this study was therefore to determine the effects of radiation on lymphatic endothelial cells (LECs) and lymphatic function. The tails of wild-type or
acid sphingomyelinase (ASM)-deficient mice were treated with 0, 15, or 30 Gy of radiation and then analyzed for LEC apoptosis and lymphatic function at various time points. To analyze the effects of
radiation fibrosis on lymphatic function, we determined the effects of
transforming growth factor (TGF)-beta1 blockade after radiation in vivo. Finally, we determined the effects of radiation and exogenous
TGF-beta1 on LECs in vitro. Radiation caused mild
edema that resolved after 12-24 wk. Interestingly, despite resolution of tail
edema, irradiated animals displayed persistent lymphatic dysfunction. Radiation caused loss of capillary lymphatics and was associated with a dose-dependent increase in LEC apoptosis. ASM-/- mice had significantly less LEC apoptosis; however, this finding did not translate to improved lymphatic function at later time points. Short-term blockade of
TGF-beta1 function after radiation markedly decreased tissue
fibrosis and significantly improved lymphatic function but did not alter LEC apoptosis.
Radiation therapy decreases lymphatic reserve by causing depletion of lymphatic vessels and LECs as well as promoting soft tissue
fibrosis. Short-term inhibition of
TGF-beta1 activity following radiation improves lymphatic function and is associated with decreased soft tissue
fibrosis.
ASM deficiency confers LEC protection from radiation-induced apoptosis but does not prevent lymphatic dysfunction.