1468 Lymphatic dysfunction affects both collagen degradation and collagen synthesis, leading to a paradoxical reduction in dermal fibrosis

Lymphedema (tissue swelling caused by an accumulation of lymph fluid) in the lower legs is relatively common elderly people. Dermal fibrosis and hyperkeratotic verrucous lesions setting long-standing lymphedema, called elephantiasis verrucosa nostra, can develop some patients, although mechanisms underlying these tissue changes are unknown. Here, we studied effects lymphedema on skin using k-cyclin transgenic (kCYC+/−) mice, which demonstrate severe lymphatic dysfunction. Unperturbed, kCYC+/− mice paradoxically demonstrated decreased collagen content compared to wild-type (WT) (70% WT mice). Similarly, quantitative RT-PCR, low mRNA expression levels for Col1a1, Col1a3, Tgfb1, Pdgfb lymphedematous (10-50%). Next, fibrotic responses following daily subcutaneous injections bleomycin (BLM) (vs. saline) 4 weeks. Increased dermal thickness were observed both BLM-injected mice. However, BLM-induced (75%). RT-PCR revealed increased Col1a1 Ctgf mRNAs (230% 170%) as well Mmp13 Il6 (270% 180%) kCYC+/−mice lesional skin, suggesting that synthesis degradation enhanced lymphedema. Taken together, results suggest dysfunction affects synthesis, leading a paradoxical reduction fibrosis.