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