Pathological Changes of Lymphedematous Skin: Increased Mast Cells, Related Proteases, and Activated Transforming Growth Factor-β1.

BACKGROUND: Skin fibrosis is a clinically serious pathological process of secondary lymphedema (SLE). Previous studies have shown that mast cells (MCs) are involved in lymphedema (LE) and play a key role in the pathological process of skin fibrosis. However, the role of the protease chymase and transforming growth factor-β1 (TGF-β1) secreted by MCs in the fibrotic skins of patients with secondary lower limb LE has not been explored.

METHODS AND RESULTS: In this study, full-thickness skin biopsies of lymphedematous limbs from seven SLE patients and control samples from seven healthy controls were harvested. The skin samples were assayed by Masson, immunohistochemical, and immunofluorescence staining and were analyzed by western blot and enzyme-linked immunosorbent assay. The number of MCs and the expression of proteases, TGF-β1, and latency-associated peptide TGF-β1 (LAP TGF-β1) were analyzed. The number of MCs and the expression of chymase, TGF-β1, and LAP TGF-β1 were increased in fibrotic skin compared with normal skin. The increased expression of TGF-β1 on lymphatic vessels, endothelial cells, and in skin interstitial tissues overlapped with chymase expression.

CONCLUSIONS: Our results demonstrate that chymase and TGF-β1 expression was significantly increased in the fibrotic skin of secondary lower limb LE. The increased expression of chymase in the skin may play an important role in the development fibrosis in the lymphedematous skin. We speculate that chymase may facilitate the release of LAP TGF-β1 to generate activated TGF-β1, and the upregulation of active TGF-β1 can promote fibrosis in the SLE skin.