Blockade of Transforming Growth Factor-β1 Accelerates Lymphatic Regeneration during Wound Repair

Lymphedema is a complication of cancer treatment occurring in approximately 50% of patients who undergo lymph node resection Despite its prevalence, the etiology of this disorder remains unknown In this study we determined the effect of soft tissue fibrosis on lymphatic function and the role of transforming growth factor (TGF)-beta 1 in the regulation of this response We determined TGF beta expression patterns m matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF beta in regulating tissue fibrosis we used a mouse model of lymphedema and inhibited TGF function either systemically with a monoclonal antibody or locally by using a soluble defective TGF beta receptor Lymphedematous tissue demonstrated a nearly threefold increase in the number of cells that stained for TGF beta 1 TGF beta inhibition markedly decreased tissue fibrosis increased lymphangiogenesis and improved lymphatic function compared with controls In addition inhibition of TGF beta not only decreased TGF beta expression in lymphedematous tissues but also diminished inflammation migration of T helper type 2 (Th2) cells and expression of profibrotic Th2 cytokines Similarly systemic depletion of T cells markedly decreased TGF beta expression in tail tissues Inhibition of TGF beta function promoted lymphatic regeneration decreased tissue fibrosis decreased chronic inflammation and Th2 cell migration and improved lymphatic function The use of these strategies may represent a novel means of preventing lymphedema after lymph node resection (Am J Pathol 2010 177 3202-3214, DOI 10 2353/ajpath 2010 100594)