Blockade of transforming growth factor-beta1 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)-β1 in the regulation of this response. We determined TGF-β expression patterns in matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF-β in regulating tissue fibrosis, we used a mouse model of lymphedema and inhibited TGF-β function either systemically with a monoclonal antibody or locally by using a soluble, defective TGF-β receptor. Lymphedematous tissue demonstrated a nearly threefold increase in the number of cells that stained for TGF-β1. TGF-β inhibition markedly decreased tissue fibrosis, increased lymphangiogenesis, and improved lymphatic function compared with controls. In addition, inhibition of TGF-β not only decreased TGF-β 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-β expression in tail tissues. Inhibition of TGF-β 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.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Tomer
T
Avraham
Sanjay
S
Daluvoy
Jaime
J
Zampell
Alan
A
Yan
Yosef S
YS
Haviv
Stanley G
SG
Rockson
Babak J
BJ
Mehrara
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008209:Lymphedema / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D018418:Th2 Cells / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects* / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D053773:Transforming Growth Factor beta1