Fibrosis is a key inhibitor of lymphatic regeneration.
BACKGROUND
Lymphedema is a common debilitating sequela of lymph node dissection. Although numerous clinical studies suggest that factors that lead to fibrosis are associated with the development of lymphedema, this relationship has not been proven. The purpose of these experiments was therefore to evaluate lymphatic regeneration in the setting of variable soft-tissue fibrosis.


METHODS
A section of mouse tail skin including the capillary and collecting lymphatics was excised. Experimental animals (n = 20) were treated with topical collagen type I gel and a moist dressing, whereas control animals (n = 20) underwent excision followed by moist dressing alone. Fibrosis, acute lymphedema, lymphatic function, gene expression, lymphatic endothelial cell proliferation, and lymphatic fibrosis were evaluated at various time points.


RESULTS
Collagen gel treatment significantly decreased fibrosis, with an attendant decrease in acute lymphedema and improved lymphatic function. Tails treated with collagen gel demonstrated greater numbers of lymphatic vessels, more normal lymphatic architecture, and more proliferating lymphatic endothelial cells. These findings appeared to be independent of vascular endothelial growth factor C expression. Decreased fibrosis was associated with a significant decrease in the expression of extracellular matrix components. Finally, decreased soft-tissue fibrosis was associated with a significant decrease in lymphatic fibrosis as evidenced by the number of lymphatic endothelial cells that coexpressed lymphatic and fibroblast markers.


CONCLUSIONS
Soft-tissue fibrosis is associated with impairment in lymphatic regeneration and lymphatic function. These defects occur as a consequence of impaired lymphatic endothelial cell proliferation, abnormal lymphatic microarchitecture, and lymphatic fibrosis. Inhibition of fibrosis using a simple topical dressing can markedly accelerate lymphatic repair and promote regeneration of normal capillary lymphatics.
Avraham
Tomer
T
New York, N.Y. From the Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center.
Clavin
Nicholas W
NW
Daluvoy
Sanjay V
SV
Fernandez
John
J
Soares
Marc A
MA
Cordeiro
Andrew P
AP
Mehrara
Babak J
BJ
D000818:Animals; D049109:Cell Proliferation; D024042:Collagen Type I / Q000008:administration & dosage; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005355:Fibrosis; D005782:Gels; D007150:Immunohistochemistry; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008209:Lymphedema / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D016133:Polymerase Chain Reaction; D012038:Regeneration / Q000502:physiology*; D013623:Tail; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
D024042:Collagen Type I; D005782:Gels; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse