TGF-β1 is a negative regulator of lymphatic regeneration during wound repair Journal Article
| Authors: | Clavin, N. W.; Avraham, T.; Fernandez, J.; Daluvoy, S. V.; Soares, M. A.; Chaudhry, A.; Mehrara, B. J. |
| Article Title: | TGF-β1 is a negative regulator of lymphatic regeneration during wound repair |
| Abstract: | Although clinical studies have identified scarring/fibrosis as significant risk factors for lymphedema, the mechanisms by which lymphatic repair is impaired remain unknown. Transforming growth factor -β1 (TGF-β1) is a critical regulator of tissue fibrosis/scarring and may therefore also play a role in the regulation of lymphatic regeneration. The purpose of this study was therefore to assess the role of TGF- β1 on scarring/fibrosis and lymphatic regeneration in a mouse tail model. Acute lymphedema was induced in mouse tails by full-thickness skin excision and lymphatic ligation. TGF-β1 expression and scarring were modulated by repairing the wounds with or without a topical collagen gel. Lymphatic function and histological analyses were performed at various time points. Finally, the effects of TGF-β1 on lymphatic endothelial cells (LECs) in vitro were evaluated. As a result, the wound repair with collagen gel significantly reduced the expression of TGF-β1, decreased scarring/ fibrosis, and significantly accelerated lymphatic regeneration. The addition of recombinant TGF-β1 to the collagen gel negated these effects. The improved lymphatic regeneration secondary to TGF-β1 inhibition was associated with increased infiltration and proliferation of LECs and macrophages. TGF-β1 caused a dose-dependent significant decrease in cellular proliferation and tubule formation of isolated LECs without changes in the expression of VEGF-C/D. Finally, the increased expression of TGF-β1 during wound repair resulted in lymphatic fibrosis and the coexpression of α-smooth muscle actin and lymphatic vessel endothelial receptor-1 in regenerated lymphatics. In conclusion, the inhibition of TGF-β1 expression significantly accelerates lymphatic regeneration during wound healing. An increased TGF-β1 expression inhibits LEC proliferation and function and promotes lymphatic fibrosis. These findings imply that the clinical interventions that diminish TGF-β1 expression may be useful in promoting more rapid lymphatic regeneration. Copyright © 2008 the American Physiological Society. |
| Keywords: | controlled study; protein expression; histopathology; nonhuman; pathophysiology; cell proliferation; mouse; animal; metabolism; animals; mice; animal tissue; cell infiltration; animal experiment; animal model; cell motion; drug effect; pathology; risk factor; mice, inbred c57bl; time; time factors; c57bl mouse; endothelium cell; gel; lymph vessel; lymph vessel endothelium; lymphangiogenesis; lymphedema; skin; tail; wound healing; fibrosis; gels; lymphatic vessels; vascular endothelial growth factor c; recombinant proteins; recombinant protein; collagen; transforming growth factor beta1; fibroblast; fibroblasts; cell movement; myofibroblast; macrophage; macrophages; ligation; scar; intradermal drug administration; administration, cutaneous; transforming growth factor-β1; cicatrix; excisional wound healing; recombinant transforming growth factor beta; recombinant transforming growth factor beta1; endothelium, lymphatic |
| Journal Title: | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume: | 295 |
| Issue: | 5 |
| ISSN: | 0363-6135 |
| Publisher: | American Physiological Society |
| Date Published: | 2008-11-01 |
| Start Page: | H2113 |
| End Page: | H2127 |
| Language: | English |
| DOI: | 10.1152/ajpheart.00879.2008 |
| PUBMED: | 18849330 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 23" - "Export Date: 17 November 2011" - "CODEN: AJPPD" - "Source: Scopus" |
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