TGF-β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation Journal Article
| Authors: | Baik, J. E.; Park, H. J.; Kataru, R. P.; Savetsky, I. L.; Ly, C. L.; Shin, J.; Encarnacion, E. M.; Cavali, M. R.; Klang, M. G.; Riedel, E.; Coriddi, M.; Dayan, J. H.; Mehrara, B. J. |
| Article Title: | TGF-β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation |
| Abstract: | Background: Secondary lymphedema is a common complication of cancer treatment, and previous studies have shown that the expression of transforming growth factor-beta 1 (TGF-beta 1), a pro-fibrotic and anti-lymphangiogenic growth factor, is increased in this disease. Inhibition of TGF-beta 1 decreases the severity of the disease in mouse models; however, the mechanisms that regulate this improvement remain unknown. Methods: Expression of TGF-beta 1 and extracellular matrix molecules (ECM) was assessed in biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL). The effects of TGF-beta 1 inhibition using neutralizing antibodies or a topical formulation of pirfenidone (PFD) were analyzed in mouse models of lymphedema. We also assessed the direct effects of TGF-beta 1 on lymphatic endothelial cells (LECs) using transgenic mice that expressed a dominant-negative TGF-beta receptor selectively on LECs (LECDN-RII). Results: The expression of TGF-beta 1 and ECM molecules is significantly increased in BCRL skin biopsies. Inhibition of TGF-beta 1 in mouse models of lymphedema using neutralizing antibodies or with topical PFD decreased ECM deposition, increased the formation of collateral lymphatics, and inhibited infiltration of T cells. In vitro studies showed that TGF-beta 1 in lymphedematous tissues increases fibroblast, lymphatic endothelial cell (LEC), and lymphatic smooth muscle cell stiffness. Knockdown of TGF-beta 1 responsiveness in LECDN-RII resulted in increased lymphangiogenesis and collateral lymphatic formation; however, ECM deposition and fibrosis persisted, and the severity of lymphedema was indistinguishable from controls. Conclusions: Our results show that TGF-beta 1 is an essential regulator of ECM deposition in secondary lymphedema and that inhibition of this response is a promising means of treating lymphedema. |
| Keywords: | gene; inflammation; fibrosis; lymphatic vessels; pirfenidone; breast-cancer; quality-of-life; growth-factor-beta; tgf-beta; transforming growth-factor-beta-1; animal-models; pulmonary-fibrosis; knockout mice; adenoviral vegf-c |
| Journal Title: | Clinical and Translational Medicine |
| Volume: | 12 |
| Issue: | 6 |
| ISSN: | 2001-1326 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2022-06-01 |
| Start Page: | e758 |
| Language: | English |
| ACCESSION: | WOS:000804551500001 |
| DOI: | 10.1002/ctm2.758 |
| PROVIDER: | wos |
| PMCID: | PMC9160979 |
| PUBMED: | 35652284 |
| Notes: | Author Michele R. Cavalli's last name is misspelled in publisher record and PDF -- Source: Wos |
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