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Inhibition of TGF\u2010\u03b21 decreases the severity of the disease in mouse models; however, the mechanisms that regulate this improvement remain unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of TGF\u2010\u03b21 and extracellular matrix molecules (ECM) was assessed in biopsy specimens from patients with unilateral breast cancer\u2010related lymphedema (BCRL). The effects of TGF\u2010\u03b21 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\u2010\u03b21 on lymphatic endothelial cells (LECs) using transgenic mice that expressed a dominant\u2010negative TGF\u2010\u03b2 receptor selectively on LECs (LEC<jats:sup>DN\u2010RII<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expression of TGF\u2010\u03b21 and ECM molecules is significantly increased in BCRL skin biopsies. Inhibition of TGF\u2010\u03b21 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\u2010\u03b21 in lymphedematous tissues increases fibroblast, lymphatic endothelial cell (LEC), and lymphatic smooth muscle cell stiffness. Knockdown of TGF\u2010\u03b21 responsiveness in LEC<jats:sup>DN\u2010RII<\/jats:sup> resulted in increased lymphangiogenesis and collateral lymphatic formation; however, ECM deposition and fibrosis persisted, and the severity of lymphedema was indistinguishable from controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results show that TGF\u2010\u03b21 is an essential regulator of ECM deposition in secondary lymphedema and that inhibition of this response is a promising means of treating lymphedema.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.758","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T08:24:23Z","timestamp":1654158263000},"source":"Crossref","is-referenced-by-count":82,"title":["TGF\u2010\u03b21 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation"],"prefix":"10.1002","volume":"12","author":[{"given":"Jung 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