Inhibition Of Fibrosis Decreases The Pathology Of Lymphedema
Gabriela D. García Nores, MD, Jason C. Gardenier, MD, Raghu P. Kataru, PhD, Geoffrey E. Hespe, BS, Jessie Z. Yu, MD, Jung-Ju Huang, MD, Babak J. Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lymphedema is characterized by fibrosis, and there is accumulating evidence that this process plays a key role in the pathology of the disease. We have previously shown that the expression of the profibrotic growth factor TGF-β is increased in lymphedematous tissues. The purpose of this study was to evaluate the efficacy of this topical compound for prevention and treatment of lymphedema.
We developed a novel topical antifibrotic compound and tested its efficacy using mouse tail and popliteal lymphatic ablation models. Control animals were treated with vehicle only. Adipose deposition, lymphatic function, perilymphatic inflammation, and lymphangiogenesis were analyzed. In addition, to test the hypothesis that this topical formulation can treat established lymphedema, we analyzed the efficacy of this treatment using a transgenic model of lymphedema 6 months after lymphedema was established.
Our topical anti-TGF-β compound markedly decreased fibrosis, swelling, and adipose deposition. These changes correlated with improved lymphatic transport function as compared to controls (p<0.001). Similarly, transgenic mice with established lymphedema also had decreased fibrosis, adipose deposition and perilymphatic inflammation when compared to controls. Furthermore, this treatment resulted in significantly decreased perilymphatic T cell inflammation (p<0.005) and markedly increased lymphangiogenesis as assessed by near infra-red imaging and histology.
Treatment with a topical anti-TGF-β compound markedly decreased fibrosis and chronic T cell inflammation and improved lymphangiogenesis in various models of lymphedema and lymphatic dysfunction. These results are exciting as they suggest that topical treatments may be useful clinically.
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