Abstract
Although surgery and radiation are beneficial for treating cancer, they can also lead to malfunctions of the lymphatic system such as secondary lymphedema. This abnormality of the lymphatic system is characterized by severe swelling, adipogenesis, inflammation, and fibrosis in the lymphedematous region. Moreover, the proliferation of fibrotic tissue in the lymphedematous region generates edema that is no longer spontaneously reversible. No treatment for fibrosis has been validated in patients with lymphedema. In our efforts to develop a therapeutic agent for lymphedema fibrosis, we used a newly established mouse hind limb model. Previous studies have demonstrated that hyaluronic acid accumulates in the lymphedematous region. Thus, we challenged mice with of hyaluronidase (HYAL), with the aim of reducing fibrogenesis. After subcutaneous injections in the lymphedematous mouse leg every two days, the volume of lymphedema had reduced significantly by 7 days post-operation. Histochemical analysis indicated that collagen accumulation and myofibroblast differentiation were decreased in epidermal tissues after HYAL injection. Moreover, it was associated with upregulation of interferon-gamma, increased numbers of Th1 cells, and downregulation of interleukin-4 and interleukin-6 in the lymphedematous region and spleen. These results indicate that hydrolysis of hyaluronic acid can boost an anti-fibrotic immune response in the mouse lymphedema model.
Highlights
Fibrosis is part of a two-stage repair process in which connective tissue replaces normal parenchymal tissue via fibroblast proliferation and activation[7]
Western blot analysis revealed that two molecular markers of lymphedema vascular endothelial growth factor receptor 3 (VEGFR-3) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) were upregulated in the mice with lymphedema compared with the control and sham-operated mice
We established lower limb lymphedema mouse model through removing the superficial inguinal lymph node, the popliteal lymph node, the deep inguinal lymph node, and the femoral lymphatic vessel. This mouse model presented tissue swelling and formation of edema occurred as consequences of abnormal lymphatic system and exhibited typical expression patterns of lymphedema markers such as VEGFR-3, LYVE-1, and α-SMA, in addition to collagen accumulation
Summary
Fibrosis is part of a two-stage repair process in which connective tissue replaces normal parenchymal tissue via fibroblast proliferation and activation[7]. Fibroblast activation is characterized by apoptosis, resistance to the overproduction of connective tissue matrix, and an increase in the number of myofibroblasts (which are differentiated from fibroblasts)[8] These fibroblasts are regulated by T-helper 1 (TH1) and T-helper 2 (TH2) cells via various cytokines. Since fibrosis is an important factor in lymphedema and severe accumulation of HA has been observed in lymphedematous regions, we treated mice with lymphedema with hyaluronidase to degrade HA. We hypothesized that this treatment would alleviate lymphedema by decreasing fibrogenesis, promoting wound healing, and inducing cytokine expression changes
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