Fibrosis worsens chronic lymphedema in rodent tissues

Abstract

Secondary lymphedema in humans is a common consequence of lymph node dissection (LND) to treat breast cancer. A peculiar characteristic of the disease is that lifelong swelling often precipitously appears several years after the surgical treatment, often due to an inflammatory stimulus. Although the incidence of secondary lymphedema dramatically increases after radiation therapy, the relationship between fibrotic scarring and the eventual appearance of lymphedema remains unclear. To clarify the role of fibrosis in secondary lymphedema initiation, we chemically increased fibrosis in rodent tissues with bleomycin and assessed the ability of the local lymphatic system to prevent lymphedema, either acutely or in a chronic state induced by inflammation. We found that bleomycin injections exacerbated fibrotic matrix deposition in an acute mouse tail lymphedema model (P < 0.005), reduced wound closure (P < 0.005), and impaired the ability of tail lymphatics to regenerate (P < 0.005) and reduce the swelling (P < 0.05). When fibrosis was worsened with bleomycin after axillary LND in the rat foreleg, the ability of the foreleg lymphatic system to reduce the chronic state swelling induced by stimulated inflammation was severely impaired (P < 0.005). Indocyanine green lymphography in axillary LND-recovered rat forelegs revealed a worsened lymphatic drainage due to inflammation and bleomycin pretreatment. Although inflammation reduced the drainage of dextran fluid tracer from control forelegs (P < 0.05), the reduction in fluid drainage was more severe after axillary LND when fibrosis was first increased (P < 0.005). These findings demonstrate that fibrosis reduces the lymphatic capacity to functionally regenerate and prevent the chronic appearance of lymphedema.

The Unresolved Pathophysiology of Lymphedema

“…In addition, fibrosis in the skin and subcutaneous tissue may worsen lymphatic vessel dysfunction by directly inhibiting lymphatic endothelial cell proliferation and preventing the sprouting and branching of new lymphatic vessels. This is supported by findings in mice and rat models demonstrating that fibrosis negatively regulates lymphatic flow and lymphangiogenesis, which in turn aggravate swelling, fluid transport and lymph drainage (Lynch et al, 2015). However, when fibrosis was inhibited, lymphatic vessel repair and transport were improved, slowing down the progression of lymphedema (Avraham et al, 2009(Avraham et al, , 2010Savetsky et al, 2014).…”

Lymphatic pumping: mechanics, mechanisms and malfunction

“…This process is accelerated by the application of vascular endothelial growth factor C (VEGF-C), which promotes lymphangiogenesis (Yoon et al 2003;Rutkowski et al 2006), or the blockade of IL-4 and TGFβ, which otherwise inhibit lymphangiogenesis (Clavin et al 2008;Avraham et al 2010Avraham et al , 2013. Similar patterns emerge in experiments using the rat axillary node oxazolone/dissection model, suggesting that fibrosis plays an important role in inflammation-induced swelling in that preparation (Lynch et al 2015).…”

“…Similar patterns emerge in experiments using the rat axillary node oxazolone/dissection model, suggesting that fibrosis plays an important role in inflammation‐induced swelling in that preparation (Lynch et al . ).…”

Lymphatic Dysfunction, Leukotrienes, and Lymphedema

“…Although it is commonly accepted that lymph stasis and chronic inflammation eventually cause tissue fibrotic remodeling, there is evidence that fibrosis can also, conversely, impact edema and inflammation. In one study, administration of bleomycin around the postsurgical wound site significantly exacerbates tissue swelling, lymphatic vessel regeneration, and lymph drainage (141). Thus, edema-induced chronic inflammation and fibrosis may act bidirectionally to promote lymphedema progression.…”