Animal Models for the Study of Lymphatic Insufficiency

Abstract

Lymphedema is the term commonly employed to describe the spectrum of pathological states that arise as a consequence of functional lymphatic insufficiency. These human disease entities currently lack an effective cure. Satisfactory therapeutic strategies for both primary and secondary lymphedema will require additional insight into the complex cellular mechanisms and responses that comprise both normal lymphatic function and its regional derangement in states of pathologic dysfunction. Such insights must, initially, be derived from suitable animal models of the chronic human disease process. Historically, efforts to replicate the untreated disease of human lymphedema in animals, through surgery, irradiation, and toxicology, have been fraught with difficulty. The major impediments to the creation of satisfactory animal models have included an inability to reproduce the chronic disease in a stable, reproducible format. Recently, with the promise of potentially successful growth factor-mediated therapeutic lymphangiogenesis, and with the enhanced availability of investigative tools to assess therapeutic responses to molecular therapies, there has been a resurgence of interest in the development of viable animal models of lymphatic insufficiency. Current research has led to the development of genetic and postsurgical models of lymphedema that closely simulate the human conditions of primary and secondary lymphatic insufficiency, respectively. Such models will help to refine the assessment of various therapeutic approaches and their potential applicability to human disease interventions.

Acquired Lymphedema: An Urgent Need for Adequate Animal Models

“…Surprisingly, all dogs showed improvement of their lymphedema irrespective of the group, suggesting that lympho-lymphatic anastomosis in microsurgical lymph node transplantation has little clinical relevance. Regrettably, no dog presented a complete resolution of the disease (6).…”

“…This model was used to study lymphaticovenous microanastomoses (as reviewed in ref. 6). Researchers showed that postoperative pressure gradients between the lymph and venous blood were inversed when lymphedema tended to resolve, thus causing lymph reflux and thrombosis of the anastomosis.…”

“…6) extensively irradiated the groin of 15 dogs preoperatively with a single dose of 15 Gray (Gy). An extensive excision of all connective tissue, muscle fascia, and deep lymphatics was then performed.…”

“…6) irradiated dogs in the knee with a single dose of 12 Gy. A surgical excision of a circumferential strip of skin and s.c. tissue followed.…”

Insufficient Lymph Drainage Causes Abnormal Lipid Accumulation and Vein Wall Degeneration

“…This was considered to be indicative of insufficient drainage of the lymph that had flowed from the extracellular fluid into the lymph vessels. 8,9) Normal lymph vessels are straight in form, but in cases of lymphostasis, their lumens become enlarged, as is seen in , and 28 days after the procedure, the lymphatic vessels in the lymphatic insufficiency model tissue exhibited significantly greater diameters than those in the control tissue (*P <0 .05). (C) At 28 days after the procedure, the number of lymphatic vessels in the lymphatic insufficiency model tissue was lower than that seen in the control tissue (n = 5, *P <0.05).…”