An Experimental Model for Chronic Lymphedema

Kanter, Mitchel A.; Slavin, Sumner A.; Kaplan, William D.

doi:10.1097/00006534-199004000-00012

Cited by 60 publications

(43 citation statements)

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“…This time frame is sufficient to observe key features of chronic edema, including collagen breakdown and remodeling, lymphatic hyperplasia, and abnormal lipid accumulation in the skin, consistent with pathological features observed in longer studies in other models (Kanter et al, 1990;Olszewski, 1973;Szuba et al, 2002). Responsive changes in the dermal matrix during swelling -initial degradation followed by compensatory rebuilding -were also temporally correlated to lipid accumulation and macrophage infiltration throughout the tissue, both chronic indicators of lymphedema (Piller, 1990;Schirger et al, 1962).…”

Section: Discussionsupporting

confidence: 79%

“…Existing models of secondary lymphedema in the dog hindlimb (Han et al, 1985;Olszewski, 1973), rat hindlimb (Kanter et al, 1990;Wang and Zhong, 1985), or rabbit ear (Szuba et al, 2002) disrupt lymphatic transport through the excision of a circumferential band of skin and subcutaneous tissue. These models can sustain significant lymphedema for 3-4weeks and result in a chronic increase in limb or ear volume.…”

Section: Introductionmentioning

confidence: 99%

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Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9

Rutkowski¹,

Moya²,

Johannes³

et al. 2006

Microvascular Research

210

199

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Disturbances in the microcirculation can lead to secondary lymphedema, a common pathological condition that, despite its frequency, still lacks a cure. Lymphedema is clinically well described, but while the genetic underpinnings that cause lymphatic malformations and primary lymphedema are being discovered, the pathophysiology and pathobiology of secondary lymphedema remain poorly understood, partly due to the lack of well-described experimental models. Here, we provide a detailed characterization of secondary lymphedema in the mouse tail and correlate the evolution of tissue swelling to changes in tissue architecture, infiltration of immune cells, deposition of lipids, and proliferation and morphology of the lymphatic vessels. We show that sustained swelling leads to lymphatic hyperplasia and upregulation of vascular endothelial growth factor (VEGF)-C, which may exacerbate the edema because the hyperplastic vessels are poorly functional. The onset of lymphatic hyperplasia occurred prior to the onset of lipid accumulation and peak VEGF-C expression. Langerhans dendritic cells were seen in the dermis migrating from the epidermis to the lymphatic capillaries in edematous tissue. Furthermore, these results were consistent between two different normal mouse strains, but swelling was significantly greater in a matrix metalloproteinase (MMP)-9 null strain. Thus, by characterizing this highly reproducible model of secondary lymphedema, we conclude that VEGF-C upregulation and lymphatic hyperplasia resulting from dermal lymphatic ligation and lymphedema leads to decreased drainage function and that MMP-9 may be important in counteracting tissue swelling.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9

Rutkowski¹,

Moya²,

Johannes³

et al. 2006

Microvascular Research

210

199

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“…43 Employing a modification of the method of Kanter et al, 44 the investigators explored the capacity of surgery alone (unilateral microsurgical ablation of regional groin lymphatics and lymph nodes), radiation alone, or combined surgery and radiation, to elicit a lymphedema response. A vertical incision in the mid-groin permitted the identification and excision of femoral lymphatics and adjacent groin lymph nodes.…”

Section: Historical Animal Modelsmentioning

confidence: 99%

“…Kanter et al 44 Rat Irradiation and surgical lymphatic 1 division at the groin siently, has attributes of the human disease. 54 This animal expresses a soluble form of the VEGFR3 receptor that, in vitro, has been demonstrated to be a potent inhibitor of VEGF-C and VEGF-D signaling.…”

Section: Current Animal Modelsmentioning

confidence: 99%

Animal Models for the Study of Lymphatic Insufficiency

Shin¹,

Szuba²,

Rockson³

2003

Lymphatic Research and Biology

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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.

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“…Although several experimental animal models, including dog hindlimb (Han et al, 1985), rat hindlimb (Kanter et al, 1990) or rabbit ear (Szuba et al, 2002) have been used for the study of secondary lymphedema by disturbing lymphatic transport through the removal of a circumferential band of skin and subcutaneous tissue, a new mouse model of acquired lymphatic insufficiency, reported by Tabibiazar et al (2006), appears to be suited for molecular studies on this aspect. Therefore, in this study, we used a mouse lymphedema model to detect and identify the free radicals using electron spin resonance (ESR) and spin-trapping methods.…”

Section: Introductionmentioning

confidence: 99%

The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model

Chang

Uen

Chou

et al. 2013

Pharmaceutical Biology

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Context: Oxidative stress may contribute to lymphedema and subsequent tissue damage. However, the causal role of oxidative stress in lymphedema remains unclear. Objective: We attempted to detect and identify the free radicals formed in lymphedema fluid and assessed the protective mechanisms and effects of specific enzyme inhibitors and natural antioxidants. Materials and methods: To study the level of postsurgical oxidative stress with lymphedema in a mouse tail model, we used an electron spin resonance (ESR) method and an ascorbyl radical's ESR spectrum as an oxidative stress biomarker. The drug-treatment group received an i.p. injection with indomethacin (2 mg/kg), baicalein (15 mg/kg), MK-886 (3 mg/kg), zileuton (6.25 mg/kg), diphenyleneiodonium (DPI; 1 mg/kg), sulforaphane (30 mg/kg), oryzanol (30 mg/ kg) or sesamol (30 mg/kg) once daily for 14 d from the day of operation. All animals were sacrificed on day 14. Results: Administration of indomethacin, sulforaphane, oryzanol and sesamol significantly suppressed both the tail volume (56.9%, 77.8%, 72.2% and 38.1% inhibition, respectively, p50.01) and ascorbyl radical signals (31.4%, 54.5%, 79.3% and 57.1% inhibition, respectively, p50.01), compared with the control mice. No significant differences were found between any of the baicalein, MK-886, or zileuton groups compared with the control. DPI suppressed the tail volume (25.9% inhibition, p50.01) but not the ascorbyl radical signals. Conclusion: This study showed that COX-derived oxidative stress plays a major role in the pathological mechanisms of surgically induced lymphedema. Indomethacin, sulforaphane, oryzanol and sesamol exhibit potent protective properties against surgically induced lymphedema.

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An Experimental Model for Chronic Lymphedema

Cited by 60 publications

References 0 publications

Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9

Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9

Animal Models for the Study of Lymphatic Insufficiency

The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model

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