Inflammatory Manifestations of Experimental Lymphatic Insufficiency

Abstract

BackgroundSustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic.Methods and FindingsWe studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response.ConclusionsWe have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.

IL-6 regulates adipose deposition and homeostasis in lymphedema

“…Therefore, the ALND model enables us to study the effects of lymph stasis without significant adipose deposition. In contrast, the mouse tail model used in this study enables us to analyze the effects of more profound lymphatic injury and adipose deposition, since we and others have previously shown that this treatment results in substantial subcutaneous adipose deposition and that this process is chronic lasting as long as 12 wk postop (4,11,32,33). Using a direct comparison of these models, we found that IL-6 expression, activation of its downstream mediator, and serum changes in IL-6 concentration occur to a more significant degree in the tail model as compared with the ALND model.…”

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

“…An experimental model of acute postsurgical lymphedema in the tails of mice was set up, as described by Tabibiazar et al (2006) with some modifications. In brief, male ICR mice (28-38 g) were randomly divided into three groups: a drugtreatment group, a sham-operated control group and a control group.…”

“…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.…”

Demonstration of the Usefulness of Optical Coherence Tomography in Imaging a Mouse Tail Model of Lymphedema

“…Tabibiazar et al induced lymphedema in an animal model using a mouse tail, and observed an increase in fibroblast cells, hyperkeratosis, edema in epidermis, and expanded lymphatics in the dermis and subdermis in mouse tail histological samples [7].…”