Temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema

Zampell, Jamie C.; Yan, Alan; Avraham, Tomer; Andrade, Victor Piana de; Malliaris, Stephanie D.; Aschen, Seth Z.; Rockson, Stanley G.; Mehrara, Babak J.

doi:10.1152/ajpcell.00378.2010

Cited by 48 publications

(63 citation statements)

References 55 publications

(63 reference statements)

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“…To circumvent these difficulties, we used two different mouse models to study the effects of variable degrees of lymphatic injury on IL-6 expression. We have previously shown that ALND in mice results in significant but subtle increases in arm volume peaking at 3 wk and returning to normal by 6 wk (24,39). In this model, similar to clinical findings after lymphadenectomy, the ipsilateral limb is essentially normal in appearance by 6 wk.…”

Section: Discussionsupporting

confidence: 77%

“…For example, Harvey and colleagues (17) reported that mice with a heterozygous inactivating mutation of the Prox-1 gene not only have lymphatic developmental abnormalities but also become obese as adults as compared with their wild-type littermate controls. Using a surgical mouse model of axillary lymphadenectomy in which the draining lymph nodes of the forelimb are removed, our group has shown that even this relatively minor injury increases the expression of adipose differentiation genes such as CEPB-␣ and Ppar-␥ (2) as well as early inflammatory cascades in the forelimb subcutaneous tissues (39). By comparing tissues harvested from mice that had undergone axillary lymph node dissection with a more severe model of lymphatic injury in the mouse tail, we have also shown that the degree of adipose deposition is related to the severity of lymphatic obstruction and tissue inflammation (6).…”

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confidence: 99%

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IL-6 regulates adipose deposition and homeostasis in lymphedema

Cuzzone

Weitman

Albano

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4+ cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4+ inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4+ cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

IL-6 regulates adipose deposition and homeostasis in lymphedema

Cuzzone

Weitman

Albano

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…In these models, lymphatic vessel function has been investigated using different imaging techniques [3][4][5][6][7][8]. In the ALND model, lymphatic drainage patterns were examined in response to surgical removal of the ALN alone or together with the brachial LN (BLN) [3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Characterization of internodal collecting lymphatic vessel function after surgical removal of an axillary lymph node in mice

Kwon¹,

Price²

2016

Biomed. Opt. Express

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Secondary lymphedema is an acquired lymphatic disorder, which occurs because of damage to the lymphatic system from surgery and/or radiation therapy for cancer treatment. However, it remains unknown how post-nodal collecting lymphatic vessels (CLVs) draining to the surgical wound area change in response to lymphadenectomy. We investigated functional and architectural changes of inguinal-to-axillary internodal CLVs (ICLVs) in mice after a single axillary LN (ALN) dissection using nearinfrared fluorescence imaging. Our data showed no lymph flow in the ICLVs draining from the inguinal LN (ILN) at 2 days post-surgery. External compression enabled visualization of a small segment of contractile fluorescent ICLVs, but not all the way to the axillary region. At day 6, abnormal lymphatic drainage patterns, including lateral and retrograde lymph flow via vessels branching off the ICLVs were observed, which started to disappear beginning 9 days after surgery. The administration of vascular endothelial growth factor (VEGF)-C into the wound increased resolution of altered lymphatic drainage. Lymphatic drainage from the base of the tail to the ILN did not significantly change over time. These results demonstrate that lymph flow in the CLVs is dramatically affected by a LN dissection and long-term interruption of lymph flow might cause CLV dysfunction and thus contribute to chronic lymphatic disorders. Kippenberger, "Vascular endothelial growth factor C-induced lymphangiogenesis decreases tumor interstitial fluid pressure and tumor," Transl.

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“…It has been hypothesized that an inability of the lymphatic system to adequately regenerate during normal wound repair may predispose the tissue to swell during secondary lymphedema (21,33). For this reason, attention has recently shifted to clarifying the regulation of lymphangiogenesis by molecules expressed during wound repair (2,10,11,21,33,35,37).…”

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confidence: 99%

Functional recovery of fluid drainage precedes lymphangiogenesis in acute murine foreleg lymphedema

Mendez

Brown

Slis

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Secondary lymphedema in humans is a common consequence of axillary lymph node dissection (ALND) to treat breast cancer. It is commonly hypothesized that lymphatic growth is required to increase fluid drainage and ameliorate lymphedema. Although there is a pronounced alteration in the balance of interstitial forces regulating fluid transport that sustains the chronic form of lymphedema, it is presently unknown whether changes occur to the balance of interstitial forces during acute lymphedema that may play a role in the recovery of fluid drainage. Here, we compared the relative importance of lymphangiogenesis of lymphatic vessels and interstitial flows for restoring fluid drainage and resolving acute lymphedema in the mouse foreleg after ALND. We found that removal of the axillary lymph nodes reduced lymph drainage in the foreleg at days 0 and 5 postsurgery, with fluid tracer spreading interstitially through subcutaneous tissues. Interstitial fluid drainage returned to normal by day 10, whereas functional regrowth of lymphatic vessels was first detected by indocyanine green fluorescence lymphography at day 15, demonstrating that the recovery of interstitial fluid drainage preceded the regrowth of lymphatic vessels. This was confirmed by the administration of VEGF receptor-3-neutralizing antibodies, which completely blocks lymphatic regrowth. It was found that the recovery of interstitial fluid drainage and the natural resolution of acute lymphedema produced by ALND were not hindered by VEGF receptor-3 neutralization, demonstrating that interstitial fluid drainage recovery and the resolution of acute lymphedema are lymphangiogenesis independent. The data highlight the central role of the interstitial environment in adapting to lymphatic injury to increase fluid drainage.

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Temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema

Cited by 48 publications

References 55 publications

IL-6 regulates adipose deposition and homeostasis in lymphedema

IL-6 regulates adipose deposition and homeostasis in lymphedema

Characterization of internodal collecting lymphatic vessel function after surgical removal of an axillary lymph node in mice

Functional recovery of fluid drainage precedes lymphangiogenesis in acute murine foreleg lymphedema

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