Lymph Drainage During Wound Healing in a Hindlimb Lymphedema Mouse Model

Komatsu, Emi; Nakajima, Yukari; Mukai, Kanae; Urai, Tamae; Asano, Kazushi; Okuwa, Mayumi; Sugama, Junko; Nakatani, Toshio

doi:10.1089/lrb.2016.0026

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…Lymphatics were visualized using the NIRF imaging system (Pde-neo; Hamamatsu Photonics K.K., Shizuoka, Japan) after anesthetization with 1.5% isoflurane. Pde-neo emitted light at 760 nm and detected light at wavelengths greater than 820 nm, and, thus, detected ICG flow because ICG has an excitation wavelength of 805 nm and emission wavelength of 840 nm 18 , 32 . After an injection of 2 to 10 μl ICG, we massaged the injection site using absorbent cotton wool to promote ICG absorbance.…”

Section: Methodsmentioning

confidence: 99%

Near-Infrared Fluorescence Imaging Directly Visualizes Lymphatic Drainage Pathways and Connections between Superficial and Deep Lymphatic Systems in the Mouse Hindlimb

Nakajima

Asano

Mukai

et al. 2018

Sci Rep

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Since lymphedema rarely develops in the mouse hindlimb, the underlying mechanisms remain unclear. We herein investigated the resolution of chronic hindlimb lymphedema in mice using a Near-Infrared Fluorescence (NIRF) imaging system. Nineteen 7–28-week-old BALB/c male and female mice were injected with two dyes for lymphography and dissection. Lymphadenectomy was performed on six male mice to completely obstruct lymph flow in the hindlimb. Edematous changes in both hindlimbs were compared until 60 days after surgery. The NIRF imaging system detected three lymphatic collecting systems in the mouse hindlimb: superficial lateral, superficial medial, and deep medial. It also showed connections between the superficial and deep lymphatic systems in the inguinal region. Lymphadenectomy of the iliac, inguinal, and popliteal lymph nodes caused edematous changes. However, lymph flow in these operated areas restarted within 60 days and the severity of lymphedema appeared to be low. NIRF imaging showed that the deep medial system and a connection between the superficial and deep lymphatic systems in the inguinal region drain lymph from the hindlimb. This is the one reasons why lymphedema does not develop in the mouse hindlimb. The stable obstruction of lymph flow in these three systems is desired to develop chronic lymphedema.

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Section: Methodsmentioning

confidence: 99%

Near-Infrared Fluorescence Imaging Directly Visualizes Lymphatic Drainage Pathways and Connections between Superficial and Deep Lymphatic Systems in the Mouse Hindlimb

Nakajima

Asano

Mukai

et al. 2018

Sci Rep

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“…The observation protocol for lymphography has previously been described [20]. In the mice that were anesthetized using 1.75% isoflurane inhalation, we injected 2 μl ICG (2.5 mg/ml) into the hindlimb to investigate the lymph flow after lymphatic ligation.…”

Section: Observation Of Icg Lymphographymentioning

confidence: 99%

“…When collateral LVs bridging the distal LV (over the area of lymphadenectomy) to the proximal LV or to the remaining LNs with LVs are observed in patients using lymphoscintigraphy (at the area of the lymphadenectomy), lymphedema is said to be mild or moderate [3,5,7,[10][11][12]. Moreover, animal studies involving canines, rabbits, rats, and mice have previously reported that similar collateral LVs (also known as lymphatic detours) develop following LN dissection alone or in combination with LVs [13][14][15][16][17][18][19][20][21][22]. Collateral LVs in rodents have been detected using indocyanine green (ICG) in 2 days [22], in 3 days [20], in 1 week [14,15] and in 10 days [21] after lymphadenectomy.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, animal studies involving canines, rabbits, rats, and mice have previously reported that similar collateral LVs (also known as lymphatic detours) develop following LN dissection alone or in combination with LVs [13][14][15][16][17][18][19][20][21][22]. Collateral LVs in rodents have been detected using indocyanine green (ICG) in 2 days [22], in 3 days [20], in 1 week [14,15] and in 10 days [21] after lymphadenectomy. In our previous study, mice showed well-developed detours in the abdomen after lymphadenectomy of the inguinal LN [21].…”

Section: Introductionmentioning

confidence: 99%

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Pre-collecting lymphatic vessels form detours following obstruction of lymphatic flow and function as collecting lymphatic vessels

et al. 2020

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Background Previously, we showed that lymphatic vessels (LVs) formed detours after lymphatic obstruction, contributing to preventing lymphedema. In this study, we developed detours using lymphatic ligation in mice and we identified the detours histologically. Methods and results Under anesthesia, both hindlimbs in mice were subcutaneously injected with Evans blue dye to detect LVs. We tied the right collecting LV on the abdomen that passes through the inguinal lymph node (LN) at two points. The right and left sides comprised the operation and sham operation sides, respectively. Lymphography was performed to investigate the lymph flow after lymphatic ligation until day 30, using a near-infrared fluorescence imaging system. Anti-podoplanin antibody and 5-ethynyl-2'-deoxyuridine (EdU) were used to detect LVs and lymphangiogenesis. Within 30 days, detours had developed in 62.5% of the mice. Detours observed between two ligation sites were enlarged and irregular in shape. Podoplanin + LVs, which were located in the subcutaneous tissue of the upper panniculus carnosus muscle, connected to collecting LVs at the upper portion from the cranial ligation site and at the lower portion from the caudal ligation site. EdU + cells were not observed in these detours. The sham operation side showed normal lymph flow and did not show enlarged pre-collecting LVs until day 30. Conclusions Detours after lymphatic ligation were formed not by lymphangiogenesis but through an enlargement of pre-collecting LVs that functioned as collecting LVs after lymphatic ligation.

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“…Lymphedema is known to delay wound healing. [1][2][3][4] If water and macromolecules are not cleared from the inter-stitium, the oncotic and hydrostatic pressure balance within the tissues is altered, and cell damage results contributing further to delayed wound healing. 5 In addition to these pathophysiological mechanisms, it is suspected that the balance of immune cells involved in wound healing is disrupted in lymphedema.…”

Section: Introductionmentioning

confidence: 99%

Lymphovenous Anastomosis Aids Wound Healing in Lymphedema: Relationship Between Lymphedema and Delayed Wound Healing from a View of Immune Mechanisms

Yoshida

Koshima

Hamada

et al. 2019

Advances in Wound Care

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Delayed wound healing in lymphedema is assumed to be caused by two reasons, pathophysiological and immunological effects of lymphedema. The aim of this review is to establish how impaired lymphatics alter wound healing pathophysiologically and immunologically, and to propose treatment modalities that can promote wound healing in lymphedema. Lymphaticovenular anastomoses (lymphovenous anastomoses [LVAs]) were performed on patients who had recurrent cellulitis several times with lymphorrhea and developed severe ulcers that were refractory to skin grafts, flaps, and conservative therapy. The lymphorrhea and the ulcer had healed by 4 weeks. Moreover, the lymphedema improved without compression therapy. Lymphedema is characterized pathophysiologically by localized peripheral edema that compresses the microvasculature and lymphatic vasculature and impairs tissue remodeling. Another suspected mechanism is an imbalance in the differentiation of participating immune cells. Profound suppression of T helper (Th)1 cells is likely to increase the risk of infection, and excessive differentiation of Th2 cells, including M2 macrophage polarization, may promote fibrosis, which disrupts the carefully orchestrated wound healing process. Although negative-pressure wound therapy is useful for the treatment of delayed wound healing in lymphedema, LVAs may be necessary to treat the fundamental problem of lymphedema. LVAs are considered to create a bypass to the lymph nodes through which dendritic cells (DCs) can transmit antigen information to T cells. LVAs are considered to neutralize chronic inflammation by allowing more DCs to return into the circulation, thereby improving wound healing.

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Lymph Drainage During Wound Healing in a Hindlimb Lymphedema Mouse Model

Cited by 14 publications

References 24 publications

Near-Infrared Fluorescence Imaging Directly Visualizes Lymphatic Drainage Pathways and Connections between Superficial and Deep Lymphatic Systems in the Mouse Hindlimb

Near-Infrared Fluorescence Imaging Directly Visualizes Lymphatic Drainage Pathways and Connections between Superficial and Deep Lymphatic Systems in the Mouse Hindlimb

Pre-collecting lymphatic vessels form detours following obstruction of lymphatic flow and function as collecting lymphatic vessels

Lymphovenous Anastomosis Aids Wound Healing in Lymphedema: Relationship Between Lymphedema and Delayed Wound Healing from a View of Immune Mechanisms

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