• Molecules and Cells
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• v.37 no.7
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• pp.503-510
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• 2014

Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

• IMMUNE NETWORK
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• v.14 no.4
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• pp.182-186
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• 2014

Lymphatic vessels are routes for leukocyte migration and fluid drainage. In addition to their passive roles in migration of leukocytes, increasing evidence indicates their active roles in immune regulation. Tissue inflammation rapidly induces lymphatic endothelial cell proliferation and chemokine production, thereby resulting in lymphangiogenesis. Furthermore, lymphatic endothelial cells induce T cell tolerance through various mechanisms. In this review, we focus on the current knowledge on how inflammatory cytokines affect lymphangiogenesis and the roles of lymphatic vessels in modulating immune responses.

• Archives of Plastic Surgery
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• v.45 no.2
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• pp.152-157
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• 2018

Background Intraoperative indocyanine green (ICG) lymphography can effectively detect functioning lymph vessels in edematous limbs. However, it is sometimes difficult to clearly identify their course in later-stage edematous limbs. For this reason, many surgeons rely on experience when they decide where to make the skin incision to locate the lymphatic vessels. The purpose of this study was to elucidate lymphatic vessel flow patterns in healthy upper extremities in a Korean population and to use these findings as a reference for lymphedema treatment. Methods ICG fluorescence lymphography was performed by injecting 1 mL of ICG into the second web space of the hand. After 4 hours, fluorescence images of lymphatic vessels were obtained with a near-infrared camera, and the lymphatic vessels were marked. Three landmarks were designated: the radial styloid process, the mid-portion of the cubital fossa, and the lower border of the deltopectoral groove. A straight line connecting the points was drawn, and the distance between the connected lines and the marked lymphatic vessels was measured at 8 points. Results There were 30 healthy upper extremities (15 right and 15 left). The average course of the main lymph vessels passed $26.0{\pm}11.6mm$ dorsal to the styloid process, $5.7{\pm}40.7mm$ medial to the mid-cubital fossa, and $31.3{\pm}26.1mm$ medial to the three-quarters point of the upper landmark line. Conclusions The main functioning lymphatic vessel follows the course of the cephalic vein at the forearm level, crosses the mid-cubital point, and travels medially toward the mid-axilla.

• Archives of Plastic Surgery
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• v.49 no.1
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• pp.99-107
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• 2022

Background Dermal backflow (DBF), which refers to lymphatic reflux due to lymphatic valve insufficiency, is a diagnostic finding in lymphedema. However, the three-dimensional structure of DBF remains unknown. Photoacoustic lymphangiography (PAL) is a new technique that enables the visualization of the distribution of light-absorbing molecules, such as hemoglobin or indocyanine green (ICG), and can provide three-dimensional images of superficial lymphatic vessels and the venous system. This study reports the use of PAL to visualize DBF structures in the extremities of patients with lymphedema after cancer surgery. Methods Patients with a clinical or lymphographic diagnosis of lymphedema who previously underwent surgery for cancer at one of two participating hospitals were included in this study. PAL was performed using the PAI-05 system. ICG was administered subcutaneously in the affected hand or foot, and ICG fluorescence lymphography was performed using a near-infrared camera system prior to PAL. Results Between April 2018 and January 2019, 21 patients were enrolled and examined using PAL. The DBF was composed of dense, interconnecting, three-dimensional lymphatic vessels. It was classified into three patterns according to the composition of the lymphatic vessels: a linear structure of lymphatic collectors (pattern 1), a network of lymphatic capillaries and lymphatic collectors in an underlying layer (pattern 2), and lymphatic capillaries and precollectors with no lymphatic collectors (pattern 3). Conclusions PAL showed the structure of DBF more precisely than ICG fluorescence lymphography. The use of PAL to visualize DBF assists in understanding the pathophysiology and assessing the severity of cancer-related lymphedema.

• Archives of Plastic Surgery
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• v.48 no.3
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• pp.323-328
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• 2021

Background Lymphaticovenular anastomosis (LVA) is a minimally invasive surgical procedure used to treat lymphedema. Volumetric measurements and quality-of-life assessments are often performed to assess the effectiveness of LVA, but there is no method that provides information regarding postoperative morphological changes in lymphatic vessels and veins after LVA. Photoacoustic lymphangiography (PAL) is an optical imaging technique that visualizes the distribution of light-absorbing molecules, such as hemoglobin or indocyanine green (ICG), and provides three-dimensional images of superficial lymphatic vessels and the venous system simultaneously. In this study, we performed PAL in lymphedema patients before and after LVA and compared the images to evaluate the effect of LVA. Methods PAL was performed using the PAI-05 system in three patients (one man, two women) with lymphedema, including one primary case and two secondary cases, before LVA. ICG fluorescence lymphography was performed in all cases before PAL. Follow-up PAL was performed between 5 days and 5 months after LVA. Results PAL enabled the simultaneous visualization of clear lymphatic vessels that could not be accurately seen with ICG fluorescence lymphography and veins. We were also able to observe and analyze morphological changes such as the width and the number of lymphatic vessels and veins during the follow-up PAL after LVA. Conclusions By comparing preoperative and postoperative PAL images, it was possible to analyze the morphological changes in lymphatic vessels and veins that occurred after LVA. Our study suggests that PAL would be useful when assessing the effect of LVA surgery.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1363-1367
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• 2014

This research was conducted to compare differences in colon cancer lymphatic vessel invasion (LVI) with D2-40 antibody labeling and regular HE staining, blood vessel invasion (BVI) with CD34 antibody labeling and HE staining and to assess the possibility of using D2-40-LVI/CD34-BVI in combination for predicting stage II colon cancer prognosis and guiding adjuvant chemotherapy.Anti-D2-40 and anti-CD34 antibodies were applied to tissue samples of 220 cases of stage II colon cancer to label lymphatic vessels and small blood vessels, respectively. LVI and BVI were assessed and multivariate COX regression analysis was performed for associations with colon cancer prognosis. Regular HE staining proved unable to differentiate lymphatic vessels from blood vessels, while D2-40 selectively labeled lymphatic endothelial cell cytosol and CD34 was widely expressed in large and small blood vessels of tumors as well as normal tissues. Compared to regular HE staining, D2-40-labeling for LVI and CD34-labeling for BVI significantly increased positive rate (22.3% vs 10.0% for LVI, and 19.1% vs 9.1% for BVI). Multivariate analysis indicated that TNM stage, pathology tissue type, post-surgery adjuvant chemotherapy, D2-40-LVI, and CD34-BVI were independent factors affecting whole group colon cancer prognosis, while HE staining-BVI, HE staining-LVI were not significantly related. When CD34-BVI/D2-40-LVI were used in combination for detection, the risk of death for patients with two or one positive results was 5.003 times that in the LVI(-)&BVI(-) group (95% CI 2.365 - 9.679). D2-40 antibody LVI labeling and CD34 antibody BVI labeling have higher specificity and accuracy than regular HE staining and can be used as molecular biological indicators for prognosis prediction and guidance of adjuvant chemotherapy for stage II colon cancer.

• Journal of Magnetics
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• v.18 no.2
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• pp.188-191
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• 2013

The magnetic properties for sanal's mobility inside of the lymphatic primo vascular system, the so-called Kyungrak (or meridian) system, are investigated under a low static magnetic field with the anatomy technology and optical microscope. One sanal with a size of 1 ${\mu}m$ under microscope selected and separated from the primo vessels of the primo vascular system are observed in rabbits' lymphatic vessels around abdominal aorta and placed in PBS solution with petridish. The moving displacement of sanal versus the measuring time of 20 Oe below a magnetic field of 80 Oe is stronger in dominanting dependence according to the x-direction than y-direction.

• Archives of Plastic Surgery
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• v.49 no.6
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• pp.773-781
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• 2022

Anatomies of the vascular and lymphatic systems have been vital research topics in reconstructive surgery. Harvey was a pioneer who provided the earliest descriptions of the cutaneous vasculature in the 17th century. The concept of vascular territories of the skin was first described by Manchot. The radiographic injection method in cadavers was developed by Salman, who defined more than 80 vascular territories. The arterial system has been thoroughly investigated with the development of regional and free flaps. The concept of axial and random pattern flaps was introduced by McGregor and Morgan. Manchot's vascular territories were refined by Taylor and Palmer as the angiosome concept. Detailed information about the venous circulation is essential for reconstructive surgeries. The concept of intrinsic and extrinsic venocutaneous vascular systems was introduced by Nakajima and led to the development of the venoadipofascial flap. The importance of venous augmentation in flap survival was emphasized by Chang. The lymphatic system was discovered much later than the arterial and venous systems. Aselli was credited for discovering the lacteal vessels in the 17th century; mercury was popularly used as a contrast agent to distinguish lymphatic vessels for the next three centuries. A radiographic method in cadavers was developed by Suami. Lymphatic imaging devices are constantly upgrading, and photoacoustic imaging was recently introduced for three-dimensional visualization of architecture of superficial layers of the lymphatic and venous systems.

• Molecules and Cells
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• v.37 no.3
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• pp.270-274
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• 2014

Lymphatic vessels are essential to regulate interstitial fluid homeostasis and diverse immune responses. A number of crucial factors, such as VEGFC, SOX18, PROX1, FOX2C, and GJC2, have been implicated in differentiation and/or maintenance of lymphatic endothelial cells (LECs). In humans, dysregulation of these genes is known to cause lymphedema, a debilitating condition which adversely impacts the quality of life of affected individuals. However, there are no currently available pharmacological treatments for lymphedema, necessitating identification of additional factors modulating lymphatic development and function which can be targeted for therapy. In this report, we investigate the function of genes associated with Bone Morphogenetic Protein (BMP) signaling in lymphatic development using zebrafish embryos. The knock-down of BMP type II receptors, Bmpr2a and Bmpr2b, and type I receptors, Alk3 and Alk3b, as well as SMAD5, an essential cellular mediator of BMP signaling, led to distinct lymphatic defects in developing zebrafish. Therefore, it appears that each constituent of the BMP signaling pathway may have a unique function during lymphatic development. Taken together, our data demonstrate that BMP signaling is essential for normal lymphatic vessel development in zebrafish.

• Archives of Plastic Surgery
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• v.50 no.4
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• pp.422-431
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• 2023

Background Posttraumatic lymphedema (PTL) is sparsely described in the literature. The aim of this study is to propose a comprehensive approach for prevention and treatment of PTL using lymphovenous anastomosis (LVA) and lymphatic vessels free flap, reporting our experience in the management of early-stage lymphedema. Methods A retrospective observational study was performed between October 2017 and July 2022. Functional assessment with magnetic resonance lymphangiography and indocyanine green lymphography was performed. Patients with lymphedema and functional lymphatic channels were included. Cases with limited soft tissue damage were proposed for LVA, and those with acute or prior soft tissue damage needing skin reconstruction were proposed for superficial circumflex iliac artery perforator lymphatic vessels free flap (SCIP-LV) to treat or prevent lymphedema. Primary and secondary outcomes were limb volume reduction and quality of life (QoL) improvement, respectively. Follow-up was at least 1 year. Results Twenty-eight patients were operated using this approach during the study period. LVA were performed in 12 patients; mean reduction of excess volume (REV) was 58.82% and the improvement in QoL was 49.25%. SCIP-LV was performed in seven patients with no flap failure; mean REV was 58.77% and the improvement QoL was 50.9%. Nine patients with acute injury in lymphatic critical areas were reconstructed with SCIP-LV as a preventive approach and no lymphedema was detected. Conclusion Our comprehensive approach provides an organized way to treat patients with PTL, or at risk of developing it, to have satisfactory results and improve their QoL.