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Sample records for lymphatic abnormalities

  1. Lymphatic Vessel Abnormalities Arising from Disorders of Ras Signal Transduction

    PubMed Central

    Sevick-Muraca, Eva M.; King, Philip D.

    2013-01-01

    A number of genetic diseases in man have been described in which abnormalities in the development and function of the lymphatic vascular (LV) system are prominent features. The genes that are mutated in these diseases are varied and include genes that encode lymphatic endothelial cell (LEC) growth factor receptors and their ligands and transcription factors that control LEC fate and function. In addition, an increasing number of genes have been identified that encode components of the Ras signal transduction pathway that conveys signals from cell surface receptors to regulate cell growth, proliferation and differentiation. Gene targeting studies performed in mice have confirmed that the LV system is particularly susceptible to perturbations in the Ras pathway. PMID:24183794

  2. An abnormal lymphatic phenotype is associated with subcutaneous adipose tissue deposits in Dercum’s disease

    PubMed Central

    Rasmussen, John C.; Herbst, Karen L.; Aldrich, Melissa B.; Darne, Chinmay D.; Tan, I-Chih; Zhu, Banghe; Guilliod, Renie; Fife, Caroline A.; Maus, Erik A.; Sevick-Muraca, Eva M.

    2014-01-01

    Objective Investigational, near-infrared fluorescence (NIRF) lymphatic imaging was used to assess lymphatic architecture and contractile function in participants diagnosed with Dercum’s disease, a rare, poorly understood disorder characterized by painful lipomas in subcutaneous adipose tissues. Design and Methods After informed consent and as part of an FDA-approved feasibility study to evaluate lymphatics in diseases in which their contribution has been implicated, three women diagnosed with Dercum’s disease and four control subjects were imaged. Each participant received multiple intradermal and subcutaneous injections of indocyanine green (ICG, total dose ≤400µg) in arms, legs, and/or trunk. Immediately after injection, ICG was taken up by the lymphatics and NIRF imaging was conducted. Results The lymphatics in the participants with Dercum’s disease were intact and dilated, yet sluggishly propelled lymph when compared to control lymphatics. Palpation of regions containing fluorescent lymphatic pathways revealed tender, fibrotic, tubular structures within the subcutaneous adipose tissue that were associated with painful nodules, and, in some cases, masses of fluorescent tissue indicating that some lipomas may represent tertiary lymphoid tissues. Conclusions These data support the hypothesis that Dercum’s disease may be a lymphovascular disorder and suggest a possible association between abnormal adipose tissue deposition and abnormal lymphatic structure and function. PMID:25044620

  3. Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

    PubMed Central

    Burrows, Patricia E.; Gonzalez-Garay, Manuel L.; Rasmussen, John C.; Aldrich, Melissa B.; Guilliod, Renie; Maus, Erik A.; Fife, Caroline E.; Kwon, Sunkuk; Lapinski, Philip E.; King, Philip D.; Sevick-Muraca, Eva M.

    2013-01-01

    Mutations in gene RASA1 have been historically associated with capillary malformation–arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes–Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders. PMID:23650393

  4. Hypogammaglobulinaemia associated with abnormalities of both B and T lymphocytes in patients with chronic lymphatic leukaemia.

    PubMed Central

    Hersey, P; Wotherspoon, J; Reid, G; Gunz, F W

    1980-01-01

    The underlying basis for hypogammaglobulinaemia in patients with chronic lymphatic leukaemia (CLL) was investigated by measurement if immunoglobulin produced in vitro in cultures of pokeweek mitogen-stimulated B and T lymphocytes. B and T cells were separated by sheep red blood cell rosette techniques and, by culture of these cells from CLL patients in various combinations with B or T cells from normal subjects, it was possible to measure independently the function of B lymphocytes and the helper or suppressor function of T lymphocytes. By these methods it was found that the B lymphocytes of six of eight patients failed to produce immunoglobulins in vitro. B lymphocytes from two patients appeared to produce immunoglobulins in vitro. T lymphocytes from five of the eight patients had low or undetectable helper T cell function and in six patients their T lymphocytes had excessive suppressor activity in comparison to T lymphocyte populations from normal subjects. Whether the primary abnormality in the CLL T cell populations was a deficiency of helper T cells or excess of suppressor T cells was uncertain from these studies. These results suggest that immunoglobulin production by B lymphocytes from most patients with CLL was abnormal but also that T cells from CLL patients may be abnormal in respect to their role in immunoglobulin production at an early stage of the disease. These findings may assist in understanding the pathogenesis of this disease and lead to new approaches in treatment. PMID:6445798

  5. Congenital lymphatic hypoplasia in unilateral lower limb with abnormal technetium-99m sulphur colloid uptake in both breasts

    PubMed Central

    Padma, Subramanyam; Sundaram, Palaniswamy Shanmuga

    2014-01-01

    We present a patient with Meige like lymphedema (left lower limb hypoplasia) with asymptomatic minimal accumulation of Technetium-99m sulfur colloid in bilateral breasts. We attribute the possible pathology to accumulation of interstitial fluid in hypoplastic left lower limb leading to dilatation of the remaining outflow tracts and valvular incompetence. This may be causing reversal of flow from subcutaneous tissues into the dermal plexus involving the breast. Other possibilities include formation of spontaneous lymphovenous shunt or lymphatic intercommunication at lower trunk level as a result of increased pressure leading to minimal lymph accumulation in breasts. Later a mammogram was performed which was found to be normal. MR also confirmed no cisterna chyli abnormalities or aberrant lymphatic channels in lower thorax region that may be the explanation for the abnormal sulphur colloid uptake in both breasts. PMID:25400372

  6. Lymphatic obstruction

    MedlinePlus

    ... certain directions based on the structure of the lymphatic system. This helps the lymph fluid drain through the ... always appropriate or effective. Alternative Names Lymphedema Images Lymphatic system Yellow nail syndrome References Feldman JL, Jackson KA, ...

  7. Lymphatic Diseases

    MedlinePlus

    The lymphatic system is a network of tissues and organs. It is made up of Lymph - a fluid that contains ... They are part of the system, too. The lymphatic system clears away infection and keeps your body fluids ...

  8. Functional imaging in tumor-associated lymphatics

    NASA Astrophysics Data System (ADS)

    Kwon, Sunkuk; Sevick-Muraca, Eva M.

    2011-03-01

    The lymphatic system plays an important role in cancer cell dissemination; however whether lymphatic drainage pathways and function change during tumor progression and metastasis remains to be elucidated. In this report, we employed a non-invasive, dynamic near-infrared (NIR) fluorescence imaging technique for functional lymphatic imaging. Indocyanine green (ICG) was intradermally injected into tumor-free mice and mice bearing C6/LacZ rat glioma tumors in the tail or hindlimb. Our imaging data showed abnormal lymphatic drainage pathways and reduction/loss of lymphatic contractile function in mice with lymph node (LN) metastasis, indicating that cancer metastasis to the draining LNs is accompanied by transient changes of the lymphatic architectural network and its function. Therefore, functional lymphatic imaging may provide a role in the clinical staging of cancer.

  9. Lymphatic filariasis.

    PubMed

    2008-02-01

    (1) Lymphatic filariasis is a set of parasitic diseases that are endemic in tropical and subtropical regions and can be disabling in the long term. (2) The standard antiparasitic drug for adults is oral diethylcarbamazine. Ivermectin is an alternative, especially for patients with intercurrent onchocercosis or loasis.

  10. Preclinical Lymphatic Imaging

    PubMed Central

    Zhang, Fan; Niu, Gang; Lu, Guangming; Chen, Xiaoyuan

    2011-01-01

    Non-invasive in vivo imaging of lymphatic vessels and lymphatic nodes is expected to fulfill the purpose of analyzing lymphatic vessels and their function, understanding molecular mechanisms of lymphangiogenesis and lymphatic spread of tumors, and utilizing lymphatic molecular markers as a prognostic or diagnostic indicator. In this review, we provide a comprehensive summary of in vivo imaging modalities for detecting lymphatic vessels, lymphatic drainage, lymphatic nodes, which include conventional lymphatic imaging techniques such as dyes and radionuclide scintigraphy as well as novel techniques for lymphatic imaging such as optical imaging, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) using lymphatic biomarkers, photoacoustic imaging and combinations of multiple modalities. The field of lymphatic imaging is ever evolving, and technological advances, combined with the development of new contrast agents, continue to improve the research of lymphatic vascular system in health and disease states as well as to improve the accuracy of diagnosis in the relevant diseases. PMID:20862613

  11. Lymphatic Education & Research Network

    MedlinePlus

    Lymphatic Education & Research Network Donate Now Become a Supporting Member X Living with LYMPHEDEMA AND Lymphatic Disease FAQs About ... 261 Madison Avenue, New York, NY 10016 | Lymphatic Education & Research Network is a 501(c)(3) under ...

  12. Lymphatic Anomalies Registry

    ClinicalTrials.gov

    2016-07-26

    Lymphatic Malformation; Generalized Lymphatic Anomaly (GLA); Central Conducting Lymphatic Anomaly; CLOVES Syndrome; Gorham-Stout Disease ("Disappearing Bone Disease"); Blue Rubber Bleb Nevus Syndrome; Kaposiform Lymphangiomatosis; Kaposiform Hemangioendothelioma/Tufted Angioma; Klippel-Trenaunay Syndrome; Lymphangiomatosis

  13. Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

    PubMed Central

    Glasgow, Connie G.; El-Chemaly, Souheil; Moss, Joel

    2013-01-01

    The primary function of the lymphatic system is absorbing and transporting macromolecules and immune cells to the general circulation, thereby regulating fluid, nutrient absorption and immune cell trafficking. Lymphangiogenesis plays an important role in tissue inflammation and tumour cell dissemination. Lymphatic involvement is seen in lymphangioleiomyomatosis (LAM) and idiopathic pulmonary fibrosis (IPF). LAM, a disease primarily affecting females, involves the lung (cystic destruction), kidney (angiomyolipoma) and axial lymphatics (adenopathy and lymphangioleiomyoma). LAM occurs sporadically or in association with tuberous sclerosis complex (TSC). Cystic lung destruction results from proliferation of LAM cells, which are abnormal smooth muscle-like cells with mutations in the TSC1 or TSC2 gene. Lymphatic abnormalities arise from infiltration of LAM cells into the lymphatic wall, leading to damage or obstruction of lymphatic vessels. Benign appearing LAM cells possess metastatic properties and are found in the blood and other body fluids. IPF is a progressive lung disease resulting from fibroblast proliferation and collagen deposition. Lymphangiogenesis is associated with pulmonary destruction and disease severity. A macrophage subset isolated from IPF bronchoalveolar lavage fluid (BALF) express lymphatic endothelial cell markers in vitro, in contrast to the same macrophage subset from normal BALF. Herein, we review lymphatic involvement in LAM and IPF. PMID:22941884

  14. Lymphatic vessels in osteoarthritic human knees.

    PubMed

    Walsh, D A; Verghese, P; Cook, G J; McWilliams, D F; Mapp, P I; Ashraf, S; Wilson, D

    2012-05-01

    The distribution and function of lymphatic vessels in normal and diseased human knees are understood incompletely. This study aimed to investigate whether lymphatic density is associated with clinical, histological or radiographic parameters in osteoarthritis (OA). Sections of synovium from 60 knees from patients with OA were compared with 60 post mortem control knees (from 37 individuals). Lymphatic vessels were identified using immunohistochemistry for podoplanin, and quantified as lymphatic vessel density (LVD) and lymphatic endothelial cell (LEC) fractional area. Effusion status was determined by clinical examination, radiographs were scored for OA changes, and inflammation grading used haematoxylin and eosin stained sections of synovium. Lymphatic vessels were present in synovia from both disease groups, but were not identified in subchondral bone. Synovial lymphatic densities were independent of radiological severity and age. Synovia from patients with OA displayed lower LVD (z=-3.4, P=0.001) and lower LEC fractional areas (z=-4.5, P<0.0005) than non-arthritic controls. In patients with OA, low LVD was associated with clinically detectable effusion (z=-2.2, P=0.027), but not with histological evidence of synovitis. The negative associations between lymphatics and OA/effusion appeared to be independent of other measured confounders. Lymphatic vessels are present in lower densities in OA synovia. Abnormalities of synovial fluid drainage may confound the value of effusion as a clinical sign of synovitis in OA. Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  15. Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats.

    PubMed

    Ribera, Jordi; Pauta, Montse; Melgar-Lesmes, Pedro; Tugues, Sònia; Fernández-Varo, Guillermo; Held, Kara F; Soria, Guadalupe; Tudela, Raúl; Planas, Anna M; Fernández-Hernando, Carlos; Arroyo, Vicente; Jiménez, Wladimiro; Morales-Ruiz, Manuel

    2013-01-01

    The lymphatic network plays a major role in maintaining tissue fluid homoeostasis. Therefore several pathological conditions associated with oedema formation result in deficient lymphatic function. However, the role of the lymphatic system in the pathogenesis of ascites and oedema formation in cirrhosis has not been fully clarified. The aim of this study was to investigate whether the inability of the lymphatic system to drain tissue exudate contributes to the oedema observed in cirrhosis. Cirrhosis was induced in rats by CCl(4) inhalation. Lymphatic drainage was evaluated using fluorescent lymphangiography. Expression of endothelial nitric oxide synthase (eNOS) was measured in primary lymphatic endothelial cells (LyECs). Inhibition of eNOS activity in cirrhotic rats with ascites (CH) was carried out by L-N(G)-methyl-L-arginine (L-NMMA) treatment (0.5 mg/kg/day). The (CH) rats had impaired lymphatic drainage in the splanchnic and peripheral regions compared with the control (CT) rats. LyECs isolated from the CH rats showed a significant increase in eNOS and nitric oxide (NO) production. In addition, the lymphatic vessels of the CH rats showed a significant reduction in smooth muscle cell (SMC) coverage compared with the CT rats. CH rats treated with L-NMMA for 7 days showed a significant improvement in lymphatic drainage and a significant reduction in ascites volume, which were associated with increased plasma volume. This beneficial effect of L-NMMA inhibition was also associated with a significant increase in lymphatic SMC coverage. The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.

  16. Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis

    PubMed Central

    Connor, Alicia L.; Kelley, Philip M.; Tempero, Richard M.

    2015-01-01

    Post natal inflammatory lymphangiogenesis presumably requires precise regulatory processes to properly assemble proliferating lymphatic endothelial cells (LECs). The specific mechanisms that regulate the assembly of LECs during new lymphatic vessel synthesis are unclear. Dynamic endothelial shuffling and rearrangement has been proposed as a mechanism of blood vessel growth. We developed genetic lineage tracing strategies using an inductive transgenic technology to track the fate of entire tandem dimer tomato positive (tdT) lymphatic vessels or small, in some cases clonal, populations of LECs. We coupled this platform with a suture induced mouse model of corneal lymphangiogenesis and used different analytic microscopy techniques including serial live imaging to study the spatial properties of proliferating tdT+ LEC progenies. LEC precursors and their progeny expanded from the corneal limbal lymphatic vessel and were assembled contiguously to comprise a subunit within a new lymphatic vessel. VE-cadherin blockade induced morphologic abnormalities in newly synthesized lymphatic vessels, but did not disrupt the tdT+ lymphatic endothelial lineage assembly. Analysis of this static and dynamic data based largely on direct in vivo observations supports a model of lymphatic endothelial lineage assemblage during corneal inflammatory lymphangiogenesis. PMID:26658452

  17. The Lymphatic Circulation in Adaptations to the Fontan Circulation.

    PubMed

    Menon, Sabarinath; Chennapragada, Murthy; Ugaki, Shinya; Sholler, Gary F; Ayer, Julian; Winlaw, David S

    2017-06-01

    Failing Fontan continues to be major problem for patients on the univentricular pathway. Failing Fontan is often complicated by chylothorax, plastic bronchitis and protein loosing enteropathy. The role of lymphatic circulation in Fontan circulation is still being researched. Newer imaging modalities give insight into the role of abnormal dilatation and retrograde flow in lymphatic channels post Fontan. Interventional strategies targeting abnormal lymphatic channels, provides an alternative management strategy for patients with failing Fontan. This review focuses on the role of lymphatic system in adaptations to Fontan circulation.

  18. Lymphatic system anomalies in Crouzon syndrome

    PubMed Central

    Bourgeois, Pierre; Moniotte, Stéphane

    2009-01-01

    Crouzon syndrome is a rare genetic disorder characterised mainly by distinctive malformations of the skull and facial region and caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. No study reported on oedemas related to lymphatic system abnormalities in these patients. A case of Crouzon syndrome displaying classic facial anomalies but also with bilateral lower limb oedema is reported in whom lymphoscintigraphic investigation of the limbs clearly delineated the presence of lymphatic system anomalies. PMID:21686735

  19. Spleen and Lymphatic System

    MedlinePlus

    ... A Week of Healthy Breakfasts Shyness Spleen and Lymphatic System KidsHealth > For Teens > Spleen and Lymphatic System A A A What's in this article? Why ... español El bazo y el sistema linfático The lymphatic system is an extensive drainage network that helps keep ...

  20. Tie1 is required for lymphatic valve and collecting vessel development

    PubMed Central

    Qu, Xianghu; Zhou, Bin; Baldwin, H. Scott

    2015-01-01

    Tie1 is a receptor tyrosine kinase with broad expression in embryonic endothelium. Reduction of Tie1 levels in mouse embryos with a hypomorphic Tie1 allele resulted in abnormal lymphatic patterning and architecture, decreased lymphatic draining efficiency, and ultimately, embryonic demise. Here we report that Tie1 is present uniformly throughout the lymphatics and from late embryonic/early postnatal stages, becomes more restricted to lymphatic valve regions. To investigate later events of lymphatic development, we employed Cre-loxP recombination utilizing a floxed Tie1 allele and an Nfatc1Cre line, to provide loxP excision predominantly in lymphatic endothelium and developing valves. Interestingly, unlike the early prenatal defects previously described by ubiquitous endothelial deletion, excision of Tie1 with Nfatc1Cre resulted in abnormal lymphatic defects in postnatal mice and was characterized by agenesis of lymphatic valves and a deficiency of collecting lymphatic vessels. Attenuation of Tie1 signaling in lymphatic endothelium prevented initiation of lymphatic valve specification by Prox1 high expression lymphatic endothelial cells that is associated with the onset of turbulent flow in the lymphatic circulation. Our findings reveal a fundamental role for Tie signaling during lymphatic vessel remodeling and valve morphogenesis and implicate it as a candidate gene involved in primary lymphedema. PMID:25576926

  1. Imaging the lymphatic system.

    PubMed

    Munn, Lance L; Padera, Timothy P

    2014-11-01

    Visualization of the lymphatic system is clinically necessary during diagnosis or treatment of many conditions and diseases; it is used for identifying and monitoring lymphedema, for detecting metastatic lesions during cancer staging and for locating lymphatic structures so they can be spared during surgical procedures. Imaging lymphatic anatomy and function also plays an important role in experimental studies of lymphatic development and function, where spatial resolution and accessibility are better. Here, we review technologies for visualizing and imaging the lymphatic system for clinical applications. We then describe the use of lymphatic imaging in experimental systems as well as some of the emerging technologies for improving these methodologies. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis.

    PubMed

    Meinecke, Anna-Katharina; Nagy, Nadine; Lago, Gabriela D'Amico; Kirmse, Santina; Klose, Ralph; Schrödter, Katrin; Zimmermann, Annika; Helfrich, Iris; Rundqvist, Helene; Theegarten, Dirk; Anhenn, Olaf; Orian-Rousseau, Véronique; Johnson, Randall S; Alitalo, Kari; Fischer, Jens W; Fandrey, Joachim; Stockmann, Christian

    2012-06-14

    Pulmonary fibrosis is a progressive disease with unknown etiology that is characterized by extensive remodeling of the lung parenchyma, ultimately resulting in respiratory failure. Lymphatic vessels have been implicated with the development of pulmonary fibrosis, but the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains enigmatic. Here we show in a murine model of pulmonary fibrosis that lymphatic vessels exhibit ectopic mural coverage and that this occurs early during the disease. The abnormal lymphatic vascular patterning in fibrotic lungs was driven by expression of platelet-derived growth factor B (PDGF-B) in lymphatic endothelial cells and signaling through platelet-derived growth factor receptor (PDGFR)-β in associated mural cells. Because of impaired lymphatic drainage, aberrant mural cell coverage fostered the accumulation of fibrogenic molecules and the attraction of fibroblasts to the perilymphatic space. Pharmacologic inhibition of the PDGF-B/PDGFR-β signaling axis disrupted the association of mural cells and lymphatic vessels, improved lymphatic drainage of the lung, and prevented the attraction of fibroblasts to the perilymphatic space. Our results implicate aberrant mural cell recruitment to lymphatic vessels in the pathogenesis of pulmonary fibrosis and that the drainage capacity of pulmonary lymphatics is a critical mediator of fibroproliferative changes.

  3. [Sonographic imaging of lymphatic vessels compared to other methods].

    PubMed

    Matter, D; Grosshans, E; Muller, J; Furderer, C; Mathelin, C; Warter, S; Bellocq, J P; Maillot, C

    2002-05-01

    This paper reviews for the first time the normal and abnormal appearances of lymphatic channels of the skin using ultrasound. After a review of anatomy and histology, the authors present the current imaging modalities available for lymph vessel imaging. The ultrasound examination is presented with a description of the author's technique as well as the technical requirements of the ultrasound unit (12 MHz linear probe with a resolution of 400 microns). They present the ultrasound appearance of normal lymphatic channels and their relationships to the dermis, hypodermis and lymph nodes, and at last the ultrasound appearance of abnormal lymphatic pathways

  4. Spleen and Lymphatic System

    MedlinePlus

    ... Get Weight Loss Surgery? A Week of Healthy Breakfasts Shyness Spleen and Lymphatic System KidsHealth > For Teens > Spleen and Lymphatic System Print A A A What's in this article? Why They're Important Basic Anatomy How It Works Things That Can ...

  5. Blood flow reprograms lymphatic vessels to blood vessels

    PubMed Central

    Chen, Chiu-Yu; Bertozzi, Cara; Zou, Zhiying; Yuan, Lijun; Lee, John S.; Lu, MinMin; Stachelek, Stan J.; Srinivasan, Sathish; Guo, Lili; Vincente, Andres; Mericko, Patricia; Levy, Robert J.; Makinen, Taija; Oliver, Guillermo; Kahn, Mark L.

    2012-01-01

    Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain–containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate–specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow. PMID:22622036

  6. Blood flow reprograms lymphatic vessels to blood vessels.

    PubMed

    Chen, Chiu-Yu; Bertozzi, Cara; Zou, Zhiying; Yuan, Lijun; Lee, John S; Lu, MinMin; Stachelek, Stan J; Srinivasan, Sathish; Guo, Lili; Vicente, Andres; Vincente, Andres; Mericko, Patricia; Levy, Robert J; Makinen, Taija; Oliver, Guillermo; Kahn, Mark L

    2012-06-01

    Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.

  7. Near-infrared fluorescence lymphatic imaging in a patient treated for venous occlusion

    PubMed Central

    Rasmussen, John C.; Aldrich, Melissa B.; Guilliod, Renie; Fife, Caroline E.; O’Donnell, Thomas F.; Sevick-Muraca, Eva M.

    2015-01-01

    Although lower extremity edema/lymphedema can result from venous and/or lymphatic abnormalities, effective treatment depends upon understanding their relative contributions to the condition. Herein we use near-infrared fluorescence lymphatic imaging in a 16 year-old female diagnosed with unilateral lymphedema of the right leg and previously treated with left iliac vein stenting in an attempt to alleviate lymphedema. The imaging shows that abnormal lymphatic anatomy, rather than venous occlusion, was likely responsible for unilateral swelling.

  8. Near-infrared fluorescence lymphatic imaging of Klippel-Trénaunay syndrome.

    PubMed

    Rasmussen, John C; Zvavanjanja, Rodrick C; Aldrich, Melissa B; Greives, Matthew R; Sevick-Muraca, Eva M

    2017-07-01

    The relationship between lymphatic and venous malformations in Klippel-Trénaunay syndrome is difficult to assess. Herein the authors describe near-infrared fluorescence lymphatic imaging to assess the lymphatics of a subject with a large port-wine stain and right leg edema. Although lymphatic vessels in the medial, affected knee appeared dilated and perhaps tortuous, no definitive abnormal lymphatic pooling or propulsion was observed. The lymphatics in the affected limb were well defined but less numerous than in the contralateral limb, and active, contractile function was observed in all vessels. As demonstrated, near-infrared fluorescence lymphatic imaging enables the clinical assessment of lymphatics in lymphovenous malformations. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  9. Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves

    PubMed Central

    Cha, Boksik; Geng, Xin; Mahamud, Md. Riaj; Fu, Jianxin; Mukherjee, Anish; Kim, Yeunhee; Jho, Eek-hoon; Kim, Tae Hoon; Kahn, Mark L.; Xia, Lijun; Dixon, J. Brandon; Chen, Hong; Srinivasan, R. Sathish

    2016-01-01

    Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2. PMID:27313318

  10. Mechanobiology of lymphatic contractions.

    PubMed

    Munn, Lance L

    2015-02-01

    The lymphatic system is responsible for controlling tissue fluid pressure by facilitating flow of lymph (i.e. the plasma and cells that enter the lymphatic system). Because lymph contains cells of the immune system, its transport is not only important for fluid homeostasis, but also immune function. Lymph drainage can occur via passive flow or active pumping, and much research has identified the key biochemical and mechanical factors that affect output. Although many studies and reviews have addressed how tissue properties and fluid mechanics (i.e. pressure gradients) affect lymph transport [1-3] there is less known about lymphatic mechanobiology. As opposed to passive mechanical properties, mechanobiology describes the active coupling of mechanical signals and biochemical pathways. Lymphatic vasomotion is the result of a fascinating system affected by mechanical forces exerted by the flowing lymph, including pressure-induced vessel stretch and flow-induced shear stresses. These forces can trigger or modulate biochemical pathways important for controlling the lymphatic contractions. Here, I review the current understanding of lymphatic vessel function, focusing on vessel mechanobiology, and summarize the prospects for a comprehensive understanding that integrates the mechanical and biomechanical control mechanisms in the lymphatic system.

  11. Bleomycin sclerotherapy for lymphatic malformation after unsuccessful surgical excision: case report.

    PubMed

    Vlahovic, A; Gazikalovic, A; Adjic, O

    2015-10-01

    Lymphatic malformations (LMs) are benign cystic masses resulting from the abnormal development of lymphatic channels. Lymphatic malformations occur primarily in the head and neck region. Surgical excision of lymphatic malformation is followed by high rate of recurrence and a high risk of complications. Bleomycin is an established antineoplastic drug. It can be used as a sclerosing agent in vascular anomalies. We present a child who was unsuccessfully treated with four surgical resections, with peripheral palsy of facial nerve as complication. The lymphatic malformation was successfully treated in our institution with intralesional administration of bleomycin.

  12. Lymphatic and venous function in lipoedema.

    PubMed

    Harwood, C A; Bull, R H; Evans, J; Mortimer, P S

    1996-01-01

    Lipoedema is a common but infrequently recognized condition causing bilateral enlargement of the legs in women. Although generally considered to be the result of an abnormal deposition of subcutaneous fat with associated oedema, the precise mechanisms responsible for oedema formation have yet to be fully established. In order to evaluate the possible role of lymphatic or venous dysfunction in the pathogenesis of lipoedema, 10 patients were investigated by photoplethysmography (venous function) and quantitative lymphoscintigraphy (lymphatic function). The results were compared with those from patients with primary lymphoedema and those from healthy volunteers. The results demonstrated minor abnormalities of venous function in only two patients. One patient had moderately impaired lymphatic function in both legs and seven patients had a marginal degree of impairment in one or both legs. However, in none of these cases did the impairment attain the low levels seen in true lymphoedema. Lipoedema appears to be a distinct clinical entity best classified as a lipodystrophy rather than a direct consequence of any primary venous or lymphatic insufficiency.

  13. Genetics of lymphatic anomalies

    PubMed Central

    Brouillard, Pascal; Boon, Laurence; Vikkula, Miikka

    2014-01-01

    Lymphatic anomalies include a variety of developmental and/or functional defects affecting the lymphatic vessels: sporadic and familial forms of primary lymphedema, secondary lymphedema, chylothorax and chylous ascites, lymphatic malformations, and overgrowth syndromes with a lymphatic component. Germline mutations have been identified in at least 20 genes that encode proteins acting around VEGFR-3 signaling but also downstream of other tyrosine kinase receptors. These mutations exert their effects via the RAS/MAPK and the PI3K/AKT pathways and explain more than a quarter of the incidence of primary lymphedema, mostly of inherited forms. More common forms may also result from multigenic effects or post-zygotic mutations. Most of the corresponding murine knockouts are homozygous lethal, while heterozygotes are healthy, which suggests differences in human and murine physiology and the influence of other factors. PMID:24590274

  14. Smooth muscle–endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation

    PubMed Central

    Lutter, Sophie; Xie, Sherry; Tatin, Florence

    2012-01-01

    Active lymph transport relies on smooth muscle cell (SMC) contractions around collecting lymphatic vessels, yet regulation of lymphatic vessel wall assembly and lymphatic pumping are poorly understood. Here, we identify Reelin, an extracellular matrix glycoprotein previously implicated in central nervous system development, as an important regulator of lymphatic vascular development. Reelin-deficient mice showed abnormal collecting lymphatic vessels, characterized by a reduced number of SMCs, abnormal expression of lymphatic capillary marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and impaired function. Furthermore, we show that SMC recruitment to lymphatic vessels stimulated release and proteolytic processing of endothelium-derived Reelin. Lymphatic endothelial cells in turn responded to Reelin by up-regulating monocyte chemotactic protein 1 (MCP1) expression, which suggests an autocrine mechanism for Reelin-mediated control of endothelial factor expression upstream of SMC recruitment. These results uncover a mechanism by which Reelin signaling is activated by communication between the two cell types of the collecting lymphatic vessels—smooth muscle and endothelial cells—and highlight a hitherto unrecognized and important function for SMCs in lymphatic vessel morphogenesis and function. PMID:22665518

  15. Evaluation of lymphatic dysplasia in patients with congenital pleural effusion and ascites using indocyanine green lymphography.

    PubMed

    Shibasaki, Jun; Hara, Hisako; Mihara, Makoto; Adachi, Shinya; Uchida, Yasushi; Itani, Yasufumi

    2014-05-01

    To investigate the use of indocyanine green (ICG) lymphography in the diagnosis and assessment of the severity of lymphatic dysfunction in infants and neonates with congenital lymphatic pleural effusion and ascites. We performed ICG lymphography on 10 neonates and infants with congenital lymphatic pleural effusion and ascites. After the subcutaneous injection of ICG, circumferential fluorescent images of lymphatic drainage channels in the extremities and trunk were identified using an infrared camera system. The lymphographic findings were classifiable into 2 patterns-those showing a linear lymphatic pattern, suggesting normal lymphatic flow, and those showing lymphatic channels with retrograde lymphatic flow (dermal backflow pattern), suggesting an abnormal lymphatic flow. We analyzed the severity of the ICG lymphography findings and the clinical outcomes. Based on the ICG lymphography, the severity of lymphatic dysplasia were classified into 4 categories: mild dysplasia, moderate dysplasia, severe dysplasia, and lymphatic hypoplasia. All cases diagnosed with mild (n = 3) or moderate dysplasia (n = 2) survived, and 2 of the 4 cases diagnosed with severe dysplasia died. The duration of endotracheal intubation ranged from 1 to 17 days (median, 7) in the patients with mild or moderate dysplasia and from 25 to 110 days (median, 77) in those with severe dysplasia. The ICG lymphographic findings were consistent with the clinical conditions. This imaging technique may be important to the future clinical management of lymphatic dysplasia in neonates and infants. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Spleen and Lymphatic System (For Parents)

    MedlinePlus

    ... Your 1- to 2-Year-Old Spleen and Lymphatic System KidsHealth > For Parents > Spleen and Lymphatic System A ... help fight off infection. About the Spleen and Lymphatic System One of the lymphatic system's major jobs is ...

  17. Spleen and Lymphatic System (For Parents)

    MedlinePlus

    ... TV, Video Games, and the Internet Spleen and Lymphatic System KidsHealth > For Parents > Spleen and Lymphatic System Print ... help fight off infection. About the Spleen and Lymphatic System One of the lymphatic system's major jobs is ...

  18. Mechanical Forces and Lymphatic Transport

    PubMed Central

    Breslin, Jerome W.

    2014-01-01

    This review examines current understanding of how the lymphatic vessel network can optimize lymph flow in response to various mechanical forces. Lymphatics are organized as a vascular tree, with blind-ended initial lymphatics, precollectors, prenodal collecting lymphatics, lymph nodes, postnodal collecting lymphatics and the larger trunks (thoracic duct and right lymph duct) that connect to the subclavian veins. The formation of lymph from interstitial fluid depends heavily on oscillating pressure gradients to drive fluid into initial lymphatics. Collecting lymphatics are segmented vessels with unidirectional valves, with each segment, called a lymphangion, possessing an intrinsic pumping mechanism. The lymphangions propel lymph forward against a hydrostatic pressure gradient. Fluid is returned to the central circulation both at lymph nodes and via the larger lymphatic trunks. Several recent developments are discussed, including: evidence for the active role of endothelial cells in lymph formation; recent developments on how inflow pressure, outflow pressure, and shear stress affect pump function of the lymphangion; lymphatic valve gating mechanisms; collecting lymphatic permeability; and current interpretations of the molecular mechanisms within lymphatic endothelial cells and smooth muscle. Improved understanding of the physiological mechanisms by lymphatic vessels sense mechanical stimuli, integrate the information, and generate the appropriate response is key for determining the pathogenesis of lymphatic insufficiency and developing treatments for lymphedema. PMID:25107458

  19. What Is the Lymphatic System?

    MedlinePlus

    ... 9) 2017 NLN International Conference What is the Lymphatic System? To better understand lymphedema , we first must understand the normal lymphatic system (see diagram) . This system functions parallel to the ...

  20. What Is the Lymphatic System?

    MedlinePlus

    ... information and to apply now! What is the Lymphatic System? To better understand lymphedema , we first must understand the normal lymphatic system (see diagram) . This system functions parallel to the ...

  1. Lymphatics and the breast

    MedlinePlus Videos and Cool Tools

    ... a very worrisome role in the spread of breast cancer. Components of the lymphatic system called lymph nodes ... may result in the formation of a secondary cancer mass in a different location of the body. Regular breast self examinations can help to detect tumors earlier ...

  2. [Pleural lymphatics and effusions].

    PubMed

    Mordant, P; Arame, A; Legras, A; Le Pimpec Barthes, F; Riquet, M

    2013-06-01

    The pleural lymphatic system has a great absorption capacity. Its most known function is fluid resorption. The pleura which cover the lungs (visceral pleura), the mediastinum, diaphragm and thoracic wall (parietal pleura) are formed by a mesothelial cell layer (mesothelium). This permeable layer is in direct contact with the vascular endothelium. The mesothelium is based over a connective tissue (interstitium) containing the blood and lymphatic vessels. The primary lymphatic vessels drain interstitium but are also in direct contact with pleural space by the stoma or openings, situated in the lower parts of parietal pleura, i.e: diaphragm, over lower ribs and mediastinum but not existing in the adjacent visceral pleura. In addition, a part of interstitial pulmonary fluid entered in the pleural cavity by passing the visceral pleura would be absorbed by these openings. The resorption process is active and directly related to the function of smooth muscles of lymphatic vessels. Besides resorption, we must emphasize that this "pumping" activity is permanent and the origin of negative pressure (the pleural void) in pleural cavity, a unique property. The other resorbed elements are molecules, bacterial and cellular debris, cells, red blood and cancer cells. Copyright © 2013. Published by Elsevier Masson SAS.

  3. Vascular Endothelial Growth Factor Receptor-2 Promotes the Development of the Lymphatic Vasculature

    PubMed Central

    Dellinger, Michael T.; Meadows, Stryder M.; Wynne, Katherine; Cleaver, Ondine; Brekken, Rolf A.

    2013-01-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1wt/Cre;Vegfr2flox/flox mice possess significantly fewer dermal lymphatic vessels than Vegfr2flox/flox mice. Although Lyve-1wt/Cre;Vegfr2flox/flox mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1Cre mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1wt/Cre;Vegfr2flox/flox embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1wt/Cre;Vegfr2flox/flox mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system. PMID:24023956

  4. Vascular endothelial growth factor receptor-2 promotes the development of the lymphatic vasculature.

    PubMed

    Dellinger, Michael T; Meadows, Stryder M; Wynne, Katherine; Cleaver, Ondine; Brekken, Rolf A

    2013-01-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1(wt/Cre);Vegfr2(flox/flox) mice possess significantly fewer dermal lymphatic vessels than Vegfr2(flox/flox) mice. Although Lyve-1(wt/Cre);Vegfr2(flox/flox) mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1(Cre) mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1(wt/Cre);Vegfr2(flox/flox) embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1(wt/Cre);Vegfr2(flox/flox) mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system.

  5. Diffuse pulmonary lymphatic disease presenting as interstitial lung disease in adulthood: report of 3 cases.

    PubMed

    Boland, Jennifer M; Tazelaar, Henry D; Colby, Thomas V; Leslie, Kevin O; Hartman, Thomas E; Yi, Eunhee S

    2012-10-01

    Diffuse pulmonary lymphatic diseases are typically diagnosed shortly after birth or in childhood, but rarely may become evident in adulthood. We report 3 adult patients who presented with diffuse interstitial lung disease clinically and radiologically but on biopsy were found to have diffuse pulmonary lymphatic disease (2 cases of pulmonary lymphangiectasis and 1 case of pulmonary lymphangiomatosis). These patients presented with the insidious onset of symptoms including shortness of breath and cough. Imaging studies of the chest showed diffuse pulmonary interstitial opacities, often with a perilymphatic distribution. The clinical differential diagnostic considerations before surgical lung biopsy included infection, neoplasm, and interstitial lung disease. The histopathologic features included abnormal vessels and associated fibrosis following lymphatic routes, namely visceral pleura, bronchovascular bundles, and interlobular septa. Lymphangiectasis was characterized by dilation of normally distributed lymphatic spaces, whereas lymphangiomatosis showed a complex anastamosing proliferation of lymphatic vascular spaces without significant dilatation. The dilated lymphatic spaces often had undergone muscularization, which could easily lead to misclassification as veins. Immunohistochemical staining for the lymphatic endothelial marker D2-40 was helpful in correctly classifying these lesions. Diffuse pulmonary lymphatic disease can rarely present in adulthood, wherein the histologic findings can be subtle and could be overlooked as nonspecific reactive changes or misdiagnosed as an idiopathic interstitial lung disease. Recognition of the characteristic lymphangitic distribution of abnormally dilated or reduplicated lymphatic spaces is key to the correct diagnosis.

  6. Lymphatic filariasis and onchocerciasis.

    PubMed

    Taylor, Mark J; Hoerauf, Achim; Bockarie, Moses

    2010-10-02

    Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. The lymphatic vasculature in disease.

    PubMed

    Alitalo, Kari

    2011-11-07

    Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.

  8. FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

    PubMed Central

    Sabine, Amélie; Bovay, Esther; Demir, Cansaran Saygili; Kimura, Wataru; Jaquet, Muriel; Agalarov, Yan; Zangger, Nadine; Scallan, Joshua P.; Graber, Werner; Gulpinar, Elgin; Kwak, Brenda R.; Mäkinen, Taija; Martinez-Corral, Inés; Ortega, Sagrario; Delorenzi, Mauro; Kiefer, Friedemann; Davis, Michael J.; Djonov, Valentin; Miura, Naoyuki; Petrova, Tatiana V.

    2015-01-01

    Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease. PMID:26389677

  9. Mechanosensing in developing lymphatic vessels.

    PubMed

    Planas-Paz, Lara; Lammert, Eckhard

    2014-01-01

    The lymphatic vasculature is responsible for fluid homeostasis, transport of immune cells, inflammatory molecules, and dietary lipids. It is composed of a network of lymphatic capillaries that drain into collecting lymphatic vessels and ultimately bring fluid back to the blood circulation. Lymphatic endothelial cells (LECs) that line lymphatic capillaries present loose overlapping intercellular junctions and anchoring filaments that support fluid drainage. When interstitial fluid accumulates within tissues, the extracellular matrix (ECM) swells and pulls the anchoring filaments. This results in opening of the LEC junctions and permits interstitial fluid uptake. The absorbed fluid is then transported within collecting lymphatic vessels, which exhibit intraluminal valves that prevent lymph backflow and smooth muscle cells that sequentially contract to propel lymph.Mechanotransduction involves translation of mechanical stimuli into biological responses. LECs have been shown to sense and respond to changes in ECM stiffness, fluid pressure-induced cell stretch, and fluid flow-induced shear stress. How these signals influence LEC function and lymphatic vessel growth can be investigated by using different mechanotransduction assays in vitro and to some extent in vivo.In this chapter, we will focus on the mechanical forces that regulate lymphatic vessel expansion during embryonic development and possibly secondary lymphedema. In mouse embryos, it has been recently shown that the amount of interstitial fluid determines the extent of lymphatic vessel expansion via a mechanosensory complex formed by β1 integrin and vascular endothelial growth factor receptor-3 (VEGFR3). This model might as well apply to secondary lymphedema.

  10. Neither normal nor diseased placentas contain lymphatic vessels.

    PubMed

    Castro, E; Tony Parks, W; Galambos, C

    2011-04-01

    Scant data on placental lymphatic vessels have pointed to the absence of lymphatic circulation. A recent study on mesenchymal dysplasia (MD), however, has identified pathologic lymphangiogenesis using the D2-40 lymphatic marker. These conflicting data have prompted us to investigate whether lymphatic vessels are present in normal developing placentas and in placental disorders characterized by cistern formation. Seventeen human placentas without significant pathological abnormality ranging from 12 to 39 weeks of gestational age were studied. Cisternal placental disorders were represented by mesenchymal dysplasia (n = 1), partial hydatitiform mole (n = 2), spontaneous abortion (n = 3) and complete hydatiform mole (n = 2). To identify lymphatic vessels, we used lymphatic endothelial markers Prox-1 and D2-40. The pan-endothelial marker CD31 was used to highlight overall placental vasculature and to determine if the lining cells of cisterns were of endothelial origin. Lymphatic marker positivity was assessed in maternal (decidual) as well as in fetal (chorionic villous) vasculature. No staining with Prox-1 or D2-40 was identified in fetal vessels in developing or term placentas, or in selected cisternal placental disorders, although both markers highlighted a number of thin-walled decidual vessels. Cistern lining cells were negative for Prox-1, D2-40 and CD31. D2-40 consistently marked stromal cells in chorionic villi and highlighted perivascular/pericellular extracellular matrix. We established that no lymphatic vasculature is present in the chorionic villi during development, at term or in selected edematous placental disorders. The cisternal lining cells are not endothelial cells; most likely they are of stromal cell origin. Lymphangiogenesis is a part of decidual vascular remodeling during gestation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Thoracic involvement in generalised lymphatic anomaly (or lymphangiomatosis).

    PubMed

    Luisi, Francesca; Torre, Olga; Harari, Sergio

    2016-06-01

    Generalised lymphatic anomaly (GLA), also known as lymphangiomatosis, is a rare disease caused by congenital abnormalities of lymphatic development. It usually presents in childhood but can also be diagnosed in adults. GLA encompasses a wide spectrum of clinical manifestations ranging from single-organ involvement to generalised disease. Given the rarity of the disease, most of the information regarding it comes from case reports. To date, no clinical trials concerning treatment are available. This review focuses on thoracic GLA and summarises possible diagnostic and therapeutic approaches. Copyright ©ERS 2016.

  12. Postnatal Deletion of Podoplanin in Lymphatic Endothelium Results in Blood Filling of the Lymphatic System and Impairs Dendritic Cell Migration to Lymph Nodes.

    PubMed

    Bianchi, Roberta; Russo, Erica; Bachmann, Samia B; Proulx, Steven T; Sesartic, Marko; Smaadahl, Nora; Watson, Steve P; Buckley, Christopher D; Halin, Cornelia; Detmar, Michael

    2017-01-01

    The lymphatic vascular system exerts major physiological functions in the transport of interstitial fluid from peripheral tissues back to the blood circulation and in the trafficking of immune cells to lymph nodes. Previous studies in global constitutive knockout mice for the lymphatic transmembrane molecule podoplanin reported perinatal lethality and a complex phenotype with lung abnormalities, cardiac defects, lymphedema, blood-filled lymphatic vessels, and lack of lymph node organization, reflecting the importance of podoplanin expression not only by the lymphatic endothelium but also by a variety of nonendothelial cell types. Therefore, we aimed to dissect the specific role of podoplanin expressed by adult lymphatic vessels. We generated an inducible, lymphatic-specific podoplanin knockout mouse model (Pdpn(ΔLEC)) and induced gene deletion postnatally. Pdpn(ΔLEC) mice were viable, and their lymphatic vessels appeared morphologically normal with unaltered fluid drainage function. Intriguingly, Pdpn(ΔLEC) mice had blood-filled lymph nodes and vessels, most frequently in the neck and axillary region, and displayed a blood-filled thoracic duct, suggestive of retrograde filling of blood from the blood circulation into the lymphatic system. Histological and fluorescence-activated cell sorter analyses revealed normal lymph node organization with the presence of erythrocytes within lymph node lymphatic vessels but not surrounding high endothelial venules. Moreover, fluorescein isothiocyanate painting experiments revealed reduced dendritic cell migration to lymph nodes in Pdpn(ΔLEC) mice. These results reveal an important role of podoplanin expressed by lymphatic vessels in preventing postnatal blood filling of the lymphatic vascular system and in contributing to efficient dendritic cell migration to the lymph nodes. © 2016 American Heart Association, Inc.

  13. Lymphatic System in Cardiovascular Medicine.

    PubMed

    Aspelund, Aleksanteri; Robciuc, Marius R; Karaman, Sinem; Makinen, Taija; Alitalo, Kari

    2016-02-05

    The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease. © 2016 American Heart Association, Inc.

  14. Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice

    PubMed Central

    Proulx, Steven T.; Dillard, Miriam E.; Johnson, Nicole; Detmar, Michael

    2016-01-01

    Prox1 heterozygous mice have a defective lymphatic vasculature and develop late-onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, and causes an increase in adipose tissue. We characterized the lymphatics of Prox1+/– mice to determine whether the extent of obesity correlated with the severity of lymphatic defects. The lymphatic vasculature in Prox1+/– mice exhibited reduced tracer clearance from the ear skin, dysfunctional perfusion of the lower legs, and reduced tracer uptake into the deep lymphatic collectors during mechanostimulation prior to the onset of obesity. Ear lymphatic vessels and leg collectors in Prox1+/– mice were disorganized and irregular, further confirming that defective lymphatic vessels are associated with obesity in Prox1+/– mice. We now provide conclusive in vivo evidence that demonstrates that leaky lymphatics mediate obesity in Prox1+/– mice, as restoration of lymphatic vasculature function was sufficient to rescue the obesity features in Prox1+/– mice. Finally, depth-lipomic profiling of lymph contents showed that free fatty acids induce adipogenesis in vitro. PMID:26973883

  15. LYMPHATIC VESSELS IN HEALTH AND DISEASE

    PubMed Central

    Kesler, Cristina T.; Liao, Shan; Munn, Lance L.; Padera, Timothy P.

    2012-01-01

    The lymphatic vasculature plays vital roles in tissue fluid balance, immune defense, metabolism and cancer metastasis. In adults, lymphatic vessel formation and remodeling occurs primarily during inflammation, development of the corpus luteum, wound healing, and tumor growth. Unlike the blood circulation, where unidirectional flow is sustained by the pumping actions of the heart, pumping actions intrinsic to the lymphatic vessels themselves are important drivers of lymphatic flow. This review summarizes critical components that control lymphatic physiology. PMID:23209022

  16. Mapping superficial lymphatic territories in the rabbit.

    PubMed

    Soto-Miranda, Miguel A; Suami, Hiroo; Chang, David W

    2013-06-01

    Little is known about the anatomy of the lymphatic system in the rabbit with regard to relationships between the lymphatic vessel and lymph node. According to our previous studies in human cadavers and canines, the superficial lymphatic system could be divided into lymphatic territories. The aim of this study was to completely map the superficial lymphatic system in the rabbit. We used our microinjection technique and histological analysis for dissecting studies and recently developed indocyanine green (ICG) fluorescent lymphography for demonstrating dynamic lymph flow in living rabbits. Real-time ICG fluorescent lymphography was performed in two living New Zealand White rabbits, and direct dye microinjection of the lymphatic vessels was performed in eight dead rabbits. To assess the relationships between the vascular and lymphatic systems in rabbits, we performed radiocontrast injection into arteries in two dead rabbits prior to the lymphatic injection. The ICG fluorescent lymphography revealed eight lymphatic territories in the preauricular, submandibular, root of the lateral neck, axillary, lumbar, inguinal, root of the tail, and popliteal regions. We injected blue acrylic dye into every lymphatic vessel 0.1 mm in diameter or larger. We then dissected and chased the stained lymphatic vessels proximally until the vessels connected to the first tier lymph node. This procedure was repeated throughout the body until all the relationships between the lymphatic vessels and lymph nodes were defined. The lymphatic system of the rabbit could be defined as eight lymphatic territories, each with its own lymphatic vessels and lymph node.

  17. Lymphatic Biodistribution of Polylactide Nanoparticles

    PubMed Central

    Chaney, Eric J.; Tang, Li; Tong, Rong; Cheng, Jianjun; Boppart, Stephen A.

    2013-01-01

    Tumor metastases occur through both the cardiovascular and lymphatic circulations. However, the majority of nanoparticle biodistribution studies have been focused on the cardiovascular circulation. In this study, we report the formulation of Cy5-labeled polylactide (Cy5-PLA) nanoparticles with controlled size and surface features and the subsequent evaluation of their lymphatic biodistribution. Cy5-PLA nanoparticles were formulated through Cy5/(BDI)ZnN(TMS)2-mediated [(BDI) = 2-((2,6-diisopropylphenyl) amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene] ring-opening polymerization of lactide followed by nanoprecipitation. Their lymphatic biodistribution was evaluated by using whole-body fluorescence imaging of nude mice and ex vivo fluorescence imaging of the resected organs. This technique has the potential for providing optical contrast and drug delivery through the lymphatic circulation for the treatment of metastatic cancer. PMID:20487681

  18. Distribution and alteration of lymphatic vessels in knee joints of normal and osteoarthritic mice.

    PubMed

    Shi, Jixiang; Liang, Qianqian; Zuscik, Michael; Shen, Jie; Chen, Di; Xu, Hao; Wang, Yong-Jun; Chen, Yan; Wood, Ronald W; Li, Jia; Boyce, Brendan F; Xing, Lianping

    2014-03-01

    To investigate the distribution and alteration of lymphatic vessels and draining function in knee joints of normal and osteoarthritic mice. For the mouse models of osteoarthritis (OA), we used mice with meniscal-ligamentous injury or mice with conditional knockout of the gene for cartilage transforming growth factor β (TGFβ) type II receptor. The severity of cartilage loss and joint destruction was assessed histologically. Capillary and mature lymphatic vessels were identified and analyzed using double immunofluorescence staining and a whole-slide digital imaging system. Lymphatic drainage of knee joints was examined using near-infrared lymphatic imaging. Patient joint specimens obtained during total knee or hip arthroplasty were evaluated to verify the content validity of the mouse findings. Lymphatic vessels were distributed in soft tissues (mainly around the joint capsule, ligaments, fat pads, and muscles of normal knees). The number of lymphatic vessels, particularly the number of capillaries, was significantly increased in joints of mice with mild OA, while the number of mature lymphatic vessels was markedly decreased in joints of mice with severe OA. OA knees exhibited significantly decreased lymph clearance. The number of both capillary and mature lymphatic vessels was significantly decreased in the joints of patients with OA. The whole-slide digital imaging system is a powerful tool, enabling the identification and assessment of lymphatic microvasculature in the entire mouse knee. Lymphatic capillaries and mature vessels are present in various soft tissues around articular spaces. Abnormalities of lymphatic vessels and draining function, including significantly reduced numbers of mature vessels and impaired clearance, are present in OA joints. Copyright © 2014 by the American College of Rheumatology.

  19. Distribution and Alteration of Lymphatic Vessels in Knee Joints of Normal and Osteoarthritic Mice

    PubMed Central

    Shi, Jixiang; Liang, Qianqian; Zuscik, Michael; Shen, Jie; Chen, Di; Xu, Hao; Wang, Yong-Jun; Chen, Yan; Wood, Ronald W.; Li, Jia; Boyce, Brendan F.; Xing, Lianping

    2014-01-01

    Objective To investigate the distribution and alteration of lymphatic vessels and draining function in knee joints of normal and osteoarthritic mice. Methods For the mouse models of osteoarthritis (OA), we used mice with meniscal-ligamentous injury or mice with conditional knockout of the gene for cartilage transforming growth factor β (TGF β) type II receptor. The severity of cartilage loss and joint destruction was assessed histologically. Capillary and mature lymphatic vessels were identified and analyzed using double immunofluorescence staining and a whole-slide digital imaging system. Lymphatic drainage of knee joints was examined using near-infrared lymphatic imaging. Patient joint specimens obtained during total knee or hip arthroplasty were evaluated to verify the content validity of the mouse findings. Results Lymphatic vessels were distributed in soft tissues (mainly around the joint capsule, ligaments, fat pads, and muscles of normal knees). The number of lymphatic vessels, particularly the number of capillaries, was significantly increased in joints of mice with mild OA, while the number of mature lymphatic vessels was markedly decreased in joints of mice with severe OA. OA knees exhibited significantly decreased lymph clearance. The number of both capillary and mature lymphatic vessels was significantly decreased in the joints of patients with OA. Conclusion The whole-slide digital imaging system is a powerful tool, enabling the identification and assessment of lymphatic microvasculature in the entire mouse knee. Lymphatic capillaries and mature vessels are present in various soft tissues around articular spaces. Abnormalities of lymphatic vessels and draining function, including significantly reduced numbers of mature vessels and impaired clearance, are present in OA joints. PMID:24574226

  20. Lymphatic Regulation of Cellular Trafficking

    PubMed Central

    Jackson, David G.

    2016-01-01

    Lymphatic vessels play vital roles in immune surveillance and immune regulation by conveying antigen loaded dendritic cells, memory T cells, macrophages and neutrophils from the peripheral tissues to draining lymph nodes where they initiate as well as modify immune responses. Until relatively recently however, there was little understanding of how entry and migration through lymphatic vessels is organized or the specific molecular mechanisms that might be involved. Within the last decade, the situation has been transformed by an explosion of knowledge generated largely through the application of microscopic imaging, transgenic animals, specific markers and function blocking mAbs that is beginning to provide a rational conceptual framework. This article provides a critical review of the recent literature, highlighting seminal discoveries that have revealed the fascinating ultrastructure of leucocyte entry sites in lymphatic vessels, as well as generating controversies over the involvement of integrin adhesion, chemotactic and haptotactic mechanisms in DC entry under normal and inflamed conditions. It also discusses the major changes in lymphatic architecture that occur during inflammation and the different modes of leucocyte entry and trafficking within inflamed lymphatic vessels, as well as presenting a timely update on the likely role of hyaluronan and the major lymphatic endothelial hyaluronan receptor LYVE-1 in leucocyte transit. PMID:27808282

  1. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome.

    PubMed

    Dagenais, Susan L; Hartsough, Rebecca L; Erickson, Robert P; Witte, Marlys H; Butler, Matthew G; Glover, Thomas W

    2004-10-01

    The molecular events involved in lymphatic development are poorly understood. Hence, the genes responsible for hereditary lymphedema are of great interest due to the potential for providing insights into the mechanisms of lymphatic development, the diagnosis, prevention and treatment of lymphedema, and lymphangiogenesis during tumor growth. Mutations in the FOXC2 transcription factor cause a major form of hereditary lymphedema, the lymphedema-distichiasis syndrome. We have conducted a study of Foxc2 expression during mouse development using immunohistochemistry, and examined its expression in lymphatics compared to its paralog Foxc1 and to Vegfr-3, Prox1 and other lymphatic and blood vascular proteins. We have found that Foxc2 is expressed in lymphatic primordia, jugular lymph sacs, lymphatic collectors and capillaries, as well as in podocytes, developing eyelids and other tissues associated with abnormalities in lymphedema-distichiasis syndrome.

  2. Successful treatment of plastic bronchitis by selective lymphatic embolization in a Fontan patient.

    PubMed

    Dori, Yoav; Keller, Marc S; Rychik, Jack; Itkin, Maxim

    2014-08-01

    Plastic bronchitis is a rare and often fatal complication of single-ventricle surgical palliation after total cavopulmonary connection. Although lymphatic abnormalities have been postulated to play a role in the disease process, the etiology and pathophysiology of this complication remain incompletely understood. Here we report on the etiology of plastic bronchitis in a child with total cavopulmonary connection as demonstrated by magnetic resonance (MR) lymphangiography. We also report on a new treatment of this disease. The patient underwent noncontrast T2-weighted MR lymphatic mapping and dynamic contrast MR lymphangiography with bi-inguinal intranodal contrast injection to determine the anatomy and flow pattern of lymph in his central lymphatic system. The MRI scan demonstrated the presence of a dilated right-sided peribronchial lymphatic network supplied by retrograde lymphatic flow through a large collateral lymphatic vessel originating from the thoracic duct. After careful analysis of the MRI scans we performed selective lymphatic embolization of the pathologic lymphatic network and supplying vessel. This provided resolution of plastic bronchitis for this patient. Five months after the procedure, the patient remains asymptomatic off respiratory medications.

  3. Achondrogenesis type II (Langer-Saldino) in association with jugular lymphatic obstruction sequence.

    PubMed

    Wenstrom, K D; Williamson, R A; Hoover, W W; Grant, S S

    1989-07-01

    The prenatal diagnosis of achondrogenesis in association with cystic hygroma is described. Ultrasound findings of severe short-limbed dwarfism, decreased vertebral ossification, and normal ossification of the calvarium were all consistent with achondrogenesis type II. Although the unusual finding of associated cystic hygroma raised the suspicion of a concurrent chromosome abnormality, the karyotype of both fetal lymphocytes and fetal fibroblasts was normal. Autopsy confirmed dilated lymphatic channels in the basal endothelial layer of the skin, cystic hygroma, and coarctation of the aorta. Although previously unreported, we suggest that the features of this case of achondrogenesis indicate an association with lymphatic stasis and jugular lymphatic obstruction sequence in this syndrome.

  4. Lymphatic Regeneration Within Porous VEGF-C Hydrogels for Secondary Lymphedema

    DTIC Science & Technology

    2004-07-01

    AD Award Number: DAMD17-01-1-0152 TITLE: Lymphatic Regeneration Within Porous VEGF-C Hydrogels for Secondary Lymphedema PRINCIPAL INVESTIGATOR...Lymphatic Regeneration Within Porous VEGF-C Hydrogels for DAMD17-01-1-0152 Secondary Lymphedema 6. A UTHOR(S) Mauricio A. Contreras, M.D. 7. PERFORMING...ABSTRACT (Maximum 200 Words) Introduction: Lymphedema is an abnormal swelling, in which lymph production exceeds drainage capabilities. This occurs as a

  5. General surgery, translational lymphology and lymphatic surgery.

    PubMed

    Campisi, C; Witte, M H; Fulcheri, E; Campisi, C; Bellini, C; Villa, G; Campisi, C; Santi, P L; Parodi, A; Murdaca, G; Puppo, F; Boccardo, F

    2011-12-01

    A wide clinical experience in General Surgery has brought about a remarkable knowledge about lymphatic disorders both primary and secondary ones. Diagnostic and histopathological studies of lymphatic diseases allowed to better understand etiological aspects and pathophysiological mechanisms responsible of complex clinical features correlated to lymphatic dysfunctions. Translational lymphologic basic and clinical researches permitted to improve therapeutical approaches both from the medical and surgical point of view. Thus, strategies of treatment were proposed to prevent lymphatic injuries, to avoid lymphatic complications and to treat lymphatic diseases early in order to be able even to cure these pathologies.

  6. Altered lymphatics in an ovine model of congenital heart disease with increased pulmonary blood flow.

    PubMed

    Datar, Sanjeev A; Johnson, Eric G; Oishi, Peter E; Johengen, Michael; Tang, Eric; Aramburo, Angela; Barton, Jubilee; Kuo, Hsuan-Chang; Bennett, Stephen; Xoinis, Konstantine; Reel, Bhupinder; Kalkan, Gokhan; Sajti, Eniko; Osorio, Oscar; Raff, Gary W; Matthay, Michael A; Fineman, Jeffrey R

    2012-03-15

    Abnormalities of the lymphatic circulation are well recognized in patients with congenital heart defects. However, it is not known how the associated abnormal blood flow patterns, such as increased pulmonary blood flow (PBF), might affect pulmonary lymphatic function and structure. Using well-established ovine models of acute and chronic increases in PBF, we cannulated the efferent lymphatic duct of the caudal mediastinal node and collected and analyzed lymph effluent from the lungs of lambs with acutely increased PBF (n = 6), chronically increased PBF (n = 6), and age-matched normal lambs (n = 8). When normalized to PBF, we found that lymph flow was unchanged following acute increases in PBF but decreased following chronic increases in PBF. The lymph:plasma protein ratio decreased with both acute and chronic increases in PBF. Lymph bioavailable nitric oxide increased following acute increases in PBF but decreased following chronic increases in PBF. In addition, we found perturbations in the transit kinetics of contrast material through the pleural lymphatics of lambs with chronic increases in PBF. Finally, there were structural changes in the pulmonary lymphatic system in lambs with chronic increases in PBF: lymphatics from these lambs were larger and more dilated, and there were alterations in the expression of vascular endothelial growth factor-C, lymphatic vessel endothelial hyaluronan receptor-1, and Angiopoietin-2, proteins known to be important for lymphatic growth, development, and remodeling. Taken together these data suggest that chronic increases in PBF lead to both functional and structural aberrations of lung lymphatics. These findings have important therapeutic implications that warrant further study.

  7. Lymphatic regulation in nonmammalian vertebrates.

    PubMed

    Hedrick, Michael S; Hillman, Stanley S; Drewes, Robert C; Withers, Philip C

    2013-08-01

    All vertebrate animals share in common the production of lymph through net capillary filtration from their closed circulatory system into their tissues. The balance of forces responsible for net capillary filtration and lymph formation is described by the Starling equation, but additional factors such as vascular and interstitial compliance, which vary markedly among vertebrates, also have a significant impact on rates of lymph formation. Why vertebrates show extreme variability in rates of lymph formation and how nonmammalian vertebrates maintain plasma volume homeostasis is unclear. This gap hampers our understanding of the evolution of the lymphatic system and its interaction with the cardiovascular system. The evolutionary origin of the vertebrate lymphatic system is not clear, but recent advances suggest common developmental factors for lymphangiogenesis in teleost fishes, amphibians, and mammals with some significant changes in the water-land transition. The lymphatic system of anuran amphibians is characterized by large lymphatic sacs and two pairs of lymph hearts that return lymph into the venous circulation but no lymph vessels per se. The lymphatic systems of reptiles and some birds have lymph hearts, and both groups have extensive lymph vessels, but their functional role in both lymph movement and plasma volume homeostasis is almost completely unknown. The purpose of this review is to present an evolutionary perspective in how different vertebrates have solved the common problem of the inevitable formation of lymph from their closed circulatory systems and to point out the many gaps in our knowledge of this evolutionary progression.

  8. Fluid-solid modeling of lymphatic valves

    NASA Astrophysics Data System (ADS)

    Caulk, Alexander; Ballard, Matthew; Nepiyushchikh, Zhanna; Dixon, Brandon; Alexeev, Alexander

    2015-11-01

    The lymphatic system performs important physiological functions such as the return of interstitial fluid to the bloodstream to maintain tissue fluid balance, as well as the transport of immune cells in the body. It utilizes contractile lymphatic vessels, which contain valves that open and close to allow flow in only one direction, to directionally pump lymph against a pressure gradient. We develop a fluid-solid model of geometrically representative lymphatic valves. Our model uses a hybrid lattice-Boltzmann lattice spring method to capture fluid-solid interactions with two-way coupling between a viscous fluid and lymphatic valves in a lymphatic vessel. We use this model to investigate the opening and closing of lymphatic valves, and its effect on lymphatic pumping. This helps to broaden our understanding of the fluid dynamics of the lymphatic system.

  9. Lymphatics and blood vessels.

    PubMed

    Millikan, Larry E

    2011-01-01

    The traditional nomenclature of vascular lesions has been enlarged and modified with the usage of newer diagnostic techniques. Digital technology has enhanced the precision of older analog tools such as Doppler flow studies. Angiograms have also more precisely delineated flow patterns to allow planned surgical intervention as an important therapeutic option. With the newer classification, it now is possible to plan and anticipate the course of lesions and medically intervene in tumors that potentially will enlarge and impinge on essential structures. Now, the routine workup will clarify if there is internal involvement (eg, liver, etc) and detect proliferative potential mandating medical or surgical intervention. Watchful waiting, the traditional approach is now changing with the newer delineation of syndromes such as PHACE (posterior fossa, hemangioma, arterial lesions, cardiac abnormalities/aortic coarctation, eye abnormalities), which mandate the fullest evaluation and, in many instances, the collaboration of multispecialty groups to treat those lesions as the data and group consensus determines.

  10. lyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish.

    PubMed

    Okuda, Kazuhide S; Astin, Jonathan W; Misa, June P; Flores, Maria V; Crosier, Kathryn E; Crosier, Philip S

    2012-07-01

    We have generated novel transgenic lines that brightly mark the lymphatic system of zebrafish using the lyve1 promoter. Facilitated by these new transgenic lines, we generated a map of zebrafish lymphatic development up to 15 days post-fertilisation and discovered three previously uncharacterised lymphatic vessel networks: the facial lymphatics, the lateral lymphatics and the intestinal lymphatics. We show that a facial lymphatic vessel, termed the lateral facial lymphatic, develops through a novel developmental mechanism, which initially involves vessel growth through a single vascular sprout followed by the recruitment of lymphangioblasts to the vascular tip. Unlike the lymphangioblasts that form the thoracic duct, the lymphangioblasts that contribute to the lateral facial lymphatic vessel originate from a number of different blood vessels. Our work highlights the additional complexity of lymphatic vessel development in the zebrafish that may increase its versatility as a model of lymphangiogenesis.

  11. Evidence for SH2 Domain-Containing 5′-Inositol Phosphatase-2 (SHIP2) Contributing to a Lymphatic Dysfunction

    PubMed Central

    Agollah, Germaine D.; Gonzalez-Garay, Manuel L.; Rasmussen, John C.; Tan, I-Chih; Aldrich, Melissa B.; Darne, Chinmay; Fife, Caroline E.; Guilliod, Renie; Maus, Erik A.; King, Philip D.; Sevick-Muraca, Eva M.

    2014-01-01

    The lymphatic vasculature plays a critical role in a number of disease conditions of increasing prevalence, such as autoimmune disorders, obesity, blood vascular diseases, and cancer metastases. Yet, unlike the blood vasculature, the tools available to interrogate the molecular basis of lymphatic dysfunction/disease have been lacking. More recently, investigators have reported that dysregulation of the PI3K pathway is involved in syndromic human diseases that involve abnormal lymphatic vasculatures, but there have been few compelling results that show the direct association of this molecular pathway with lymphatic dysfunction in humans. Using near-infrared fluorescence lymphatic imaging (NIRFLI) to phenotype and next generation sequencing (NGS) for unbiased genetic discovery in a family with non-syndromic lymphatic disease, we discovered a rare, novel mutation in INPPL1 that encodes the protein SHIP2, which is a negative regulator of the PI3K pathway, to be associated with lymphatic dysfunction in the family. In vitro interrogation shows that SHIP2 is directly associated with impairment of normal lymphatic endothelial cell (LEC) behavior and that SHIP2 associates with receptors that are associated in lymphedema, implicating its direct involvement in the lymphatic vasculature. PMID:25383712

  12. Essential Role of the Coxsackie - and Adenovirus Receptor (CAR) in Development of the Lymphatic System in Mice

    PubMed Central

    Zaini, Mohamad Amr; Haiko, Paula; Tammela, Tuomas; Alitalo, Kari; Philipson, Lennart; Fuxe, Jonas; Sollerbrant, Kerstin

    2012-01-01

    The coxsackie- and adenovirus receptor (CAR) is a cell adhesion molecule predominantly associated with epithelial tight junctions in adult tissues. CAR is also expressed in cardiomyocytes and essential for heart development up to embryonic day 11.5, but not thereafter. CAR is not expressed in vascular endothelial cells but was recently detected in neonatal lymphatic vessels, suggesting that CAR could play a role in the development of the lymphatic system. To address this, we generated mice carrying a conditional deletion of the CAR gene (Cxadr) and knocked out CAR in the mouse embryo at different time points during post-cardiac development. Deletion of Cxadr from E12.5, but not from E13.5, resulted in subcutaneous edema, hemorrhage and embryonic death. Subcutaneous lymphatic vessels were dilated and structurally abnormal with gaps and holes present at lymphatic endothelial cell-cell junctions. Furthermore, lymphatic vessels were filled with erythrocytes showing a defect in the separation between the blood and lymphatic systems. Regionally, erythrocytes leaked out into the interstitium from leaky lymphatic vessels explaining the hemorrhage detected in CAR-deficient mouse embryos. The results show that CAR plays an essential role in development of the lymphatic vasculature in the mouse embryo by promoting appropriate formation of lymphatic endothelial cell-cell junctions. PMID:22624044

  13. Essential role of the coxsackie- and adenovirus receptor (CAR) in development of the lymphatic system in mice.

    PubMed

    Mirza, Momina; Pang, Mei-Fong; Zaini, Mohamad Amr; Haiko, Paula; Tammela, Tuomas; Alitalo, Kari; Philipson, Lennart; Fuxe, Jonas; Sollerbrant, Kerstin

    2012-01-01

    The coxsackie- and adenovirus receptor (CAR) is a cell adhesion molecule predominantly associated with epithelial tight junctions in adult tissues. CAR is also expressed in cardiomyocytes and essential for heart development up to embryonic day 11.5, but not thereafter. CAR is not expressed in vascular endothelial cells but was recently detected in neonatal lymphatic vessels, suggesting that CAR could play a role in the development of the lymphatic system. To address this, we generated mice carrying a conditional deletion of the CAR gene (Cxadr) and knocked out CAR in the mouse embryo at different time points during post-cardiac development. Deletion of Cxadr from E12.5, but not from E13.5, resulted in subcutaneous edema, hemorrhage and embryonic death. Subcutaneous lymphatic vessels were dilated and structurally abnormal with gaps and holes present at lymphatic endothelial cell-cell junctions. Furthermore, lymphatic vessels were filled with erythrocytes showing a defect in the separation between the blood and lymphatic systems. Regionally, erythrocytes leaked out into the interstitium from leaky lymphatic vessels explaining the hemorrhage detected in CAR-deficient mouse embryos. The results show that CAR plays an essential role in development of the lymphatic vasculature in the mouse embryo by promoting appropriate formation of lymphatic endothelial cell-cell junctions.

  14. Conditional ablation of LYVE-1+ cells unveils defensive roles of lymphatic vessels in intestine and lymph nodes.

    PubMed

    Jang, Jeon Yeob; Koh, Young Jun; Lee, Seung-Hun; Lee, Junyeop; Kim, Kyoo Hyun; Kim, Daesoo; Koh, Gou Young; Yoo, Ook Joon

    2013-09-26

    To unveil the organotypic role and vulnerability of lymphatic vessels, we generated a lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-Cre/iDTR double-transgenic mouse and ablated LYVE-1-expressing lymphatic vessels in adult mice in a diphtheria toxin (DT)-inducible manner based on selective expression of LYVE-1 in most lymphatic vessels. Strikingly, lymphatic vessels in the small intestine and lymph nodes were rapidly ablated, but lymphatic vessels in the other organs were relatively intact at 24 hours after DT administration. Unexpectedly, LYVE-1-Cre/iDTR mice died of sepsis without visible edema at 24 and 60 hours after DT administration. The cause of death appeared to be related to acute failure of immune surveillance systems in the small intestine and draining lymph nodes. Of note, acute loss of lymphatic lacteals in intestinal villi appeared to trigger distortion of blood capillaries and the whole architecture of the villi, whereas acute loss of lymphatic vessels in lymph nodes caused dysfunction of lymph drainage and abnormal distribution of dendritic cells and macrophages. Thus, intact lymphatic vessels are required for structural and functional maintenance of surrounding tissues in an organotypic manner, at least in the intestine and lymph nodes.

  15. Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation.

    PubMed

    Lala, Shailee; Mulliken, John B; Alomari, Ahmad I; Fishman, Steven J; Kozakewich, Harry P; Chaudry, Gulraiz

    2013-07-01

    Gorham-Stout disease (GSD) is a rare vascular disorder of lymphatic origin characterized by progressive osteolysis. Generalized lymphatic anomaly (GLA) is a multisystem disorder that also commonly affects bone. We hypothesized that Gorham-Stout disease is different from other osseous lymphatic anomalies. We proposed to discriminate these entities by analyzing findings on skeletal imaging. Clinical data, imaging studies, and histopathologic findings were retrospectively reviewed in patients presenting to our Vascular Anomalies Center with lymphatic anomalies of bone. Within a cohort of 51 patients with lymphatic disorder and radiological evidence of bony involvement, two distinct categories emerged. Nineteen patients met the imaging criteria for GSD: progressive osteolysis with resorption and cortical loss. Thirty-two were categorized as GLA: Discrete radiolucencies and increasing numbers of bone affected over time, but without evidence of progressive osteolysis. The ribs were the most common site in both groups, followed by the cranium, clavicle, and cervical spine in GSD, and thoracic spine, humerus, and femur in GLA. Fewer bones were involved in GSD, with relative sparing of the appendicular skeleton. Associated infiltrative soft tissue abnormality was seen in 18 in GSD, but only six with GLA. Macrocystic lymphatic malformations were identified in 14 with GLA, but none with GSD. There are significant radiological differences between GSD and GLA, although there are some overlapping features. The major distinguishing characteristic is the progressive osteolysis seen in GSD. Findings suggestive of GLA are more extensive involvement, particularly of the appendicular skeleton, presence of discretemacrocystic lymphatic malformations and visceral organ lesions.

  16. [Urological pathology of lymphatic origin].

    PubMed

    Domènech, A; Serrano, A; Forner-Cordero, I; Gómez, F; Maldonado, D; Domínguez, C

    2016-01-25

    Lymphatic disease is a rarely cause of some very unspecific genitourinary manifestations, assuming a diagnostic challenge in most cases. The aim of this paper is to warn about the possible etiology of these urological lymphatic presentations and discuss its management. Retrospective review of clinical data in pediatric patients with urological pathology of lymphatic origin between 2008-2014. Three patients, two boys and a girl, were included. The complaints were: redundant prepuce, inguinal scrotal tumor and urinary incontinence. Clinical, diagnosis and treatment protocol is described. The first case is a male with genital lymphedema presented at birth as a redundant prepuce and the subsequent emergence of lower limb lymphedema, treated with compression bandages. The second case, a groin lymphangioma which debuted as a sudden painless inguinal tumor simulating a cord cyst, it was sclerosed and treated with OK- 432. Finally, a preteen who consulted for involuntary leakage of urine, genital lymphedema likely primary cause (lymphodisplasia) or malformation was diagnosed, which improved with two Lipiodol® embolization. Genitourinary manifestations can be the debut of more complex lymphatic pathology, so it is necessary to consider this cause, uncommon and nonspecific. Its management must be conservative initially by compression bandages, OK-432 or embolization with Lipiodol®.

  17. Immunopathogenesis of lymphatic filarial disease.

    PubMed

    Babu, Subash; Nutman, Thomas B

    2012-11-01

    Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ~40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont Wolbachia, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products, Wolbachia, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process-the first initiated by the parasite and host innate immune system and the second propagated mainly by the host's adaptive immune system and by other factors (including secondary infections).

  18. Blood and Lymphatic Vessel Formation

    PubMed Central

    Bautch, Victoria L.; Caron, Kathleen M.

    2015-01-01

    Blood and lymphatic vessels deliver oxygen and nutrients, remove waste and CO2, and regulate interstitial pressure in tissues and organs. These vessels begin life early in embryogenesis using transcription factors and signaling pathways that regulate differentiation, morphogenesis, and proliferation. Here we describe how these vessels develop in the mouse embryo, and the signals that are important to their development. PMID:25731762

  19. Endpoints for lymphatic filariasis programs.

    PubMed

    Grady, Caroline A; de Rochars, Madsen Beau; Direny, Abdel N; Orelus, Jean Nicolas; Wendt, Joyanna; Radday, Jeanne; Mathieu, Els; Roberts, Jacquelin M; Streit, Thomas G; Addiss, David G; Lammie, Patrick J

    2007-04-01

    In 2000, annual mass administration of diethlycarbamazine and albendazole began in Leogane Commune, Haiti, to interrupt transmission of lymphatic filariasis (LF). After 5 years of treatment, microfilaremia, antigenemia, and mosquito infection rates were significantly reduced, but LF transmission was not interrupted. These finding have implications for other LF elimination programs.

  20. New Horizons for Imaging Lymphatic Function

    PubMed Central

    Sharma, Ruchi; Wendt, Juliet A.; Rasmussen, John C.; Adams, Kristen E.; Marshall, Milton V.; Sevick-Muraca, Eva M.

    2011-01-01

    In this review, we provide a comprehensive summary of noninvasive imaging modalities used clinically for the diagnosis of lymphatic diseases, new imaging agents for assessing lymphatic architecture and cancer status of lymph nodes, and emerging near-infrared (NIR) fluorescent optical imaging technologies and agents for functional lymphatic imaging. Given the promise of NIR optical imaging, we provide example results of functional lymphatic imaging in mice, swine, and humans, showing the ability of this technology to quantify lymph velocity and frequencies of propulsion resulting from the contractility of lymphatic structures. PMID:18519956

  1. Lymphatic malformations: current cellular and clinical investigations.

    PubMed

    Perkins, Jonathan A; Manning, Scott C; Tempero, Richard M; Cunningham, Michael J; Edmonds, Joseph L; Hoffer, Fredric A; Egbert, Mark A

    2010-06-01

    Summarize current knowledge of lymphatic malformation development, biology, and clinical outcome measures. Panel presentation of lymphatic malformation biology and measurement of head and neck malformation treatment outcomes. Characterization of lymphatic malformation endothelial and stromal cells may lead to biologically based treatment. Traditionally, lymphatic malformation treatment outcomes have been measured according to reduction of malformation size. Currently, methods to measure functional outcomes following lymphatic malformation treatment are lacking. This is particularly apparent when the malformation directly involves the upper aerodigestive tract. The etiology and pathogenesis of head and neck lymphatic malformations are poorly understood, but understanding is improving through ongoing investigation. Reduction of lymphatic malformation size is generally possible, but further work is necessary to optimize methods for measuring therapeutic outcomes in problematic areas. Copyright 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.

  2. Current treatment paradigms in the management of lymphatic malformations.

    PubMed

    Renton, John P; Smith, Richard J H

    2011-01-01

    Lymphatic malformations (LMs) are benign abnormalities of the lymphatic system that can be significantly infiltrative and intimately involve critical structures of the head and neck, making their management difficult. Historically, LMs have been managed by surgical excision, but this treatment approach results in significant morbidity and a high recurrence rate secondary to subtotal resection. As an alternative to surgery a variety of drugs have been used as intralesional sclerosants and immunotherapeutics. These agents offer improved outcomes with lower morbidity as compared to surgery when targeted to macrocystic LMs. However intralesional therapy is not effective in the treatment of microcystic LMs. The development of treatments that are effective for all types of LMs will require further understanding of lymphangiogenesis and the pathogenesis of LMs.

  3. Gastrointestinal Lymphatics in Health and Disease

    PubMed Central

    Alexander, J.S.; Ganta, Vijay C.; Jordan, P.A.; Witte, Marlys H.

    2010-01-01

    Lymphatics perform essential transport and immune cell regulatory functions to maintain homeostasis in the gastrointestinal (GI) system. Although blood and lymphatic vessels function as parallel and integrated systems, our understanding of lymphatic structure, regulation and functioning lags far behind that of the blood vascular system. This chapter reviews lymphatic flow, differences in lymphangiogenic and hemangiogenic factors, lymphatic fate determinants and structural features, and examines how altered molecular signaling influences lymphatic function in organs of the GI system. Innate errors in lymphatic development frequently disturb GI functioning and physiology. Expansion of lymphatics, a prominent feature of GI inflammation, may also play an important role in tissue restitution following injury. Destruction or dysregulation of lymphatics, following injury, surgery or chronic inflammation also appears to exacerbate GI disease activity and morbidity. Understanding the physiological roles played by GI lymphatics is essential to elucidating their underlying contributions to forms of congenital and acquired forms of GI pathology, and will provide novel approaches for treatment of these conditions. PMID:20022228

  4. Lymphatic Vascular Response to Acute Inflammation

    PubMed Central

    Lachance, Pier-Anne; Hazen, Amy; Sevick-Muraca, Eva M.

    2013-01-01

    During acute inflammation, functioning lymphatics are believed to reduce edema and to provide a transiting route for immune cells, but the extent at which the dermal lymphatic remodeling impacts lymphatic transport or the factors regulating these changes remains unclear. Herein we quantify the increase in lymphatic endothelial cells (LECs) and examine the expression of pro-angiogenenic and lymphangiogenic factors during acute cutaneous hypersensitivity (CHS). We found that LECs actively proliferate during CHS but that this proliferation does not affect the lymphatic vessel density. Instead, lymphatic remodeling is accompanied by lymphatic vessel leakiness and lower ejection of lymph fluid, which is observed only in the proximal lymphatic vessel draining the inflamed area. LECs and the immune cells release growth factors and cytokines during inflammation, which impact the lymphatic microenvironment and function. We identified that FGF-2, PLGF-2, HGF, EGF, and KC/CXCL17 are differentially expressed within tissues during acute CHS, but both VEGF-C and VEGF-D levels do not significantly change. Our results indicate that VEGF-C and VEGF-D are not the only players and other factors may be responsible for the LECs proliferation and altered lymphatic function in acute CHS. PMID:24086691

  5. Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor.

    PubMed

    Bäckhed, Fredrik; Crawford, Peter A; O'Donnell, David; Gordon, Jeffrey I

    2007-01-09

    Lymphatic vessels develop from specialized venous endothelial cells. Using knockout mice, we found that fasting-induced adipose factor (Fiaf) is required for functional partitioning of postnatal intestinal lymphatic and blood vessels. In wild-type animals, levels of intestinal Fiaf expression rise during the first postnatal day and peak at day 2, which coincides with the onset of the lymphatico-venous partitioning abnormality in Fiaf-/- mutants on a mixed 129/SvJ:C57BL/6 genetic background. Fiaf deficiency is not associated with disruption of the blood vasculature or with lymphatic endothelial recruitment of smooth muscle cells. We identified Prox1, a critical regulator of lymphangiogenesis, as a downstream target for Fiaf signaling in the intestinal lymphatic endothelium. This organ-specific lymphovascular abnormality can be rescued by allowing embryonic Fiaf-/- intestinal isografts to develop in Fiaf+/+ recipients.

  6. Lymphatic Imaging: Focus on Imaging Probes

    PubMed Central

    Niu, Gang; Chen, Xiaoyuan

    2015-01-01

    In view of the importance of sentinel lymph nodes (SLNs) in tumor staging and patient management, sensitive and accurate imaging of SLNs has been intensively explored. Along with the advance of the imaging technology, various contrast agents have been developed for lymphatic imaging. In this review, the lymph node imaging agents were summarized into three groups: tumor targeting agents, lymphatic targeting agents and lymphatic mapping agents. Tumor targeting agents are used to detect metastatic tumor tissue within LNs, lymphatic targeting agents aim to visualize lymphatic vessels and lymphangionesis, while lymphatic mapping agents are mainly for SLN detection during surgery after local administration. Coupled with various signal emitters, these imaging agents work with single or multiple imaging modalities to provide a valuable way to evaluate the location and metastatic status of SLNs. PMID:25897334

  7. HA-ving lymphatics improves lung transplantation

    PubMed Central

    Maltzman, Jonathan S.; Reed, Hasina Outtz; Kahn, Mark L.

    2015-01-01

    Lung allografts are prone to rejection, even though recipients undergo aggressive immunosuppressive therapy. Lymphatic vessels serve as conduits for immune cell trafficking and have been implicated in the mediation of allograft rejection. In this issue of the JCI, Cui et al. provide compelling evidence that lymphatic vessel formation improves lung allograft survival in a murine transplant model. Moreover, their data suggest a potential mechanism for the beneficial effects of lymphatics that does not involve immune cell or antigen transport. Together, the results of this study provide new insight into the role of lymphatic vessels in transplant tolerance. PMID:26524589

  8. The discovery of the synovial lymphatic stomata and lymphatic reabsorption in knee effusion.

    PubMed

    Ping, Zepeng; Jiang, Tingting; Wang, Chong; Chen, Zhongyi; Chen, Zhongliang; Wang, Jiaxiong; Wang, Li; Wang, Beibei; Xu, Dandan; Liu, Changming; Li, Zhongjie; Li, Ji-Cheng

    2015-06-01

    To illustrate the mechanism of lymphatic reabsorption in knee joint effusion. The current investigation employed transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques to reveal the ultrastructure of the knee synovial membrane in New Zealand rabbits and human. Ultrastructural changes of the synovial lymphatic stomata were observed by using trypan blue absorption and sodium hydroxide (NaOH) digestion methods, and the animal models of synovitis. New Zealand rabbits and human synovial membranes were composed of two types of synovial cells: type A and type B. No lymphatic stomata were found among type A synovial cells, whereas lymphatic stomata with the diameters ranging 0.74-3.26 µm were found in type B synovial cells, and some stomata were closed. After the NaOH digestion, a number of sieve pores, similar to lymphatic stomata in size and shape, were observed in the dense fibrous connective tissue underneath the type B synovial cells. After injecting trypan blue into the rabbit knee joint cavity, absorption of trypan blue through the lymphatic stomata was observed, suggesting the absorption function of the synovial lymphatic stomata. In the rabbit knee joint synovitis models, the synovial lymphatic stomata diameter enlarged. Some macrophages migrated from the lymphatic stomata, indicating that the synovial lymphatic stomata were involved in the joint effusion absorption and inflammatory response. Our study is the first to report the existence of synovial lymphatic stomata in the New Zealand rabbits and human knee joints. Lymphatic stomata may have an important role in the reabsorption of joint effusion.

  9. Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography.

    PubMed

    Liu, N F; Yan, Z X; Wu, X F

    2012-09-01

    The study aims to investigate lymphatic-system malformations and proposes a classification of primary lymphoedema based on comprehensive imaging data of both lymph vessel- and lymph-node abnormalities. A total of 378 patients with primary lymphoedema of the lower extremity were examined with magnetic resonance lymphangiography (MRL) using gadobenate dimeglumine as contrast agent. Lymph vessels and drainage lymph nodes were evaluated, leading to the proposal of the classification of primary lymphoedema and the relative proportions. A total of 63 (17%) patients exhibited defects of the inguinal lymph nodes with mild or moderate dilatation of afferent lymph vessels. A total of 123 (32%) patients exhibited lymphatic anomalies as lymphatic aplasia, hypoplasia or hyperplasia with no obvious defect of the drainage lymph nodes. The involvement of both lymph vessel- and lymph-node abnormalities in the affected limb was found in 192 (51%) patients. The primary lymphoedema was classified as three major types as: (1) lymph nodes affected only; (2) lymph vessel affected only with three subtypes and (3) both lymph vessel and lymph node affected with subgroups. A comprehensive classification of lymphatic-system malformation in primary lymphoedema is proposed, which clearly defines the location and pathologic characteristics of both lymphatics and lymph node and may lead to further study of the aetiology as well as rational treatment of the disease. Copyright © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  10. Lymphangiogenesis and Lymphatic Metastasis in Breast Cancer

    PubMed Central

    Ran, Sophia; Volk, Lisa; Hall, Kelly; Flister, Michael J.

    2009-01-01

    Lymphatic metastasis is the main prognostic factor for survival of patients with breast cancer and other epithelial malignancies. Mounting clinical and experimental data suggest that migration of tumor cells into the lymph nodes is greatly facilitated by lymphangiogenesis, a process that generates new lymphatic vessels from pre-existing lymphatics with the aid of circulating lymphatic endothelial progenitor cells. The key protein that induces lymphangiogenesis is vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by vascular endothelial growth factor-C and -D (VEGF-C and VEGF-D). These lymphangiogenic factors are commonly expressed in malignant, tumor-infiltrating and stromal cells, creating a favorable environment for generation of new lymphatic vessels. Clinical evidence demonstrates that increased lymphatic vessel density in and around tumors is associated with lymphatic metastasis and reduced patient survival. Recent evidence shows that breast cancers induce remodeling of the local lymphatic vessels and the regional lymphatic network in the sentinel and distal lymph nodes. These changes include an increase in number and diameter of tumor-draining lymphatic vessels. Consequently, lymph flow away from the tumor is increased, which significantly increases tumor cell metastasis to draining lymph nodes and may contribute to systemic spread. Collectively, recent advances in the biology of tumor-induced lymphangiogenesis suggest that chemical inhibitors of this process may be an attractive target for inhibiting tumor metastasis and cancer-related death. Nevertheless, this is a relatively new field of study and much remains to be established before the concept of tumor-induced lymphangiogenesis is accepted as a viable anti-metastatic target. This review summarizes the current concepts related to breast cancer lymphangiogenesis and lymphatic metastasis while highlighting controversies and unanswered questions. PMID:20036110

  11. LYMPHATIC INJURY AND REGENERATION IN CARDIAC ALLOGRAFTS

    PubMed Central

    Soong, Thing Rinda; Pathak, Arvind; Asano, Hiroshi; Fox-Talbot, Karen; Baldwin, William M

    2009-01-01

    Background: Severed donor heart lymphatics are not anastomosed to recipient lymphatics in cardiac transplantation. We evaluated the effects of cellular infiltrates of T cells and macrophages on the morphology of lymphatics in heart grafts. Methods: Dark Agouti (DA) hearts were transplanted to Lewis or control DA rats on sub-therapeutic doses of cyclosporin. Transplants were examined by immunohistology and quantitative immunofluorescence microscopy using LYVE-1 as a lymphatic marker and CD8 and CD68 as markers for cellular infiltration at selected intervals from 1 to 8 weeks post-transplantation. Results: Allograft inner myocardial lymphatic density decreased by more than 30-fold at 1 week, and recovered to only 15% of the native level at 8 weeks post-transplantation. In contrast, allograft lymphatics in and near the epicardium showed no significant density decline, but increased in size by more than 5-fold at 2 weeks, and sustained about a 3-fold increase at 8 weeks post-transplantation. Lymphatic changes correlated temporally with the extent of T cell and macrophage infiltration in allografts, which peaked at 2-3 weeks post-transplantation. When grafts were retransplanted from allogeneic to isogeneic recipients at 3 weeks post-transplantation, inner lymphatic density returned close to native level within 2 weeks after retransplantation. Conclusions: This is the first characterization of regional and morphological effects of immunological responses on heart lymphatics after transplantation. Elimination of alloimmune responses produces rapid restoration of inner lymphatic vessels, suggesting that lymphatics injured during rejection can recover when rejection is reversed during the post-transplantation course. PMID:20118845

  12. Studies of lymphatic drainage from testes by lymphoscintigraphy

    SciTech Connect

    Yeh, S.D.J.; Morse, M.J.; Grando, R.; Kleinert, E.L.; Whitmore, W.F. Jr.

    1985-05-01

    Severe lymphedema of lower extremity may cause functional disability and foster recurrent lymphangitis. Surgical transportation of the testis to the thigh offers the possibility of enhancing lymphatic drainage from the leg via spermatic cord lymphatics. Testicular lymphoscintigraphy was employed to assess the quality of testicular lymphatic drainage prior to testis transposition. Images of abdomen and measurement of testis radioactivity were made serially after injection of Au 198 colloid into the testis of dogs before and after litigation of the spermatic cord. In the intact dogs, the residual radioactivities in the testis (5 dogs) were 53.5 +- 13.25, 41.6 +- 7.80 and 26.3 +- 5.66% at 2, 4 and 24 hours post injection. After ligation of spermatic cord, the residual activities in the testis were 95.0 +- 3.33, 86.4 +- 6.49 and 74.2 +- 6.28% at corresponding intervals post injection. Paraaortic nodes and liver were visualized in the abdominal images 1 hour after injection in the intact animals but only poorly seen in dogs following ligation. /sup 99m/Tc antimony colloid was used similarly in 5 patients who had severe lymphedema and abnormal pelvic lymphoscintigraphy following bipedal injection. With intratesticular injection, paraaortic lymph nodes and liver were visualized in 7 studies between 3 to 5 hours. Poor visualization was noted in two studies in patients who had previous radiation to the abdomen. The findings suggest that this simple technic can aid in the assessment of testicular lymphatic drainage and help to select patients for appropriate surgical intervention.

  13. Lymphatic filariasis in the Philippines.

    PubMed

    Kron, M; Walker, E; Hernandez, L; Torres, E; Libranda-Ramirez, B

    2000-08-01

    Lymphatic filariasis caused by Wuchereria bancrofti and Brugia malayi is endemic throughout most of the southern half of the Philippine archipelago. Economic and manpower shortages prior to 1996 made it difficult to acquire new prevalence data and vector control data concurrently from all provinces. Nevertheless, analysis of cumulative prevalence data on filariasis indicates the persistence of filariasis in each of the three major island groups - Luzon, Visayas and Mindanao - including 45 out of 77 provinces. Here, Michael Kron and colleagues summarize the prevalence data, and review host, parasite and vector characteristics relevant to the design and implementation of disease control initiatives in the Philippines planned for the year 2000.

  14. Lymphatic pumping: mechanics, mechanisms and malfunction.

    PubMed

    Scallan, Joshua P; Zawieja, Scott D; Castorena-Gonzalez, Jorge A; Davis, Michael J

    2016-10-15

    A combination of extrinsic (passive) and intrinsic (active) forces move lymph against a hydrostatic pressure gradient in most regions of the body. The effectiveness of the lymph pump system impacts not only interstitial fluid balance but other aspects of overall homeostasis. This review focuses on the mechanisms that regulate the intrinsic, active contractions of collecting lymphatic vessels in relation to their ability to actively transport lymph. Lymph propulsion requires not only robust contractions of lymphatic muscle cells, but contraction waves that are synchronized over the length of a lymphangion as well as properly functioning intraluminal valves. Normal lymphatic pump function is determined by the intrinsic properties of lymphatic muscle and the regulation of pumping by lymphatic preload, afterload, spontaneous contraction rate, contractility and neural influences. Lymphatic contractile dysfunction, barrier dysfunction and valve defects are common themes among pathologies that directly involve the lymphatic system, such as inherited and acquired forms of lymphoedema, and pathologies that indirectly involve the lymphatic system, such as inflammation, obesity and metabolic syndrome, and inflammatory bowel disease.

  15. Organization and developmental aspects of lymphatic vessels.

    PubMed

    Ohtani, Osamu; Ohtani, Yuko

    2008-05-01

    The lymphatic system plays important roles in maintaining tissue fluid homeostasis, immune surveillance of the body, and the taking up dietary fat and fat-soluble vitamins A, D, E and K. The lymphatic system is involved in many pathological conditions, including lymphedema, inflammatory diseases, and tumor dissemination. A clear understanding of the organization of the lymphatic vessels in normal conditions would be critically important to develop new treatments for diseases involving the lymphatic vascular system. Therefore, the present paper reviews the organization of the lymphatic vascular system of a variety of organs, including the thyroid gland, lung and pleura, small intestine, cecum and colon in the rat, the diaphragm in the rat, monkey, and human, Peyer's patches and the appendix in the rabbit, and human tonsils. Methods employed include scanning electron microscopy of lymphatic corrosion casts and tissues with or without treatment of alkali maceration technique, transmission electron microscopy of intact tissues, confocal microscopy in conjunction with immunohistochemistry to some lymphatic-specific markers (i.e., LYVE-1 and VEGFR-3), and light microscopy in conjunction with enzyme-histochemistry to 5'-nucleotidase. Some developmental aspects of the lymphatic vessels and lymphedema are also discussed.

  16. Dendritic Cell Interactions with Lymphatic Endothelium

    PubMed Central

    Russo, Erica; Nitschké, Maximilian

    2013-01-01

    Abstract Afferent lymphatic vessels fulfill essential immune functions by transporting leukocytes and lymph-borne antigen to draining lymph nodes (dLNs). An important cell type migrating through lymphatic vessels are dendritic cells (DCs). DCs reside in peripheral tissues like the skin, where they take up antigen and transport it via the lymphatic vascular network to dLNs for subsequent presentation to T cells. As such, DCs play a key role in the induction of adaptive immune responses during infection and vaccination, but also for the maintenance of tolerance. Although the migratory pattern of DCs has been known for long time, interactions between DCs and lymphatic vessels are only now starting to be unraveled at the cellular level. In particular, new tools for visualizing lymphatic vessels in combination with time-lapse microscopy have recently generated valuable insights into the process of DC migration to dLNs. In this review we summarize and discuss current approaches for visualizing DCs and lymphatic vessels in tissues for imaging applications. Furthermore, we review the current state of knowledge about DC migration towards, into and within lymphatic vessels, particularly focusing on the cellular interactions that take place between DCs and the lymphatic endothelium. PMID:24044757

  17. Lymphatic imaging in unsedated infants and children

    NASA Astrophysics Data System (ADS)

    Rasmussen, John C.; Balaguru, Duraisamy; Douglas, William I.; Breinholt, John P.; Greives, Matthew R.; Aldrich, Melissa B.; Sevick-Muraca, Eva M.

    2017-02-01

    Primary lymphedema and lymphatic malformations in the pediatric population remains poorly diagnosed and misunderstood due to a lack of information on the underlying anatomy and function of the lymphatic system. Diagnostics for the lymphatic vasculature are limited, consisting of lymphoscintigraphy or invasive lymphangiography, both of which require sedation that can restrict use in infants and children. As a result, therapeutic protocols for pediatric patients with lymphatic disorders remain sparse and with little evidence to support them. Because near-infrared fluorescence (NIRF) imaging enables image acquisition on the order of tenths of seconds with trace administration of fluorescent dye, sedation is not necessary. The lack of harmful radiation and radioactive contrast agents further facilitates imaging. Herein we summarize our experiences in imaging infants and children who are suspected to have disorders of the lymphatic vascular system using indocyanine green (ICG) and who have developed chylothorax following surgery for congenital heart defects. The results show both anatomical as well as functional lymphatic deficits in children with congenital disease. In the future, NIRF lymphatic imaging could provide new opportunities to tailor effective therapies and monitor responses. The opportunity to use expand NIRF imaging for pediatric diagnostics beyond the lymphatic vasculature is also afforded by the rapid acquisition following trace administration of NIRF contrast agent.

  18. Emerging Roles of Lymphatic Vasculature in Immunity

    PubMed Central

    2017-01-01

    The lymphatic vasculature has been regarded as a passive conduit for interstitial fluid and responsible for the absorption of macromolecules such as proteins or lipids and transport of nutrients from food. However, emerging data show that the lymphatic vasculature system plays an important role in immune modulation. One of its major roles is to coordinate antigen transport and immune-cell trafficking from peripheral tissues to secondary lymphoid organs, lymph nodes. This perspective was recently updated with the notion that the interaction between lymphatic endothelial cells and leukocytes controls the immune-cell migration and immune responses by regulating lymphatic flow and various secreted molecules such as chemokines and cytokines. In this review, we introduce the lymphatic vasculature networks and genetic transgenic models for research on the lymphatic vasculature system. Next, we discuss the contribution of lymphatic endothelial cells to the control of immune-cell trafficking and to maintenance of peripheral tolerance. Finally, the physiological roles and features of the lymphatic vasculature system are further discussed regarding inflammation-induced lymphangiogenesis in a pathological condition, especially in mucosal tissues such as the gastrointestinal tract and respiratory tract. PMID:28261022

  19. Lymphatic Lipid Transport: Sewer or Subway?

    PubMed Central

    Dixon, J. Brandon

    2010-01-01

    The lymphatics began receiving attention in the scientific community as early as 1622, when Gasparo Aselli noted the appearance of milky white vessels in the mesentery of a well-fed dog. Since this time, the lymphatic system has been historically regarded as the sewer of the vasculature, passively draining fluid and proteins from the interstitial spaces (along with lipid from the gut) into the blood. Recent reports, however, suggest that the lymphatic role in lipid transport is an active and intricate process and when lymphatic function is compromised, there are systemic consequences to lipid metabolism and transport. This review highlights these recent findings and suggests future directions for understanding the interplay between lymphatic and lipid biology in health and disease. PMID:20541951

  20. The Lymphatic System: Integral Roles in Immunity

    PubMed Central

    Randolph, Gwendalyn J.; Ivanov, Stoyan; Zinselmeyer, Bernd H.; Scallan, Joshua P.

    2017-01-01

    The lymphatic vasculature is not considered a formal part of the immune system, but it is critical to immunity. One of its major roles is in the coordination of the trafficking of antigen and immune cells. However, other roles in immunity are emerging. Lymphatic endothelial cells, for example, directly present antigen or express factors that greatly influence the local environment. We cover these topics herein and discuss how other properties of the lymphatic vasculature, such as mechanisms of lymphatic contraction (which immunologists traditionally do not take into account), are nonetheless integral in the immune system. Much is yet unknown, and this nascent subject is ripe for exploration. We argue that to consider the impact of lymphatic biology in any given immunological interaction is a key step toward integrating immunology with organ physiology and ultimately many complex pathologies. PMID:27860528

  1. Apelin Inhibits Diet-Induced Obesity by Enhancing Lymphatic and Blood Vessel Integrity

    PubMed Central

    Sawane, Mika; Kajiya, Kentaro; Kidoya, Hiroyasu; Takagi, Masaya; Muramatsu, Fumitaka; Takakura, Nobuyuki

    2013-01-01

    Angiogenesis is tightly associated with the outgrowth of adipose tissue, leading to obesity, which is a risk factor for type 2 diabetes and hypertension, mainly because expanding adipose tissue requires an increased nutrient supply from blood vessels. Therefore, induction of vessel abnormality by adipokines has been well-studied, whereas how altered vascular function promotes obesity is relatively unexplored. Also, surviving Prox1 heterozygous mice have shown abnormal lymphatic patterning and adult-onset obesity, indicating that accumulation of adipocytes could be closely linked with lymphatic function. Here, we propose a new antiobesity strategy based on enhancement of lymphatic and blood vessel integrity with apelin. Apelin knockout (KO) mice fed a high-fat diet (HFD) showed an obese phenotype associated with abnormal lymphatic and blood vessel enlargement. Fatty acids present in the HFD induced hyperpermeability of endothelial cells, causing adipocyte differentiation, whereas apelin promoted vascular stabilization. Moreover, treatment of apelin KO mice with a selective cyclooxygenase-2 inhibitor, celecoxib, that were fed an HFD improved vascular function and also attenuated obesity. Finally, apelin transgenic mice showed decreased subcutaneous adipose tissue attributable to inhibition of HFD-induced hyperpermeability of vessels. These results indicate that apelin inhibits HFD-induced obesity by enhancing vessel integrity. Apelin could serve as a therapeutic target for treating obesity and related diseases. PMID:23378608

  2. Lymphatic filariasis in children: adenopathy and its evolution in two young girls.

    PubMed

    Dreyer, G; Figueredo-Silva, J; Carvalho, K; Amaral, F; Ottesen, E A

    2001-09-01

    Lymphatic filariasis is a widespread infectious disease of children in endemic areas, but little is known about the early lymphatic damage in children and its evolution, either with or without treatment. Two girls (ages 6 and 12 years) from a Wuchereria bancrofti endemic region of Brazil presented with chronic inguinal adenopathy. Neither had microfilaremia. By ultrasound both were shown to have living adult worms in their enlarged inguinal nodes and had occult local lymphatic damage (lymphangiectasis). One girl spontaneously developed acute adenitis in the affected node prior to any intervention; this adenitis resolved within 10 days and was associated with the progressive disappearance over 45-90 days of all local abnormalities detectable by ultrasound. In the other child, after treatment with a single dose of diethylcarbamazine (DEC), the same clinical picture of transient adenitis and resolving abnormalities (detectable by ultrasound) occurred. These findings demonstrated filariasis as the cause of adenopathy in children, and also both spontaneous and treatment-induced worm-death, with subsequent reversal of lymphatic abnormalities.

  3. Lymphatics in the alimentary tract of children in health and disease: study on mucosal biopsies using the monoclonal antibody d2-40.

    PubMed

    Zeng, Yiping; Wang, Fenghua; Williams, Elizabeth D; Chow, Chung Wo

    2005-01-01

    Primary intestinal lymphangiectasia and intestinal lymphatic hypoplasia are 2 causes of protein-losing enteropathy in children and share many common clinical features. For the diagnosis of lymphatic hypoplasia on endoscopic biopsies of the intestine, i.e., based on a negative finding in a small specimen, a very sensitive and specific method for identifying lymphatics is essential. In the present study, lymphatic vessels were labelled using D2-40 immunostaining in mucosal biopsy specimens of the alimentary tract of children in whom no histologic abnormality was noted and of those who had different relatively common pediatric conditions, including inflammatory and neoplastic diseases. Using this method, lymphatic vessels were well visualized even in young infants and not destroyed by diseases. The presence of the muscularis mucosae in specimens was important for adequate assessment. In the duodenum and esophagus, lymphatics were observed in every single section; in the stomach, ileum, and colon, they were less regular and several sections were sometimes required. The extreme sensitivity of this method for demonstrating lymphatic vessels in the duodenum makes it ideal for the histologic diagnosis of intestinal lymphatic hypoplasia. In 4 patients who were considered to have this diagnosis based on clinical features, full-thickness intestinal biopsies and electron microscopy, D2-40 immunostaining confirmed the absence or marked paucity of lymphatics.

  4. [Lymphatic system and water homeostasis].

    PubMed

    Borodin, Iu I; Golubeva, I A; Mashak, A N

    2005-01-01

    Using the methods of light and electron microscopy as well as histochemistry, the complex study of structural-cellular state of the wall of small intestine and its grouped lymphoid nodules, mesenterial and iliac lymph nodes and thymus was performed in rats subjected to the changes of a type of drinking water. Tap, distilled and radon waters were used. The organism was found to respond to the changes in the type of drinking water by both non-specific (increase in sectional area of lymphatic vessels and the number of eosinophilic granulocytes in the wall of small intestine, in lymphoid nodule number containing germinal centers in lymph nodes, in proportion of thymus connective tissue component, increased lymphocyte dehydrogenase activity) and specific reactions, which were characteristic only to a given type of water. The latter, for example, included the activation of the function of protein synthesis in endothelial cells of lymphatic capillaries of the small intestine and increased numbers of plasma cells and dividing cells in lymphoid organs in rats consuming distilled water; increased proportion of blood capillaries in the wall of the small intestine, accompanied by the ultrastructural signs of reduction of plastic processes in them in animals drinking radon water. The response of the wall of the small intestine and lymphoid organs of an animal to the effect of drinking waters, different in their mineral content and radon concentrations, was subjected to general biological regularities and took place in two phases of an adaptation process, functional stress and resistivity.

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

    PubMed Central

    Kwon, Sunkuk; Price, Roger E.

    2016-01-01

    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 near-infrared 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. PMID:27446639

  6. Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling

    PubMed Central

    Kanady, John D.; Munger, Stephanie J.; Witte, Marlys H.; Simon, Alexander M.

    2015-01-01

    Connexins (Cxs), proteins that are vital for intercellular communication in vertebrates, have recently been shown to play a critical role in lymphatic development. However, our knowledge is currently limited regarding the functional relationships of Cxs with other proteins and signaling pathways. Cell culture studies have shown that Cx37 is necessary for coordinated activation of the transcription factor NFATc1, which cooperates with Foxc2 (another transcription factor) during lymphatic endothelial development. These data suggest that Cxs, Foxc2, and NFATc1 are part of a common developmental pathway. Here, we present a detailed characterization of Foxc2 +/−Cx37 −/− mice, demonstrating that lymphatic network architecture and valve formation rely on the concurrent embryonic expression and function of Foxc2 and Cx37. Foxc2 +/−Cx37−/− mice have lymphedema in utero, exhibit craniofacial abnormalities, show severe dilation of intestinal lymphatics, display abnormal lacteal development, lack lymphatic valves, and typically die perinatally (outcomes not seen in Foxc2 +/− or Cx37−/− mice separately). We provide a rigorous, quantitative documentation of lymphatic vascular network changes that highlight the specific structural alterations that occur in Foxc2+/− Cx37−/− mice. These data provide further evidence suggesting that Foxc2 and Cx37 are elements in a common molecular pathway directing lymphangiogenesis. PMID:26079578

  7. [Morphogenesis, structure and properties of lymphatic vessels].

    PubMed

    Ratajska, Anna; Jankowska-Steifer, Ewa; Czarnowska, Elżbieta; Flaht, Aleksandra; Radomska-Leśniewska, Dorota

    2012-11-19

    In this paper, we present literature results related to structure and various manners of lymphatic vessel formation during embryonic development and in pathological events, such as tumorigenesis, wound healing, and other diseases. The functions of the lymphatic system include the collection of fluids that enter tissues from the circulation, absorption of lipids and lipid-soluble vitamins from the intestine and their subsequent transport, participation in antigen, dendritic cell, and lymphocyte migration. The lymphatic system is also a route for tumor cell and inflammatory cell transport. Native lymphatic capillaries differ from blood capillaries by having an irregular lumen, a discontinuous basement membrane, absence of pericytes, and a strong anchorage of their endothelial cells to the extracellular matrix via microfibrils built of emilin and fibrillin. Lymphatic endothelial cells express surface antigens such as Lyve-1, podoplanin, VEGFR3 (Flk4) and transcription factor Prox-1, as well as molecules which are common for blood endothelial cells and lymphatic endothelial cells (CD31, CD34, Flk-1, Tie-1, Tie-2, neuropilin 2). Lymphatic vessel formation during embryonic development starts with the occurrence of lymphatic sacs sprouting from systemic jugular veins and/or by co-option of lymphangioblasts or hematopoietic-derived cells. It can also proceed by dedifferentiation of venous endothelial cells after their detachment from the venous system, migration to the target places within the body and assembly in the lymphatic lumen. Mechanisms of lymphatic vessel formation during embryonic development and in pathological conditions, such as tumorigenesis, wound healing, and metastasis, is regulated by a plethora of growth factors and molecules, among which the most important are VEGF-C, VEGF-D, HGF, FGF, retinoic acid, IL-3, and IL-7. Macrophages and cells bearing CD45 phenotype seem to take part in the formation of lymphatics. Macrophages might act as a source of growth

  8. Potential Applications of Using 68Ga-Evans Blue PET/CT in the Evaluation of Lymphatic Disorder: Preliminary Observations.

    PubMed

    Zhang, Wei; Wu, Peilin; Li, Fang; Tong, Guansheng; Chen, Xiaoyuan; Zhu, Zhaohui

    2016-04-01

    Potentials of 68Ga-NEB as a PET tracer in the evaluation of a variety of lymphatic drainage disorders were analyzed. 68Ga-NEB was injected subcutaneously, and the PET/CT images were acquired in 13 patients with different suspected lymphatic drainage abnormality. The 68Ga-NEB PET/CT findings were compared with Tc-SC lymphoscintigraphy. 68Ga-NEB activity could be clearly observed in the lymphatic route on the PET/CT images from all the patients. In 5 (38.5%) of 13 patients tested, 68Ga-NEB PET/CT provided more information than the Tc-SC lymphoscintigraphy. 68Ga-NEB PET/CT can be used as an alternative of Tc-SC lymphoscintigraphy in the evaluation of lymphatic disorders, which enables fast results and might be more accurate than the conventional Tc-SC lymphoscintigraphy.

  9. Near-infrared fluorescence imaging of lymphatics in head and neck lymphedema

    NASA Astrophysics Data System (ADS)

    Tan, I.-Chih; Maus, Erik A.; Rasmussen, John C.; Marshall, Milton V.; Fife, Caroline E.; Smith, Latisha A.; Sevick-Muraca, Eva M.

    2011-03-01

    Treatment of lymphatic disease is complicated and controversial, due in part to the limited understanding of the lymphatic system. Lymphedema (LE) is a frequent complication after surgical resection and radiation treatment in cancer survivors, and is especially debilitating in regions where treatment options are limited. Although some extremity LE can be effectively treated with manual lymphatic drainage (MLD) therapy or compression devices to direct proximal lymph transport, head and neck LE is more challenging, due to complicated geometry and complex lymphatic structure in head and neck region. Herein, we describe the compassionate use of an investigatory technique of near-infrared (NIR) fluorescence imaging to understand the lymphatic anatomy and function, and to help direct MLD in a patient with head and neck LE. Immediately after 9 intradermal injections of 25 μg indocyanine green each around the face and neck region, NIR fluorescence images were collected using a custom-built imaging system with diffused excitation light illumination. These images were then used to direct MLD therapy. In addition, 3-dimensional (3D) surface profilometry was used to monitor response to therapy. NIR fluorescence images of functioning lymphatic vessels and abnormal structures were obtained. Precise geometries of facial structures were obtained using 3D profilometry, and detection of small changes in edema between therapy sessions was achieved. NIR fluorescence imaging provides a mapping of lymphatic architecture to direct MLD therapy and thus improve treatment efficacy in the head and neck LE, while 3D profilometry allowed longitudinal assessment of edema to evaluate the efficacy of therapy.

  10. T Cell Trafficking through Lymphatic Vessels

    PubMed Central

    Hunter, Morgan C.; Teijeira, Alvaro; Halin, Cornelia

    2016-01-01

    T cell migration within and between peripheral tissues and secondary lymphoid organs is essential for proper functioning of adaptive immunity. While active T cell migration within a tissue is fairly slow, blood vessels and lymphatic vessels (LVs) serve as speedy highways that enable T cells to travel rapidly over long distances. The molecular and cellular mechanisms of T cell migration out of blood vessels have been intensively studied over the past 30 years. By contrast, less is known about T cell trafficking through the lymphatic vasculature. This migratory process occurs in one manner within lymph nodes (LNs), where recirculating T cells continuously exit into efferent lymphatics to return to the blood circulation. In another manner, T cell trafficking through lymphatics also occurs in peripheral tissues, where T cells exit the tissue by means of afferent lymphatics, to migrate to draining LNs and back into blood. In this review, we highlight how the anatomy of the lymphatic vasculature supports T cell trafficking and review current knowledge regarding the molecular and cellular requirements of T cell migration through LVs. Finally, we summarize and discuss recent insights regarding the presumed relevance of T cell trafficking through afferent lymphatics. PMID:28066423

  11. Optimized lymphoscintigraphy and diagnostics of lymphatic oedema of the lower extremities.

    PubMed

    Dabrowski, Janusz; Merkert, Ryszard; Kuśmierek, Jacek

    2008-01-01

    The elementary diagnostic method for the detection of lymph circulation abnormalities in extremities is lymphoscintigraphy. This method provides information on the morphology and function of the lymphatic system. However, there are no generally acceptable standards for lymphoscintigraphy, which makes judgment of its clinical usefulness very difficult. In this work, a discussion is presented on the usefulness of static qualitative scintigraphy of the lymphatic system of lower extremities as well as of its quantitative interpretation, depending upon: (1) time measurement of radiopharmaceutical transport in the system, and (2) assessment of its regional uptake in lymph nodes. The effectiveness of visual assessment combined with each of the quantitative evaluations mentioned is also presented. Combination of visual evaluation of static scintigraphy with each of the listed quantitative procedures improves the sensitivity of lymphoscintigraphy in the diagnosis of lymphatic oedema of lower extremities without affecting the specificity of visual evaluation. Both combined methods are characterized by similar indices of diagnostic efficacy. This enables limitation of the quantitative evaluation of lymphatic scintigraphy to the measurement of the final uptake of RPh in the inguinal lymphatic nodes.

  12. Lymphatic vessels clean up your arteries.

    PubMed

    Fernández-Hernando, Carlos

    2013-04-01

    Reverse cholesterol transport (RCT) is the pathway by which cholesterol accumulated in peripheral tissues, including the artery wall, is transported to the liver for excretion. There is strong evidence suggesting that interventions that increase macrophage cholesterol efflux and RCT would be antiatherogenic. In this issue of the JCI, Martel et al. investigate the contribution of lymphatic vasculature to RCT. Their results support the concept that the lymphatic vessel route is critical for RCT from atherosclerotic plaques. Therefore, strategies to improve lymphatic transport might be useful for treating atherosclerotic vascular disease.

  13. Rapid Lymphatic Dissemination of Encapsulated Group A Streptococci via Lymphatic Vessel Endothelial Receptor-1 Interaction.

    PubMed

    Lynskey, Nicola N; Banerji, Suneale; Johnson, Louise A; Holder, Kayla A; Reglinski, Mark; Wing, Peter A C; Rigby, David; Jackson, David G; Sriskandan, Shiranee

    2015-09-01

    The host lymphatic network represents an important conduit for pathogen dissemination. Indeed, the lethal human pathogen group A streptococcus has a predilection to induce pathology in the lymphatic system and draining lymph nodes, however the underlying basis and subsequent consequences for disease outcome are currently unknown. Here we report that the hyaluronan capsule of group A streptococci is a crucial virulence determinant for lymphatic tropism in vivo, and further, we identify the lymphatic vessel endothelial receptor-1 as the critical host receptor for capsular hyaluronan in the lymphatic system. Interference with this interaction in vivo impeded bacterial dissemination to local draining lymph nodes and, in the case of a hyper-encapsulated M18 strain, redirected streptococcal entry into the blood circulation, suggesting a pivotal role in the manifestation of streptococcal infections. Our results reveal a novel function for bacterial capsular polysaccharide in directing lymphatic tropism, with potential implications for disease pathology.

  14. Rapid Lymphatic Dissemination of Encapsulated Group A Streptococci via Lymphatic Vessel Endothelial Receptor-1 Interaction

    PubMed Central

    Johnson, Louise A.; Holder, Kayla A.; Reglinski, Mark; Wing, Peter A. C.; Rigby, David; Jackson, David G.; Sriskandan, Shiranee

    2015-01-01

    The host lymphatic network represents an important conduit for pathogen dissemination. Indeed, the lethal human pathogen group A streptococcus has a predilection to induce pathology in the lymphatic system and draining lymph nodes, however the underlying basis and subsequent consequences for disease outcome are currently unknown. Here we report that the hyaluronan capsule of group A streptococci is a crucial virulence determinant for lymphatic tropism in vivo, and further, we identify the lymphatic vessel endothelial receptor-1 as the critical host receptor for capsular hyaluronan in the lymphatic system. Interference with this interaction in vivo impeded bacterial dissemination to local draining lymph nodes and, in the case of a hyper-encapsulated M18 strain, redirected streptococcal entry into the blood circulation, suggesting a pivotal role in the manifestation of streptococcal infections. Our results reveal a novel function for bacterial capsular polysaccharide in directing lymphatic tropism, with potential implications for disease pathology. PMID:26352587

  15. Molecular and cellular mechanisms of lymphatic vascular maturation

    PubMed Central

    Chen, Hong; Griffin, Courtney; Xia, Lijun; Srinivasan, R. Sathish

    2014-01-01

    Lymphatic vasculature is necessary for maintaining fluid homeostasis in vertebrates. During embryogenesis lymphatic endothelial cells originate from the veins as a homogeneous population. These cells undergo a series of changes at the morphological and molecular levels to become mature lymphatic vasculature that consists of lymphatic capillaries, collecting lymphatic vessels and valves. In this article we summarize our current knowledge about these steps and highlight some black boxes that require further clarification. PMID:24928499

  16. In vivo determination of collecting lymphatic vessel permeability to albumin: a role for lymphatics in exchange

    PubMed Central

    Scallan, Joshua P; Huxley, Virginia H

    2010-01-01

    While it is well established that the lymphatic vasculature is central to fluid and solute homeostasis, how it accomplishes this task is not well defined. To clarify the basic mechanisms underlying basal fluid and solute homeostasis, we assessed permeability to rat serum albumin () in mesenteric collecting lymphatic vessels and venules of juvenile male rats. Using the quantitative microfluorometric technique originally developed for blood capillaries, we tested the hypothesis that as a consequence of venules and collecting lymphatics sharing a common embryological origin, their would not differ significantly. Supporting our hypothesis, the median collecting lymphatic (3.5 ± 1.0 × 10−7 cm s−1, N= 22) did not differ significantly from the median venular (4.0 ± 1.0 × 10−7 cm s−1, N= 8, P= 0.61). For collecting lymphatics the diffusive permeability (Pd= 2.5 × 10−7 cm s−1) was obtained from the relationship of apparent and pressure. While the measured , Pd and estimated hydraulic conductivity of collecting lymphatics and venules were similar, the contribution of convective coupling differs as a result of the higher hydrostatic pressure experienced by venules relative to collecting lymphatics in vivo. In summary, the data demonstrate the capacity for collecting lymphatics to act as exchange vessels, able to extravasate solute and filter fluid. As a consequence these data provide experimental support for the theory that prenodal lymphatic vessels concentrate intraluminal protein. PMID:19917564

  17. Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation.

    PubMed

    Gordon, Emma J; Rao, Sujata; Pollard, Jeffrey W; Nutt, Stephen L; Lang, Richard A; Harvey, Natasha L

    2010-11-01

    Macrophages have been suggested to stimulate neo-lymphangiogenesis in settings of inflammation via two potential mechanisms: (1) acting as a source of lymphatic endothelial progenitor cells via the ability to transdifferentiate into lymphatic endothelial cells and be incorporated into growing lymphatic vessels; and (2) providing a crucial source of pro-lymphangiogenic growth factors and proteases. We set out to establish whether cells of the myeloid lineage are important for development of the lymphatic vasculature through either of these mechanisms. Here, we provide lineage tracing evidence to demonstrate that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse, thus excluding macrophages as a source of lymphatic endothelial progenitor cells in these settings. In addition, we demonstrate that the dermal lymphatic vasculature of PU.1(-/-) and Csf1r(-/-) macrophage-deficient mouse embryos is hyperplastic owing to elevated lymphatic endothelial cell proliferation, suggesting that cells of the myeloid lineage provide signals that act to restrain lymphatic vessel calibre in the skin during development. In contrast to what has been demonstrated in settings of inflammation, macrophages do not comprise the principal source of pro-lymphangiogenic growth factors, including VEGFC and VEGFD, in the embryonic dermal microenvironment, illustrating that the sources of patterning and proliferative signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct.

  18. Cardiac Lymphatics - A New Avenue for Therapeutics?

    PubMed

    Vuorio, Taina; Tirronen, Annakaisa; Ylä-Herttuala, Seppo

    2017-01-10

    Recent progress in lymphatic vessel biology and in novel imaging techniques has established the importance of the lymphatic vasculature as part of the cardiovascular system. The lymphatic vessel network regulates many physiological processes important for heart function such as fluid balance, transport of extravasated proteins, and trafficking of immune cells. Therefore, lymphangiogenic therapy could be beneficial in the treatment of cardiovascular diseases, for example by improving reverse cholesterol transport (RCT) from atherosclerotic lesions or by resolving edema and fibrosis after myocardial infarction. In this review we first describe recent findings on the development and function of cardiac lymphatic vessels, and subsequently focus on the prospects of pro- and anti-lymphangiogenic therapies in cardiovascular diseases.

  19. Lymphatic vessels in inflamed human dental pulp.

    PubMed

    Marchetti, C; Piacentini, C; Menghini, P

    1990-01-01

    Investigation has been performed on both the light and electron microscopic characteristics of the lymphatic vessels present in the dental pulp of human teeth which have been affected by serious carious lesions. These conditions provoke a severe inflammatory response resulting in structural and functional modifications of the tissue; increase of the tissue pressure is followed by the need for a more intensive lymphatic drainage. In the inflamed pulps, dilated lymphatic vessels with distended walls and "open junctions" between endothelial cells are detectable. On the other hand they lack certain endothelial structures which characterize the morphology of these vessels under normal conditions. In the pulpal regions affected by fibrotic proliferation shrunken vessels with irregular profiles are present. From these observations it is possible to obtain other information on the mechanisms regulating the lymphatic drainage in different structural and functional conditions of the interstitium.

  20. Comparative and Developmental Anatomy of Cardiac Lymphatics

    PubMed Central

    Ratajska, A.; Gula, G.; Flaht-Zabost, A.; Czarnowska, E.; Ciszek, B.; Jankowska-Steifer, E.; Niderla-Bielinska, J.; Radomska-Lesniewska, D.

    2014-01-01

    The role of the cardiac lymphatic system has been recently appreciated since lymphatic disturbances take part in various heart pathologies. This review presents the current knowledge about normal anatomy and structure of lymphatics and their prenatal development for a better understanding of the proper functioning of this system in relation to coronary circulation. Lymphatics of the heart consist of terminal capillaries of various diameters, capillary plexuses that drain continuously subendocardial, myocardial, and subepicardial areas, and draining (collecting) vessels that lead the lymph out of the heart. There are interspecies differences in the distribution of lymphatic capillaries, especially near the valves, as well as differences in the routes and number of draining vessels. In some species, subendocardial areas contain fewer lymphatic capillaries as compared to subepicardial parts of the heart. In all species there is at least one collector vessel draining lymph from the subepicardial plexuses and running along the anterior interventricular septum under the left auricle and further along the pulmonary trunk outside the heart and terminating in the right venous angle. The second collector assumes a different route in various species. In most mammalian species the collectors run along major branches of coronary arteries, have valves and a discontinuous layer of smooth muscle cells. PMID:24592145

  1. Advances in Lymphatic Imaging and Drug Delivery

    SciTech Connect

    Nune, Satish K.; Gunda, Padmaja; Majeti, Bharat K.; Thallapally, Praveen K.; Laird, Forrest M.

    2011-09-10

    Cancer remains the second leading cause of death after heart disease in the US. While metastasized cancers such as breast, prostate, and colon are incurable, before their distant spread, these diseases will have invaded the lymphatic system as a first step in their progression. Hence, proper evaluation of the disease state of the lymphatics which drain a tumor site is crucial to staging and the formation of a treatment plan. Current lymphatic imaging modalities with visible dyes and radionucleotide tracers offer limited sensitivity and poor resolution; however, newer tools using nanocarriers, quantum dots, and magnetic resonance imaging promise to vastly improve the staging of lymphatic spread without needless biopsies. Concurrent with the improvement of lymphatic imaging agents, has been the development of drug carriers that can localize chemotherapy to the lymphatic system, thus improving the treatment of localized disease while minimizing the exposure of healthy organs to cytotoxic drugs. This review will focus on polymeric systems that have been developed for imaging and drug delivery to the lymph system, how these new devices improve upon current technologies, and where further improvement is needed.

  2. Lymphatic fluid: exchange mechanisms and regulation

    PubMed Central

    Huxley, Virginia H; Scallan, Joshua

    2011-01-01

    Abstract Regulation of fluid and material movement between the vascular space of microvessels penetrating functioning organs and the cells therein has been studied extensively. Unanswered questions as to the regulatory mechanisms and routes remain. Significantly less is known about the lymphatic vascular system given the difficulties in seeing, no less isolating, these vessels lying deeper in these same tissues. It has become evident that the exchange microvasculature is not simply a passive biophysical barrier separating the vascular and interstitial compartments but a dynamic, multicellular structure subject to acute regulation and chronic adaptation to stimuli including inflammation, sepsis, diabetes, injury, hypoxia and exercise. Similarly lymphatic vessels range, in their simplest form, from lymphatic endothelium attached to the interstitial matrix, to endothelia and phasic lymphatic smooth muscle that act as Starling resistors. Recent work has demonstrated that among the microvascular lymphatic elements, the collecting lymphatics have barrier properties similar to venules, and thus participate in exchange. As with venules, vasoactive agents can alter both the permeability and contractile properties thereby setting up previously unanticipated gradients in the tissue space and providing potential targets for the pharmacological prevention and/or resolution of oedema. PMID:21521763

  3. Lymphatic vessel density in radical prostatectomy specimens.

    PubMed

    Cheng, Liang; Bishop, Elena; Zhou, Honghong; Maclennan, Gregory T; Lopez-Beltran, Antonio; Zhang, Shaobo; Badve, Sunil; Baldridge, Lee Ann; Montironi, Rodolfo

    2008-04-01

    Formation of new lymphatic channels, or lymphangiogenesis, has been associated with poor prognosis in a number of human cancers. Its prognostic significance in prostate cancer is uncertain. We analyzed 122 radical prostatectomy specimens. Immunohistochemistry for lymphatic vessels was performed using a mouse monoclonal antibody reactive with an O-linked sialoglycoprotein found on lymphatic endothelium (clone D2-40, Signet Laboratories, Dedham, Mass). The mean lymphatic vessel densities (LVDs) of the 3 prostate compartments were compared. Lymphatic vessel densities were correlated with other clinical and pathologic characteristics. Mean values for intratumoral, peritumoral, and normal prostate LVD were 3.0, 5.2, and 4.8 lymphatic vessels per 200x field, respectively. The intratumoral LVD was significantly lower than the peritumoral or normal LVD (P < .001), and the LVD of the latter 2 compartments was not significantly different (P = .29). The prostate LVD did not correlate with other clinical and pathologic parameters. In conclusion, LVD is reduced in the intratumoral compartment compared with the peritumoral and normal prostate compartments, whereas the latter 2 have similar LVD. In contrast to other malignancies, quantitation of lymphangiogenesis in prostatic adenocarcinoma does not appear to offer useful prognostic information.

  4. Superselective retrograde lymphatic duct embolization for management of postoperative lymphatic leak.

    PubMed

    Arslan, Bülent; Masrani, Abdulrahman; Tasse, Jordan Cameron; Stenson, Kerstin; Turba, Ülkü Cenk

    2017-01-01

    Lymphatic leak is a well-documented complication following neck dissection surgeries. When conservative methods fail to control the leak, thoracic duct embolization becomes an option. Transabdominal access is the standard for this procedure; however, it is not always feasible. We discuss a technique of selective lymphatic vessel embolization utilizing retrograde transvenous access.

  5. Superselective retrograde lymphatic duct embolization for management of postoperative lymphatic leak

    PubMed Central

    Arslan, Bülent; Masrani, Abdulrahman; Tasse, Jordan Cameron; Stenson, Kerstin; Turba, Ülkü Cenk

    2017-01-01

    Lymphatic leak is a well-documented complication following neck dissection surgeries. When conservative methods fail to control the leak, thoracic duct embolization becomes an option. Transabdominal access is the standard for this procedure; however, it is not always feasible. We discuss a technique of selective lymphatic vessel embolization utilizing retrograde transvenous access. PMID:28724508

  6. Functional lymphatic alterations in patients suffering from lipedema.

    PubMed

    Bilancini, S; Lucchi, M; Tucci, S; Eleuteri, P

    1995-04-01

    Lipedema is a chronic vascular disease almost exclusively of female sex, characterized by the deposit of fat on the legs, with an "Egyptian column" shape, orthostatic edema, hypothermia of the skin, alteration of the plantar support, and negativity of Stemmer's sign. The etiology and pathogenesis of this disease are still the object of study, and therapy is very difficult. Various authors have described morphologic and functional alterations of prelymphatic structures and of lymphatic vessels. The big veins remain untouched in the phlebograms and an alteration of the skin elasticity is demonstrated. The present authors have studied by dynamic lymphoscintigraphy 12 women patients suffering from lipedema, and compared the results with those of 5 normal subjects and 5 patients suffering from idiopathic lymphedema who were sex and age matched with the patients suffering from lipedema. The patients suffering from lipedema showed an abnormal lymphoscintigraphic pattern with a slowing of the lymphatic flow that presented some analogies to the alterations found in the patients suffering from lymphedema. A frequent asymmetry was also noticed in the lymphoscintigraphic findings that is in contrast to the symmetry of the clinical profile.

  7. Role of lymphatic vasculature in regional and distant metastases.

    PubMed

    Podgrabinska, Simona; Skobe, Mihaela

    2014-09-01

    In cancer, lymphatic vasculature has been traditionally viewed only as a transportation system for metastatic cells. It has now become clear that lymphatics perform many additional functions which could influence cancer progression. Lymphangiogenesis, induced at the primary tumor site and at distant sites, potently augments metastasis. Lymphatic endothelial cells (LECs) control tumor cell entry and exit from the lymphatic vessels. LECs also control immune cell traffic and directly modulate adaptive immune responses. This review highlights advances in our understanding of the mechanisms by which lymphatic vessels, and in particular lymphatic endothelium, impact metastasis. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. The Lymphatic System in Disease Processes and Cancer Progression

    PubMed Central

    Padera, Timothy P.; Meijer, Eelco F.J.; Munn, Lance L.

    2016-01-01

    Advances in our understanding of the structure and function of the lymphatic system have made it possible to identify its role in a variety of disease processes. Because it is involved not only in fluid homeostasis but also in immune cell trafficking, the lymphatic system can mediate and ultimately alter immune responses. Our rapidly increasing knowledge of the molecular control of the lymphatic system will inevitably lead to new and effective therapies for patients with lymphatic dysfunction. In this review, we discuss the molecular and physiological control of lymphatic vessel function and explore how the lymphatic system contributes to many disease processes, including cancer and lymphedema. PMID:26863922

  9. Lymphatic Regeneration within Porous VEGF-C Hydrogels for Secondary Lymphedema

    DTIC Science & Technology

    2006-01-01

    VEGF-C Hydrogels for Secondary Lymphedema PRINCIPAL INVESTIGATOR: Mauricio A. Contreras, M.D. CONTRACTING ORGANIZATION: Beth...for Secondary 5a. CONTRACT NUMBER Lymphedema 5b. GRANT NUMBER DAMD17-01-1-0152 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT... Lymphedema is an abnormal swelling, in which lymph production exceeds drainage capabilities. This occurs as a result of lymphatic vesdestruction during the

  10. Lymphatic Territories (Lymphosomes) in Swine: An Animal Model for Future Lymphatic Research.

    PubMed

    Ito, Ran; Suami, Hiroo

    2015-08-01

    The swine is a common preclinical large-animal model for medical research because of the resemblance of its tissue structures to those of humans. However, the lymphatic system in swine is poorly understood. The authors investigated the lymphatic system and defined territories (lymphosomes) in swine using the microinjection technique. Six swine (two male and four female 17.5- to 50-kg Sus domesticus) were used. Real-time indocyanine green fluorescence lymphography was performed in four live swine. After the animals were killed, the authors injected a radiocontrast mixture consisting of barium sulfate and hydrogen peroxide with red acrylic dye directly into lymphatic vessels in six swine carcasses. Courses of the lymphatic vessel were analyzed radiographically. The lymphatic vessels were dissected meticulously and chased until they connected to the first-tier (sentinel) lymph node. This procedure was repeated throughout the body until all the relationships between the lymphatic vessels and lymph nodes were defined. The authors successfully mapped the superficial lymphatic vessels and their corresponding lymph nodes. Indocyanine green fluorescence lymphography and subsequent radiography revealed that the swine lymphatic system contained seven lymphosomes: parotid, mandibular, dorsal cervical, ventral cervical, subiliac, inguinal, and popliteal territories. Of note, no lymph nodes existed in the superficial axillary region. The swine could be a useful large-animal model for lymphatic research because of the anatomical consistency of the lymphosomes among animals and the sizable lymphatic vessels. However, swine lack the superficial axillary lymph node found in humans, suggesting that swine may not be a good model for breast cancer-related lymphedema.

  11. Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation

    PubMed Central

    Fatima, Anees; Wang, Ying; Uchida, Yutaka; Norden, Pieter; Liu, Ting; Culver, Austin; Dietz, William H.; Culver, Ford; Millay, Meredith; Mukouyama, Yoh-suke

    2016-01-01

    The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in FOXC2 are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell–specific (LEC-specific) deletion of Foxc1, Foxc2, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both Foxc1 and Foxc2 exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of Foxc1 and Foxc2, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases. PMID:27214551

  12. Lymphoedema caused by idiopathic lymphatic thrombus.

    PubMed

    Hara, Hisako; Mihara, Makoto; Seki, Yukio; Koshima, Isao

    2013-12-01

    Primary lymphoedema includes some diseases whose genetic anomaly is detected and others whose pathology is unknown. In this article, we report a lymphatic thrombus found in a limb with lymphoedema during lymphatico-venous anastomosis (LVA). A 32-year-old man was aware of oedema in his left calcar pedis 3 years previously, which appeared without any trigger. Indocyanine green lymphography indicated lymphatic stasis in the left calf and thigh region, and we performed LVA for the patient. During the operation, we found yellow vessels, which were thought to be lymphatic vessels filled with a yellow solid substance, just beneath the superficial fascia at the left ankle. Pathological examination of the thrombi revealed hyaline material mixed with cell components. The cells were categorised as lymphatic endothelial cells, as they were positive for podoplanin. There was no evidence of malignancy. Causes of idiopathic lymphatic thrombus such as this may be one of the causes of so-called primary lymphoedema, and evaluation of such cases may be the first step towards elucidating the mechanisms involved in the development of primary lymphoedema.

  13. Cholinergic innervation of human mesenteric lymphatic vessels.

    PubMed

    D'Andrea, V; Bianchi, E; Taurone, S; Mignini, F; Cavallotti, C; Artico, M

    2013-11-01

    The cholinergic neurotransmission within the human mesenteric lymphatic vessels has been poorly studied. Therefore, our aim is to analyse the cholinergic nerve fibres of lymphatic vessels using the traditional enzymatic techniques of staining, plus the biochemical modifications of acetylcholinesterase (AChE) activity. Specimens obtained from human mesenteric lymphatic vessels were subjected to the following experimental procedures: 1) drawing, cutting and staining of tissues; 2) staining of total nerve fibres; 3) enzymatic staining of cholinergic nerve fibres; 4) homogenisation of tissues; 5) biochemical amount of proteins; 6) biochemical amount of AChE activity; 6) quantitative analysis of images; 7) statistical analysis of data. The mesenteric lymphatic vessels show many AChE positive nerve fibres around their wall with an almost plexiform distribution. The incubation time was performed at 1 h (partial activity) and 6 h (total activity). Moreover, biochemical dosage of the same enzymatic activity confirms the results obtained with morphological methods. The homogenates of the studied tissues contain strong AChE activity. In our study, the lymphatic vessels appeared to contain few cholinergic nerve fibres. Therefore, it is expected that perivascular nerve stimulation stimulates cholinergic nerves innervating the mesenteric arteries to release the neurotransmitter AChE, which activates muscarinic or nicotinic receptors to modulate adrenergic neurotransmission. These results strongly suggest, that perivascular cholinergic nerves have little or no effect on the adrenergic nerve function in mesenteric arteries. The cholinergic nerves innervating mesenteric arteries do not mediate direct vascular responses.

  14. Exercise training improves obesity-related lymphatic dysfunction.

    PubMed

    Hespe, Geoffrey E; Kataru, Raghu P; Savetsky, Ira L; García Nores, Gabriela D; Torrisi, Jeremy S; Nitti, Matthew D; Gardenier, Jason C; Zhou, Jie; Yu, Jessie Z; Jones, Lee W; Mehrara, Babak J

    2016-08-01

    Obesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells. Although previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene

  15. Interaction between the extracellular matrix and lymphatics - consequences for lymphangiogenesis and lymphatic function

    PubMed Central

    Wiig, Helge; Keskin, Doruk; Kalluri, Raghu

    2014-01-01

    The lymphatic system is important for body fluid balance as well as immunological surveillance. Due to the identification of new molecular markers during the last decade, there has been a recent dramatic increase in our knowledge on the molecular mechanisms involved in lymphatic vessel growth (lymphangiogenesis) and lymphatic function. Here we review data showing that although it is often overlooked, the extracellular matrix plays an important role in the generation of new lymphatic vessels as a response to physiological and pathological stimuli. Extracellular matrix-lymphatic interactions as well as biophysical characteristics of the stroma have consequences for tumor formation, growth and metastasis. During the recent years, anti-lymphangiogenesis has emerged as an additional therapeutic modality to the clinically applied anti-angiogenesis strategy. Oppositely, enhancement of lymphangiogenesis in situations of lymph accumulation is seen as a promising strategy to a set of conditions where few therapeutic avenues are available. Knowledge on the interaction between the extracellular matrix and the lymphatics may enhance our understanding of the underlying mechanisms and may ultimately lead to better therapies for conditions where reduced or increased lymphatic function is the therapeutic target PMID:20727409

  16. Lymphatic Vessels: The Next Frontier in Lung Transplant.

    PubMed

    Cui, Ye; Liu, Kaifeng; Lamattina, Anthony Mark; Visner, Gary; El-Chemaly, Souheil

    2017-09-01

    Lymphatic vessels are essential for the uptake of fluid, immune cells, macromolecules, and lipids from the interstitial space. During lung transplant surgery, the pulmonary lymphatic vessel continuum is completely disrupted, and, as a result, lymphatic drainage function is severely compromised. After transplantation, the regeneration of an effective lymphatic drainage system plays a crucial role in maintaining interstitial fluid balance in the lung allograft. In the meantime, these newly formed lymphatic vessels are commonly held responsible for the development of immune responses leading to graft rejection, because they are potentially capable of transporting antigen-presenting cells loaded with allogeneic antigens to the draining lymph nodes. However, despite remarkable progress in the understanding of lymphatic biology, there is still a paucity of consistent evidence that demonstrates the exact impacts of lymphatic vessels on lung graft function. In this review, we examine the current literature related to roles of lymphatic vessels in the pathogenesis of lung transplant rejection.

  17. Endothelial Cell Responses to Biomechanical Forces in Lymphatic Vessels.

    PubMed

    Sabine, Amélie; Saygili Demir, Cansaran; Petrova, Tatiana V

    2016-09-01

    Lymphatic vessels are important components of the cardiovascular and immune systems. They contribute both to the maintenance of normal homeostasis and to many pathological conditions, such as cancer and inflammation. The lymphatic vasculature is subjected to a variety of biomechanical forces, including fluid shear stress and vessel circumferential stretch. This review will discuss recent advances in our understanding of biomechanical forces in lymphatic vessels and their role in mammalian lymphatic vascular development and function. We will highlight the importance of fluid shear stress generated by lymph flow in organizing the lymphatic vascular network. We will also describe how mutations in mechanosensitive genes lead to lymphatic vascular dysfunction. Better understanding of how biomechanical and biochemical stimuli are perceived and interpreted by lymphatic endothelial cells is important for targeting regulation of lymphatic function in health and disease. Important remaining critical issues and future directions in the field will be discussed in this review. Antioxid. Redox Signal. 25, 451-465.

  18. Lattice Boltzmann simulations of lymphatic pumping

    NASA Astrophysics Data System (ADS)

    Kunert, Christian; Padera, Tim P.; Munn, Lance L.

    2012-02-01

    Lymphatic flow plays an important role in the progress of many diseases, including lymphedema and metastasis. However lymphatic pumping and flow is poorly understood. Here, we present a computer model that is based on biological observations of lymphatic pumping. Fluid flow is simulated by a D2Q9 lattice Boltzmann model. The boundary of the vessels moves according to shear-induced nitric oxide production, and wall motion transfers momentum to the fluid to induce flow. Because the model only includes local properties, it can be highly parallelized. In our case we utilize graphic processors (GPU) to achieve high performance computation. We show that the model provides stable pumping over a wide range of parameter values, with optimum flow achieved in the biological ranges. Furthermore, we investigate the efficiency by analyzing the flow rate and pumping frequency in order to compare the behavior of the model with existing in vivo data.

  19. EPHB4 kinase–inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis

    PubMed Central

    Martin-Almedina, Silvia; Holdhus, Rita; Vicente, Andres; Fotiou, Elisavet; Lin, Shin; Petersen, Kjell; Simpson, Michael A.; Hoischen, Alexander; Atton, Giles; Karapouliou, Christina; Brice, Glen; Gordon, Kristiana; Wiseman, John W.; Wedin, Marianne; Rockson, Stanley G.; Jeffery, Steve; Mortimer, Peter S.; Snyder, Michael P.; Berland, Siren; Mansour, Sahar; Makinen, Taija

    2016-01-01

    Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate. PMID:27400125

  20. Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels.

    PubMed

    Kazenwadel, Jan; Harvey, Natasha L

    2016-03-01

    Lymphatic vessels serve crucial roles in the regulation of tissue fluid homeostasis, dietary lipid absorption and immune cell trafficking. Defects in lymphatic vessel morphogenesis and function have been associated with lymphedema, obesity, hypertension and tumour metastasis. Morphogenetic events important for construction of the lymphatic vasculature during development include the specification and emergence of lymphatic endothelial progenitor cells, their differentiation and assembly into interconnected vessels and vascular remodeling, ultimately giving rise to a functional vascular network. Despite the embryonic origins of lymphatic endothelial progenitor cells being long debated, work performed over the last decade had overwhelmingly supported at least a great majority of progenitor cells arising from the venous vasculature. Here, we review the most recent advances in the field of lymphatic vessel morphogenesis, with a focus on studies that have identified novel sources of embryonic lymphatic endothelial progenitor cells, together with the cellular mechanisms by which lymphatic vessels are initially assembled. © 2015 Wiley Periodicals, Inc.

  1. Cerebral Lipiodol Embolism after Lymphatic Embolization for Plastic Bronchitis

    PubMed Central

    Kirschen, Matthew P.; Dori, Yoav; Itkin, Maxim; Licht, Daniel J.; Ichord, Rebecca; Vossough, Arastoo

    2016-01-01

    An adolescent with plastic bronchitis due to congenital heart disease had altered mental status after an interventional lymphatic procedure in which lipiodol contrast was used. Neuroimaging revealed cerebral lipiodol embolization due to direct shunting between lymphatic channels and pulmonary veins. Cerebral lipiodol embolization is a potential neurologic morbidity associated with interventional lymphatic procedures. PMID:27297208

  2. Cerebral Lipiodol Embolism after Lymphatic Embolization for Plastic Bronchitis.

    PubMed

    Kirschen, Matthew P; Dori, Yoav; Itkin, Maxim; Licht, Daniel J; Ichord, Rebecca; Vossough, Arastoo

    2016-09-01

    An adolescent with plastic bronchitis due to congenital heart disease had altered mental status after an interventional lymphatic procedure in which lipiodol contrast was used. Neuroimaging revealed cerebral lipiodol embolization due to direct shunting between lymphatic channels and pulmonary veins. Cerebral lipiodol embolization is a potential neurologic morbidity associated with interventional lymphatic procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. The human renal lymphatics under normal and pathological conditions.

    PubMed

    Ishikawa, Y; Akasaka, Y; Kiguchi, H; Akishima-Fukasawa, Y; Hasegawa, T; Ito, K; Kimura-Matsumoto, M; Ishiguro, S; Morita, H; Sato, S; Soh, S; Ishii, T

    2006-09-01

    The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics.

  4. Development of the lymphatic vascular system: a mystery unravels.

    PubMed

    Hong, Young-Kwon; Shin, Jay W; Detmar, Michael

    2004-11-01

    The blood vascular and the lymphatic system play complementary roles in tissue perfusion and fluid reabsorption. Despite its critical role in mediating tissue fluid homeostasis, intestinal lipid absorption, and the immune response, the lymphatic system has not received as much attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of lymphatic development and function. A series of recent landmark studies now significantly has advanced our understanding of the lymphatic system. Based upon the discovery and characterization of lymphatic-specific growth factors, receptors, and transcriptional regulators, the mystery of lymphatic vascular system development begins to be unraveled. The successful isolation and cultivation of blood vascular and lymphatic endothelial cells has enabled comparative molecular and cellular analyses of these two genetically and developmentally closely related cell lineages. Moreover, studies of several genetic mouse models have set the framework for a new molecular model of embryonic lymphatic vascular development and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Although these rapid advances already have led to development of the first lymphatic-targeted molecular therapies, there still remain many unanswered questions regarding almost every aspect of lymphatic vascular biology, making the lymphatic system a highly exciting and rewarding field of study.

  5. Lymphatic Muscle Cells in Rat Mesenteric Lymphatic Vessels of Various Ages

    PubMed Central

    Bridenbaugh, Eric A.; Nizamutdinova, Irina Tsoy; Jupiter, Daniel; Nagai, Takashi; Thangaswamy, Sangeetha; Chatterjee, Victor

    2013-01-01

    Abstract Background Recent studies on aging-associated changes in mesenteric lymph flow in situ demonstrated predominance of the severe negative chronotropic effect of aging on the contractility of aged mesenteric lymphatic vessels (MLV). At the same time, contraction amplitude of the aged vessels was only slightly diminished by aging and can be rapidly stimulated within 5–15 minutes. However, the detailed quantitative evaluation of potential aging-associated changes in muscle cells investiture in MLV has never been performed. Methods and Results In this study we, for the first time, performed detailed evaluation of muscle cells investiture in MLV in reference to the position of lymphatic valve in different zones of lymphangion within various age groups (3-mo, 9-mo and 24-mo Fischer-344 rats). Using visual and quantitative analyses of the images of MLV immunohistochemically labeled for actin, we confirmed that the zones located close upstream (pre-valve zones) and above lymphatic valves (valve zones) possess the lowest investiture of lymphatic muscle cells. Most of the high muscle cells investiture zones exist downstream to the lymphatic valve (post-valve zones). The muscle cells investiture of these zones is not affected by aging, while pre-valve and valve zones demonstrate significant aging-associated decrease in muscle cells investiture. Conclusions The low muscle cells investiture zones in lymphatic vessels consist of predominantly longitudinally oriented muscle cells which are positioned in pre-valve and valve zones and connect adjacent lymphangions. These cells may provide important functional impact on the biomechanics of the lymphatic valve gating and electrical coupling between lymphangions, while their aging-associated changes may delimit adaptive reserves of aged lymphatic vessels. PMID:23531183

  6. Lymphatic muscle cells in rat mesenteric lymphatic vessels of various ages.

    PubMed

    Bridenbaugh, Eric A; Nizamutdinova, Irina Tsoy; Jupiter, Daniel; Nagai, Takashi; Thangaswamy, Sangeetha; Chatterjee, Victor; Gashev, Anatoliy A

    2013-03-01

    Recent studies on aging-associated changes in mesenteric lymph flow in situ demonstrated predominance of the severe negative chronotropic effect of aging on the contractility of aged mesenteric lymphatic vessels (MLV). At the same time, contraction amplitude of the aged vessels was only slightly diminished by aging and can be rapidly stimulated within 5-15 minutes. However, the detailed quantitative evaluation of potential aging-associated changes in muscle cells investiture in MLV has never been performed. In this study we, for the first time, performed detailed evaluation of muscle cells investiture in MLV in reference to the position of lymphatic valve in different zones of lymphangion within various age groups (3-mo, 9-mo and 24-mo Fischer-344 rats). Using visual and quantitative analyses of the images of MLV immunohistochemically labeled for actin, we confirmed that the zones located close upstream (pre-valve zones) and above lymphatic valves (valve zones) possess the lowest investiture of lymphatic muscle cells. Most of the high muscle cells investiture zones exist downstream to the lymphatic valve (post-valve zones). The muscle cells investiture of these zones is not affected by aging, while pre-valve and valve zones demonstrate significant aging-associated decrease in muscle cells investiture. The low muscle cells investiture zones in lymphatic vessels consist of predominantly longitudinally oriented muscle cells which are positioned in pre-valve and valve zones and connect adjacent lymphangions. These cells may provide important functional impact on the biomechanics of the lymphatic valve gating and electrical coupling between lymphangions, while their aging-associated changes may delimit adaptive reserves of aged lymphatic vessels.

  7. Lymphatic Leak Complicating Central Venous Catheter Insertion

    SciTech Connect

    Barnacle, Alex M. Kleidon, Tricia M.

    2005-12-15

    Many of the risks associated with central venous access are well recognized. We report a case of inadvertent lymphatic disruption during the insertion of a tunneled central venous catheter in a patient with raised left and right atrial pressures and severe pulmonary hypertension, which led to significant hemodynamic instability. To our knowledge, this rare complication is previously unreported.

  8. Breast cancer metastasis and the lymphatic system

    PubMed Central

    RAHMAN, MUNAZZAH; MOHAMMED, SULMA

    2015-01-01

    Breast cancer remains the leading cause of cancer mortality worldwide, despite a significant decline in death rates due to early detection. The majority of cancer mortalities are due to the metastasis of tumor cells to other organs. Metastasis or tumor cell dissemination occurs via the hematogenous and lymphatic systems. For many carcinomas, the dissemination of tumor cells via lymphatic drainage of the tumor is the most common metastatic route. Such lymphatic drainage collects at the regional lymph nodes and the dissection and pathological examination of these nodes for lodged cancer cells is the gold standard procedure to detect metastasis. The present report provides an overview of the lymphatic system and its clinical significance as a prognostic factor, in addition to the interactions between the primary tumor and its microenvironment, and the influence of genomic subtypes on the resulting organ-specific pattern of tumor cell dissemination. It also examines the seemingly protracted asymptomatic period, during which the disseminated cells remain dormant, leading to the manifestation of metastasis decades after the successful treatment of the primary tumor. PMID:26622656

  9. The embryonic origins of lymphatic vessels: an historical review.

    PubMed

    Ribatti, Domenico; Crivellato, Enrico

    2010-06-01

    Work on the lymphatic system began in the 17th century, and by the beginning of the 19th century the anatomy of most of the lymphatic system had been described. One of the most important questions in this field has been the determination of the embryological origin of the lymphatic endothelium. Two theories were proposed. The first suggested that lymphatic endothelium derived by sprouting from venous endothelium, the so-called centrifugal theory. The second, the so-called centripetal theory, suggested that lymphatic endothelium differentiates in situ from primitive mesenchyme, and secondarily acquires connection with the vascular system. More recent evidence has provided support for both hypotheses.

  10. Lymphoscintigraphy patterns in newborns and children with congenital lymphatic dysplasia.

    PubMed

    Bellini, C; Villa, G; Sambuceti, G; Traggiai, C; Campisi, C; Bellini, T; Morcaldi, G; Massocco, D; Bonioli, E; Boccardo, F

    2014-03-01

    We performed lymphoscintigraphy on 31 patients (newborns and children) affected by congenital lymphatic dysplasia according to our previously published protocol. Congenital lymphatic dysplasia may present with various degrees of clinical severity, ranging from nonimmune hydrops fetalis with visceral effusions to lymphedema alone. We recommend that lymphoscintigraphy should be strongly considered in all patients with signs of lymphatic dysplasia, including those with minimal and initial signs of lymphatic impairment, in order to obtain a very early diagnosis and to start treatment. Lymphoscintigraphy is safe and useful in the diagnosis of lymphatic dysplasia in the newborn and children. Moreover, it is well tolerated by patients and well accepted by their parents.

  11. Blocking of the Lymphatic Vessel in Lymphedema

    PubMed Central

    Mihara, Makoto

    2017-01-01

    Objective: In this case report, we present a case wherein we observed a blocking of lymphatic vessels in indocyanine green lymphography and found a shrunken lymphatic vessel intraoperatively. Methods: We performed indocyanine green lymphography and lymphaticovenous anastomosis on a 77-year-old woman. She had previously undergone right mastectomy and axillary lymph node dissection accompanied by radiotherapy and chemotherapy for right breast cancer. She noticed swelling in the right upper limb 22 years after the surgery and consulted our hospital. Although she started wearing elastic sleeve, there was still stiffness in the right upper limb, and we decided to perform lymphaticovenous anastomosis 5 months after the first consultation. Results: In the preoperative indocyanine green lymphography, we observed a linear pattern in the medial side of the right forearm, which suddenly blocked in the middle of the forearm. At that point, we observed dilated lymphatic vessels that were suddenly shrunken at the proximal side intraoperatively. We performed lymphaticovenous anastomosis with the dilated part of this lymphatic vessel. We also performed 4 additional lymphaticovenous anastomoses. The operation time was 2 hours 10 minutes, and the amount of bleeding was minimal. The right upper limb of the patient got softer, and she was satisfied with the result 3 months after the operation. The average circumference change at the 5 points in the right upper limb was −1.26 cm (range, −2.3 to −0.3 cm). Conclusions: There was a possibility that the blocking of the lymphatic vessels was a cause of lymphedema in the upper extremity. PMID:28405261

  12. Aged lymphatic contractility: recent answers and new questions.

    PubMed

    Gashev, Anatoliy A; Chatterjee, Victor

    2013-03-01

    Abstract An overview is presented of recent findings related to biology of aging of the lymph transport system. The authors discuss recently obtained data on the aging-associated alterations of lymphatic contractility in thoracic duct and mesenteric lymphatic vessels; on comparisons of function of aged mesenteric lymphatic vessels in situ versus isolated specimens and important conclusions which arose from these studies; on aging-associated changes in functional status of mast cells located close to aged mesenteric lymphatic vessels; on evidence of presence of oxidative stress in aged lymphatic vessels and changes in arrangement of muscle cells in their walls. The authors conclude that future continuation of the research efforts in this area is necessary and will be able to provide not only novel fundamental knowledge on the biology of lymphatic aging, but also will create solid foundation for the subsequent developments of lymphatic-oriented therapeutic interventions in many diseases of the elderly.

  13. Perinatal autopsy findings in three cases of jugular lymphatic obstruction sequence and cardiac polyvalvular dysplasia.

    PubMed

    Bendon, Robert; Asamoah, Alexander

    2008-01-01

    Three infants with a prenatal diagnosis of Noonan's syndrome suffered fetal hydrops and immediate neonatal death. The infants all had the external appearance of jugular lymphatic obstruction sequence with wide-spaced nipples, redundant posterior nuchal skin, and edema of the dorsa of the feet and hands. All 3 demonstrated thick, redundant leaflets of all 4 cardiac valves, and 2 had a membranous ventricular septal defect. One female infant had a mutation of the PTPN11 gene. Two males had no common mutation of PTPN11. The males demonstrated other abnormalities in common, including small penis, testicular malformation, rosette-like appearance of the pituicytes, and an eosinophil infiltration of the pancreatic islets with islet cell hypertrophy. Detailed anatomy of cases of lymphatic obstruction sequence fetuses can be correlated with an increasing number of genetic mutations associated with Noonan's syndrome and related syndromes in mice and humans.

  14. Short time effects of radiotherapy on lymphatic vessels and restorative lymphatic pathways: experimental approaches ina mouse model.

    PubMed

    Pastouret, F; Lievens, P; Leduc, O; Bourgeois, P; Tournel, K; Lamote, J; Zirak, C; Leduc, A

    2014-06-01

    Radiotherapy (RT) is an important component in the therapeutic approach to oncologic conditions. This study presents the investigative results on the impact of RT on lymphatic vessels and on the regenerative response of the lymphatic system in a mouse model. We first irradiated 3 groups of ten mice using brachytherapy in a single treatment of 20 Gy. We then performed morphological examination of the irradiated lymphatic vessels using an in vivo microscopic transillumination technique at 2, 4, and 6 weeks. Next we evaluated lymphatic flow using lymphoscintigraphy and in vivo microscopy at 6 to 11 weeks in: 10 additional mice following irradiation as above (IR), in 10 mice following incision of a lymphatic vessel (I), and in a non-treated control group of 10 mice (N). Intact lymphatic vessels were observed in all mice at 2, 4, and 8 weeks following the single dose of radiotherapy in the first group of mice and normal lymphatic flow was fully restored in the irradiated (IR) and incised (I) mice indicating that the reparative substitution lymphatic pathways are functioning normally. We found that following irradiation with one dose of 20 Gy, lymphatic vessels were not visibly damaged and also that lymphatic flow was consistently restored and substitutive lymphatic pathways formed.

  15. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  16. Reconstructive microsurgery of lymph vessels: the personal method of lymphatic-venous-lymphatic (LVL) interpositioned grafted shunt.

    PubMed

    Campisi, C; Boccardo, F; Tacchella, M

    1995-01-01

    Our clinical observations in 64 patients affected by chronic obstructive lymphedema (either arm or leg) undergoing interposition autologous lymphatic-venous-lymphatic (LVL) anastomoses are reported. This microsurgical technique is an alternative to other lymphatic shunting methods, especially when venous dysfunction coexists in the same limb and, therefore, when direct lymphatic-venous anastomosis is accordingly inadequate. Preoperative diagnostic evaluation (including lymphatic and venous isotopic scintigraphy, Doppler venous flowmetrics, and pressure manometry) plays an essential role in assessing the conditions of both the lymphatic and venous systems and in establishing which microsurgical procedure, if any, is indicated. Our microsurgical technique consists of inserting suitably large and lengthy autologous venous grafts between lymphatic collectors above and below the site of obstruction to lymph flow. The data show that, using this technique, both limb function and edema improved, and in all patients followed up for over 5 years edema regression was permanent.

  17. Laminar flow downregulates Notch activity to promote lymphatic sprouting.

    PubMed

    Choi, Dongwon; Park, Eunkyung; Jung, Eunson; Seong, Young Jin; Yoo, Jaehyuk; Lee, Esak; Hong, Mingu; Lee, Sunju; Ishida, Hiroaki; Burford, James; Peti-Peterdi, Janos; Adams, Ralf H; Srikanth, Sonal; Gwack, Yousang; Chen, Christopher S; Vogel, Hans J; Koh, Chester J; Wong, Alex K; Hong, Young-Kwon

    2017-04-03

    The major function of the lymphatic system is to drain interstitial fluid from tissue. Functional drainage causes increased fluid flow that triggers lymphatic expansion, which is conceptually similar to hypoxia-triggered angiogenesis. Here, we have identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood endothelial cells and lymphatic endothelial cells (LECs), only LECs display reduced Notch activity and increased sprouting capacity. In response to flow, the plasma membrane calcium channel ORAI1 mediates calcium influx in LECs and activates calmodulin to facilitate a physical interaction between Krüppel-like factor 2 (KLF2), the major regulator of shear responses, and PROX1, the master regulator of lymphatic development. The PROX1/KLF2 complex upregulates the expression of DTX1 and DTX3L. DTX1 and DTX3L, functioning as a heterodimeric Notch E3 ligase, concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting. Notably, overexpression of the calcium reporter GCaMP3 unexpectedly inhibited lymphatic sprouting, presumably by disturbing calcium signaling. Endothelial-specific knockouts of Orai1 and Klf2 also markedly impaired lymphatic sprouting. Moreover, Dtx3l loss of function led to defective lymphatic sprouting, while Dtx3l gain of function rescued impaired sprouting in Orai1 KO embryos. Together, the data reveal a molecular mechanism underlying laminar flow-induced lymphatic sprouting.

  18. Lymph flow regulates collecting lymphatic vessel maturation in vivo

    PubMed Central

    Sweet, Daniel T.; Jiménez, Juan M.; Chang, Jeremy; Hess, Paul R.; Mericko-Ishizuka, Patricia; Fu, Jianxin; Xia, Lijun; Davies, Peter F.; Kahn, Mark L.

    2015-01-01

    Fluid shear forces have established roles in blood vascular development and function, but whether such forces similarly influence the low-flow lymphatic system is unknown. It has been difficult to test the contribution of fluid forces in vivo because mechanical or genetic perturbations that alter flow often have direct effects on vessel growth. Here, we investigated the functional role of flow in lymphatic vessel development using mice deficient for the platelet-specific receptor C-type lectin–like receptor 2 (CLEC2) as blood backfills the lymphatic network and blocks lymph flow in these animals. CLEC2-deficient animals exhibited normal growth of the primary mesenteric lymphatic plexus but failed to form valves in these vessels or remodel them into a structured, hierarchical network. Smooth muscle cell coverage (SMC coverage) of CLEC2-deficient lymphatic vessels was both premature and excessive, a phenotype identical to that observed with loss of the lymphatic endothelial transcription factor FOXC2. In vitro evaluation of lymphatic endothelial cells (LECs) revealed that low, reversing shear stress is sufficient to induce expression of genes required for lymphatic valve development and identified GATA2 as an upstream transcriptional regulator of FOXC2 and the lymphatic valve genetic program. These studies reveal that lymph flow initiates and regulates many of the key steps in collecting lymphatic vessel maturation and development. PMID:26214523

  19. Development of the larval lymphatic system in zebrafish.

    PubMed

    Jung, Hyun Min; Castranova, Daniel; Swift, Matthew R; Pham, Van N; Venero Galanternik, Marina; Isogai, Sumio; Butler, Matthew G; Mulligan, Timothy S; Weinstein, Brant M

    2017-06-01

    The lymphatic vascular system is a hierarchically organized complex network essential for tissue fluid homeostasis, immune trafficking and absorption of dietary fats in the human body. Despite its importance, the assembly of the lymphatic network is still not fully understood. The zebrafish is a powerful model organism that enables study of lymphatic vessel development using high-resolution imaging and sophisticated genetic and experimental manipulation. Although several studies have described early lymphatic development in the fish, lymphatic development at later stages has not been completely elucidated. In this study, we generated a new Tg(mrc1a:egfp)(y251) transgenic zebrafish that uses a mannose receptor, C type 1 (mrc1a) promoter to drive strong EGFP expression in lymphatic vessels at all stages of development and in adult zebrafish. We used this line to describe the assembly of the major vessels of the trunk lymphatic vascular network, including the later-developing collateral cardinal, spinal, superficial lateral and superficial intersegmental lymphatics. Our results show that major trunk lymphatic vessels are conserved in the zebrafish, and provide a thorough and complete description of trunk lymphatic vessel assembly. © 2017. Published by The Company of Biologists Ltd.

  20. Lymphatic System: An Active Pathway for Immune Protection

    PubMed Central

    Liao, Shan; von der Weid, Pierre-Yves

    2015-01-01

    Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases. PMID:25534659

  1. The lymphatic vasculature: development and role in shaping immunity.

    PubMed

    Betterman, Kelly L; Harvey, Natasha L

    2016-05-01

    The lymphatic vasculature is an integral component of the immune system. Lymphatic vessels are a key highway via which immune cells are trafficked, serving not simply as a passive route of transport, but to actively shape and coordinate immune responses. Reciprocally, immune cells provide signals that impact the growth, development, and activity of the lymphatic vasculature. In addition to immune cell trafficking, lymphatic vessels are crucial for fluid homeostasis and lipid absorption. The field of lymphatic vascular research is rapidly expanding, fuelled by rapidly advancing technology that has enabled the manipulation and imaging of lymphatic vessels, together with an increasing recognition of the involvement of lymphatic vessels in a myriad of human pathologies. In this review we provide an overview of the genetic pathways and cellular processes important for development and maturation of the lymphatic vasculature, discuss recent work revealing important roles for the lymphatic vasculature in directing immune cell traffic and coordinating immune responses and highlight the involvement of lymphatic vessels in a range of pathological settings. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Lymphatic system: an active pathway for immune protection.

    PubMed

    Liao, Shan; von der Weid, P Y

    2015-02-01

    Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which may include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Comparison of approaches for microscopic imaging of skin lymphatic vessels.

    PubMed

    Wu, Xiufeng; Yu, Zheyuan; Liu, Ningfei

    2012-01-01

    Assessment of skin lymphatic vessels is of great significance in understanding their roles in many pathological conditions. Our aim was to identify the optimal approach for investigation of cutaneous lymphatic system. We performed comparative studies on skin lymphatic vessels using immunohistochemistry of tissue sections, computer graphic reconstruction method together with immunohistochemically stained serial sections and whole mount fluorescence in human lower limb. Lymphatic vessels were identified with podoplanin antibody. The relative merits and drawbacks of each method in evaluation of structure, spatial organization, and distribution of cutaneous lymphatic vessels were described. Immunohistology of tissue sections enabled the investigation of the structure and distribution of the whole cutaneous lymphatic system in two-dimensional slices, whereas three-dimensional morphology of only the most superficial lymph capillary network immediately under the epidermis could be evaluated with the whole mount technique. Meanwhile, only little segmentation of skin lymphatic vessel from five immunohistochemically stained serial sections was reconstructed and evaluated due to expense and special skills required using computer graphic three-dimensional reconstruction. Furthermore, a great number of artifacts and special skills required in its processes leaded to less accurate structure of skin lymphatic vessels. Our findings demonstrated that the use of either of the proposed techniques alone could not allow a comprehensive analysis of the skin lymphatic system due to their relative drawbacks. Combination of immunohistology of tissue sections and three-dimensional whole-mount preparations appears to be the best candidate for comprehensive evaluation of skin lymphatic system. © Wiley Periodicals, Inc.

  4. Fluorescence imaging of lymphatic outflow of cerebrospinal fluid in mice.

    PubMed

    Kwon, Sunkuk; Janssen, Christopher F; Velasquez, Fred Christian; Sevick-Muraca, Eva M

    2017-10-01

    Cerebrospinal fluid (CSF) is known to be reabsorbed by the lymphatic vessels and drain into the lymph nodes (LNs) through peripheral lymphatic vessels. In the peripheral lymphatics, the contractile pumping action of lymphangions mediates lymph drainage; yet it is unknown whether lymphatic vessels draining cranial and spinal CSF show similar function. Herein, we used non-invasive near-infrared fluorescence imaging (NIRFI) to image (i) indocyanine green (ICG) distribution along the neuraxis and (ii) routes of ICG-laden CSF outflow into the lymphatics following intrathecal lumbar administration. We demonstrate lymphatic contractile function in peripheral lymphatics draining from the nasal lymphatics to the mandibular LNs. In addition, we observed afferent sciatic lymphatic vessels, which also show contractile activity and transport spinal CSF into the sciatic LNs. This drainage pattern was also visualized by NIRFI following intrathecal thoracic injection. In situ intravital imaging following intrathecal lumbar injection of blue dye shows similar distributions to that seen in vivo with ICG. NIRFI could be used as a tool to probe CSF pathology including neurological disorders by imaging CSF outflow dynamics to lymphatics. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. The lymphatic vascular system of the mouse head.

    PubMed

    Lohrberg, Melanie; Wilting, Jörg

    2016-12-01

    Histological studies of the lymphatic vascular system in adult mice are hampered because bones cannot be sectioned properly. Here, we decalcified the heads of 14-day-old mice, embedded them in paraffin and stained resultant serial sections with the lymphendothelial-specific antibodies Lyve-1 and Podoplanin. We show that the tissues with the highest lymphatic vascular density are the dermis and the oral mucous membranes. In contrast, the nasal mucous membrane is devoid of lymphatics, except for its most basal parts below the vomeronasal organ. The inferior nasal turbinate contains numerous lymphatics and is connected to the nasolacrimal duct (NLD), which is ensheathed by a dense network of lymphatics. The lymphatics of the eye lids and conjunctiva are connected to those of the inferior nasal turbinate. We suggest that cerebro-spinal fluid (CSF) can drain via the optic nerve and NLD lymphatics, whereas CSF drained via the Fila olfactoria into the nasal mucous membrane is used for moisturization of the respiratory air. Tongue, palatine and buccal mucous membranes possess numerous lymphatics, whereas the dental pulp has none. Lymphatics are present in the maxillary gland and close to the temporomandibular joint, suggesting the augmentation of lymph flow by chewing and yawning. Lymphatics can also be found in the dura mater and in the dural septae entering into deeper parts of the brain. Our findings are discussed with regard to CSF drainage and potential routes for ocular tumor dissemination.

  6. Program requirements for fellowship education in venous and lymphatic medicine.

    PubMed

    Comerota, Anthony J; Min, Robert J; Rathbun, Suman W; Khilnani, Neil; Rooke, Thom; Wakefield, Thomas W; Carman, Teresa L; Lurie, Fedor; Vedantham, Suresh; Zimmet, Steven E

    2017-08-01

    Background In every field of medicine, comprehensive education should be delivered at the graduate level. Currently, no single specialty routinely provides a standardized comprehensive curriculum in venous and lymphatic disease. Method The American Board of Venous & Lymphatic Medicine formed a task force, made up of experts from the specialties of dermatology, family practice, interventional radiology, interventional cardiology, phlebology, vascular medicine, and vascular surgery, to develop a consensus document describing the program requirements for fellowship medical education in venous and lymphatic medicine. Result The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine identify the knowledge and skills that physicians must master through the course of fellowship training in venous and lymphatic medicine. They also specify the requirements for venous and lymphatic training programs. The document is based on the Core Content for Training in Venous and Lymphatic Medicine and follows the ACGME format that all subspecialties in the United States use to specify the requirements for training program accreditation. The American Board of Venous & Lymphatic Medicine Board of Directors approved this document in May 2016. Conclusion The pathway to a vein practice is diverse, and there is no standardized format available for physician education and training. The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine establishes educational standards for teaching programs in venous and lymphatic medicine and will facilitate graduation of physicians who have had comprehensive training in the field.

  7. The human renal lymphatics under normal and pathological conditions

    PubMed Central

    Ishikawa, Y; Akasaka, Y; Kiguchi, H; Akishima-Fukasawa, Y; Hasegawa, T; Ito, K; Kimura-Matsumoto, M; Ishiguro, S; Morita, H; Sato, S; Soh, S; Ishii, T

    2006-01-01

    Ishikawa Y, Akasaka Y, Kiguchi H, Akishima-Fukasawa Y, Hasegawa T, Ito K, Kimura-Matsumoto M, Ishiguro S, Morita H, Sato S, Soh S & Ishii T (2006) Histopathology 49, 265–273 The human renal lymphatics under normal and pathological conditions Aims The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. Methods and results Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. Conclusions Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics. PMID:16918973

  8. Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis

    PubMed Central

    Lahdenranta, Johanna; Hagendoorn, Jeroen; Padera, Timothy P.; Hoshida, Tohru; Nelson, Gregory; Kashiwagi, Satoshi; Jain, Rakesh K.; Fukumura, Dai

    2009-01-01

    Lymphatic metastasis is a critical determinant of cancer prognosis. Recently, several lymphangiogenic molecules such as vafscular endothelial growth factor (VEGF)-C and -D were identified. However, the mechanistic understanding of lymphatic metastasis is still in infancy. Nitric oxide (NO) plays a crucial role in regulating blood vessel growth and function as well as lymphatic vessel function. NOS expression correlates with lymphatic metastasis. However, causal relationship between NOS and lymphatic metastasis has not been documented. To this end, we first show that both VEGF receptor-2 and -3 stimulation activate eNOS in lymphatic endothelial cells and that NO donors induce proliferation and/or survival of cultured lymphatic endothelial cells in a dose dependent manner. We find that an NOS inhibitor L-NMMA blocked regeneration of lymphatic vessels. Using intravital microscopy that allows us to visualize the steps of lymphatic metastasis, we show that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes. Genetic deletion of eNOS in the host also leads to a decrease in T241 tumor cell dissemination to the lymph nodes and macroscopic lymph node metastasis of B16F10 melanoma. These findings indicate that eNOS mediates VEGF-C induced lymphangiogenesis and, consequently, plays a critical role in lymphatic metastasis. Our findings explain the correlation between NOS and lymphatic metastasis seen in a number of human tumors and open the door for potential therapies exploiting NO signaling to treat diseases of the lymphatic system. PMID:19318557

  9. An overview of lymphatic vessels and their emerging role in cardiovascular disease.

    PubMed

    Jones, Dennis; Min, Wang

    2011-07-01

    Over the past decade, molecular details of lymphatic vessels (lymphatics) have been rapidly acquired due to the identification of lymphatic endothelial-specific markers. Separate from the cardiovascular system, the lymphatic system is also an elaborate network of vessels that are important in normal physiology. Lymphatic vessels have the unique task to regulate fluid homeostasis, assist in immune surveillance, and transport dietary lipids. However, dysfunctional lymphatic vessels can cause pathology, while normal lymphatics can exacerbate pathology. This review summarizes the development and growth of lymphatic vessels in addition to highlighting their critical roles in physiology and pathology. Also, we discuss recent work that suggests a connection between lymphatic dysfunction and cardiovascular disease.

  10. Lymphatic endothelium forms integrin-engaging 3D structures during DC transit across inflamed lymphatic vessels.

    PubMed

    Teijeira, Alvaro; Garasa, Saray; Peláez, Rafael; Azpilikueta, Arantza; Ochoa, Carmen; Marré, Diego; Rodrigues, Magda; Alfaro, Carlos; Aubá, Cristina; Valitutti, Salvatore; Melero, Ignacio; Rouzaut, Ana

    2013-09-01

    Dendritic cell (DC) transmigration across the lymphatic endothelium is critical for the initiation and sustenance of immune responses. Under noninflammatory conditions, DC transit across the lymphatic endothelial cell (LEC) has been shown to be integrin independent. In contrast, there is increasing evidence for the participation of integrins and their ligands in DC transit across lymphatic endothelium under inflammation. In this sense, we describe the formation of ICAM-1 (CD54)-enriched three-dimensional structures on LEC/DC contacts, as these DCs adhere to inflamed skin lymphatic vessels and transmigrate into them. In vitro imaging revealed that under inflammation ICAM-1 accumulated on microvilli projections surrounding 60% of adhered DCs. In contrast, these structures were scarcely formed in noninflammatory conditions. Furthermore, ICAM-1-enriched microvilli were important in promoting DC transendothelial migration and DC crawling over the LEC surface. Microvilli formation was dependent on the presence of β-integrins on the DC side and on integrin conformational affinity to ligand. Finally, we observed that LEC microvilli structures appeared in close vicinity of CCL21 depots and that their assembly was partially inhibited by CCL21-neutralizing antibodies. Therefore, under inflammatory conditions, integrin ligands form three-dimensional membrane projections around DCs. These structures offer docking sites for DC transit from the tissue toward the lymphatic vessel lumen.

  11. Interactions of immune cells and lymphatic vessels.

    PubMed

    Kataru, Raghu P; Lee, Yulia G; Koh, Gou Young

    2014-01-01

    In addition to fluid and lipid absorption, immune cell trafficking has now become recognized as one of the major functions of the lymphatic system. Recently, several critical roles of the lymphatic vessels (LVs) in modulating immune reactions during both physiological and pathological conditions have been emerging. As LVs serve as conduits for immune cells, they come to closely interact with macrophages/monocytes, dendritic cells, and T and B lymphocytes. Accumulating evidences indicate that reciprocal interactions between the LVs and immune cells exist which cause considerable influence over the process of immune cell migration, LV growth, and ultimately certain immune reactions. This chapter discusses on the interactions of macrophages/monocytes and dendritic cells with peripheral LVs and on those of sinusoidal macrophages and T and B lymphocytes with lymph node LVs.

  12. Cardiac mouse lymphatics: developmental and anatomical update.

    PubMed

    Flaht-Zabost, Aleksandra; Gula, Grzegorz; Ciszek, Bogdan; Czarnowska, Elżbieta; Jankowska-Steifer, Ewa; Madej, Maria; Niderla-Bielińska, Justyna; Radomska-Leśniewska, Dorota; Ratajska, Anna

    2014-06-01

    The adult mouse heart possesses an extensive lymphatic plexus draining predominantly the subepicardium and the outer layer of the myocardial wall. However, the development of this plexus has not been entirely explored, partially because of the lack of suitable methods for its visualization as well as prolonged lymphatic vessel formation that starts prenatally and proceeds during postnatal stages. Also, neither the course nor location of collecting vessels draining lymph from the mouse heart have been precisely characterized. In this article, we report that murine cardiac lymphatic plexus development that is limited prenatally only to the subepicardial area, postnatally proceeds from the subepicardium toward the myocardial wall with the base-to-apex gradient; this plexus eventually reaches the outer half of the myocardium with a predominant location around branches of coronary arteries and veins. Based on multiple marker immunostaining, the molecular marker-phenotype of cardiac lymphatic endothelial cells can be characterized as: Prox-1(+), Lyve-1(+), VEGFR3(+), Podoplanin(+), VEGFR2(+), CD144(+), Tie2(+), CD31(+), vWF(-), CD34(-), CD133(-). There are two major collecting vessels: one draining the right and left ventricles along the left conal vein and running upwards to the left side of the pulmonary trunk and further to the nearest lymph nodes (under the aortic arch and near the trachea), and the other one with its major branch running along the left cardiac vein and further on the surface of the coronary sinus and the left atrium to paratracheal lymph nodes. The extracardiac collectors gain the smooth muscle cell layer during late postnatal stages.

  13. Congenital Abnormalities

    MedlinePlus

    ... while you are pregnant. Combination of Genetic and Environmental Problems Some congenital abnormalities may occur if there is a genetic tendency for the condition combined with exposure to certain environmental influences within the womb during critical stages of ...

  14. In vivo albumin labeling and lymphatic imaging

    PubMed Central

    Wang, Yu; Lang, Lixin; Huang, Peng; Wang, Zhe; Jacobson, Orit; Kiesewetter, Dale O.; Ali, Iqbal U.; Teng, Gaojun; Niu, Gang; Chen, Xiaoyuan

    2015-01-01

    The ability to accurately and easily locate sentinel lymph nodes (LNs) with noninvasive imaging methods would assist in tumor staging and patient management. For this purpose, we developed a lymphatic imaging agent by mixing fluorine-18 aluminum fluoride-labeled NOTA (1,4,7-triazacyclononane-N,N',N''-triacetic acid)-conjugated truncated Evans blue (18F-AlF-NEB) and Evans blue (EB) dye. After local injection, both 18F-AlF-NEB and EB form complexes with endogenous albumin in the interstitial fluid and allow for visualizing the lymphatic system. Positron emission tomography (PET) and/or optical imaging of LNs was performed in three different animal models including a hind limb inflammation model, an orthotropic breast cancer model, and a metastatic breast cancer model. In all three models, the LNs can be distinguished clearly by the apparent blue color and strong fluorescence signal from EB as well as a high-intensity PET signal from 18F-AlF-NEB. The lymphatic vessels between the LNs can also be optically visualized. The easy preparation, excellent PET and optical imaging quality, and biosafety suggest that this combination of 18F-AlF-NEB and EB has great potential for clinical application to map sentinel LNs and provide intraoperative guidance. PMID:25535368

  15. Non-endemic cases of lymphatic filariasis.

    PubMed

    Jones, Robert T

    2014-11-01

    Several cases of lymphatic filariasis (LF) have been reported in non-endemic countries due to travellers, military personnel and expatriates spending time in and returning from endemic areas, as well as immigrants coming from these regions. These cases are reviewed to assess the scale and context of non-endemic presentations and to consider the biological factors underlying their relative paucity. Cases reported in the English, French, Spanish and Portuguese literature during the last 30 years were examined through a search of the PubMed, ProMED-mail and TropNet resources. The literature research revealed 11 cases of lymphatic filariasis being reported in non-endemic areas. The extent of further infections in recent migrants to non-endemic countries was also revealed through the published literature. The life-cycle requirements of Wuchereria and Brugia species limit the extent of transmission of LF outside of tropical regions. However, until elimination, programmes are successful in managing the disease, there remains a possibility of low rates of infection being reported in non-endemic areas, and increased international travel can only contribute to this phenomenon. Physicians need to be aware of the signs and symptoms of lymphatic filariasis, and infection should be considered in the differential diagnosis of people with a relevant travel history. © 2014 John Wiley & Sons Ltd.

  16. Lymphatic Filariasis Disseminating to the Upper Extremity

    PubMed Central

    Maldjian, Catherine; Khanna, Vineet; Tandon, Bevan; Then, Matthew; Yassin, Mohamed; Adam, Richard; Klein, Michael J.

    2014-01-01

    Lymphatic filariasis is the most common cause of acquired lymphedema worldwide (Szuba and Rockson, 1998). It is endemic to tropical and subtropical regions, and its effects are devastating. With over 100 million infected persons, it ranks second only to leprosy as the leading cause of permanent and long-term disability. Wuchereria bancrofti is the etiologic agent in 90% of cases. There is a dearth of published MRI findings with pathologically proven active infections, making this entity even more of a diagnostic dilemma. Imaging may provide the first clue that one is dealing with a parasite and may facilitate proper treatment and containment of this disease. This is the first report of pathologic correlation with MRI findings in the extremity in active filariasis. The magnetic resonance images demonstrate an enhancing, infiltrative, mass-like appearance with partial encasement of vasculature that has not been previously described in filariasis. Low signal strands in T2-hyperintense dilated lymphatic channels are seen and may depict live adult worms. We hypothesize that the low signal strands correspond to the collagen rich acellular cuticle. This, in combination with the surrounding hyperintense T2 signal, corresponding to a dilated lymphatic channel, may provide more specific MRI findings for active nematodal infection, which can prompt early biopsy, pathological correlation, and diagnosis. PMID:24707427

  17. STUDIES ON THE PERMEABILITY OF LYMPHATIC CAPILLARIES

    PubMed Central

    Leak, Lee V.

    1971-01-01

    The passageway for interstitial fluids and large molecules across the connective tissue lymph interface has been investigated in dermal lymphatic capillaries in the ears of guinea pigs. Numerous endothelial cells overlap extensively at their margins and lack adhesion devices at many points. The observations suggest that these sites are free to move as a result of slight pressure changes. Immediately following interstitial injections of tracer particles (ferritin, thorium, carbon, and latex spheres), many of the overlapped endothelial cells are separated and thus passageways are provided between the interstitium and lymphatic lumen. Tracer particles also occur in plasmalemmal invaginations along both connective tissue and luminal fronts. All of the tracer particles accumulate within large autophagic-like vacuoles. Very few particles of ferritin are observed in the endothelium after 24 hr; however, the vesicles containing the nonprotein tracer particles (carbon, thorium, and latex) increase in size and content and remain within the lymphatic endothelial cells up to 6 months. The role of vesicles in the transport of large molecules and particles is discussed in relation to the accretion of tracer particles within large vesicles and autophagic-like vacuoles in the endothelial cytoplasm. PMID:4329612

  18. Lymphatic Vessels in Regenerative Medicine and Tissue Engineering.

    PubMed

    Schaupper, Mira; Jeltsch, Michael; Rohringer, Sabrina; Redl, Heinz; Holnthoner, Wolfgang

    2016-10-01

    The lymphatic system is involved in maintaining interstitial fluid homeostasis, fat absorption, and immune surveillance. Dysfunction of lymphatic fluid uptake can lead to lymphedema. Worldwide up to 250 million people are estimated to suffer from this disfiguring and disabling disease, which places a strain on the healthcare system as well as on the affected patients. The severity of lymphatic diseases calls for the establishment of new treatment methods. One approach is to replace dysfunctional lymphatic vessels with bioengineered ones. In this study, we mainly focus on hydrogels, scaffolds with cellular constructs, interstitial flow, and extracorporeal shockwave therapy. This review provides an overview on the current status of lymphatic biology and approaches of reconstruction and regeneration of lymphatic vascular tissues.

  19. The optimum marker for the detection of lymphatic vessels.

    PubMed

    Kong, Ling-Ling; Yang, Nian-Zhao; Shi, Liang-Hui; Zhao, Guo-Hai; Zhou, Wenbin; Ding, Qiang; Wang, Ming-Hai; Zhang, Yi-Sheng

    2017-10-01

    Podoplanin, lymphatic vessel endothelial hyaluronic acid receptor-1, prospero-related homeobox-1 and vascular endothelial growth factor receptor 3 have been demonstrated to have crucial roles in the development of the lymphatic system and lymphangiogenesis process by combining with their corresponding receptors. Thus, the four markers have been widely used in labelling lymphatic vessels for the detection of lymphangiogenesis and lymphatic vessel invasion. Numerous authors have aimed to identify the roles of these four markers in the lymphatic system and the mechanisms have been partly clarified at the molecular level. The aim of the present review was to comprehensively clarify the characteristics and latent action modes of the four markers in order to determine which is the best one for the detection of lymphangiogenesis and lymphatic vessel invasion.

  20. Lymphatic vessels arise from specialized angioblasts within a venous niche.

    PubMed

    Nicenboim, J; Malkinson, G; Lupo, T; Asaf, L; Sela, Y; Mayseless, O; Gibbs-Bar, L; Senderovich, N; Hashimshony, T; Shin, M; Jerafi-Vider, A; Avraham-Davidi, I; Krupalnik, V; Hofi, R; Almog, G; Astin, J W; Golani, O; Ben-Dor, S; Crosier, P S; Herzog, W; Lawson, N D; Hanna, J H; Yanai, I; Yaniv, K

    2015-06-04

    How cells acquire their fate is a fundamental question in developmental and regenerative biology. Multipotent progenitors undergo cell-fate restriction in response to cues from the microenvironment, the nature of which is poorly understood. In the case of the lymphatic system, venous cells from the cardinal vein are thought to generate lymphatic vessels through trans-differentiation. Here we show that in zebrafish, lymphatic progenitors arise from a previously uncharacterized niche of specialized angioblasts within the cardinal vein, which also generates arterial and venous fates. We further identify Wnt5b as a novel lymphatic inductive signal and show that it also promotes the ‘angioblast-to-lymphatic’ transition in human embryonic stem cells, suggesting that this process is evolutionarily conserved. Our results uncover a novel mechanism of lymphatic specification, and provide the first characterization of the lymphatic inductive niche. More broadly, our findings highlight the cardinal vein as a heterogeneous structure, analogous to the haematopoietic niche in the aortic floor.

  1. Emerging trends in the pathophysiology of lymphatic contractile function

    PubMed Central

    Chakraborty, Sanjukta; Davis, Michael J.; Muthuchamy, Mariappan

    2015-01-01

    Lymphatic contractile dysfunction is central to a number of pathologies that affect millions of people worldwide. Due to its critical role in the process of inflammation, a dysfunctional lymphatic system also compromises the immune response, further exacerbating a number of inflammation related diseases. Despite the critical physiological functions accomplished by the transport of lymph, a complete understanding of the contractile machinery of the lymphatic system lags far behind that of the blood vasculature. However, there has been a surge of recent research focusing on different mechanisms that underlie both physiological and pathophysiological aspects of lymphatic contractile function. This review summarizes those emerging paradigms that shed some novel insights into the contractile physiology of the lymphatics in normal as well as different disease states. In addition, this review emphasizes the recent progress made in our understanding of various contractile parameters and regulatory elements that contribute to the normal functioning of the lymphatics. PMID:25617600

  2. Effect of lymphatic outflow pressure on lymphatic albumin transport in humans.

    PubMed

    Wu, J; Mack, G W

    2001-09-01

    The effects of posture on the lymphatic outflow pressure and lymphatic return of albumin were examined in 10 volunteers. Lymph flow was stimulated with a bolus infusion of isotonic saline (0.9%, 12.6 ml/kg body wt) under four separate conditions: upright rest (Up), upright rest with lower body positive pressure (LBPP), supine rest (Sup), and supine rest with lower body negative pressure (LBNP). The increase in plasma albumin content (Delta Alb) during the 2 h after bolus saline infusion was greater in Up than in LBPP: 82.9 +/- 18.5 vs. -28.4 mg/kg body wt. Delta Alb was greater in LBNP than in Sup: 92.6 vs. -22.5 +/- 18.9 mg/kg body wt (P < 0.05). The greater Delta Alb in Up and Sup with LBNP were associated with a lower estimated lymphatic outflow pressure on the basis of the difference in central venous pressure (Delta CVP). During LBPP, CVP was increased compared with Up: 3.8 +/- 1.4 vs. -1.2 +/- 1.2 mmHg. During LBNP, CVP was reduced compared with Sup: -3.0 +/- 2.2 vs. 1.7 +/- 1.0 mmHg. The translocation of protein into the vascular space after bolus saline infusion reflects lymph return of protein and is higher in Up than in Sup. Modulation of CVP with LBPP or LBNP in Up and Sup, respectively, reversed the impact of posture on lymphatic outflow pressure. Thus posture-dependent changes in lymphatic protein transport are modulated by changes in CVP through its mechanical impact on lymphatic outflow pressure.

  3. Tissue Engineering of Dermal Blood and Lymphatic Microvascular Networks

    DTIC Science & Technology

    2014-03-06

    SECURITY CLASSIFICATION OF: This proposal focused on establishing the conditions necessary to induce lymphatic endothelial cell (EC) tube...morphogenesis in 3D collagen matrices with the long-term goal of establishing separate networks of lymphatic tubes and co-existing, but not interconnecting...networks of blood EC-lined tubes. In addition, we hoped that pericytes, which support blood EC tube networks, but not lymphatic vessel networks, would

  4. Lymphatic vessels in the healthy human dental pulp.

    PubMed

    Marchetti, C; Poggi, P; Calligaro, A; Casasco, A

    1991-01-01

    The lymphatic vessels of the dental pulp have been studied in non-carious teeth of young people. A network of lymphatic vessels drains the pulpal tissue. The lymphatic capillaries are characterized by a thin wall with an irregular profile. Cellular projections rise from the endothelial cells. Micropinocytotic vesicles and intercellular adjoining structures are the main mechanisms for the lymph formation. Multivesicular structures, Weibel-Palade bodies and paracrystalline inclusions have been observed.

  5. Tissue-engineered lymphatic graft for the treatment of lymphedema

    PubMed Central

    Kanapathy, Muholan; Patel, Nikhil M.; Kalaskar, Deepak M.; Mosahebi, Afshin; Mehrara, Babak J.; Seifalian, Alexander M.

    2015-01-01

    Background Lymphedema is a chronic debilitating condition and curative treatment is yet to be found. Tissue engineering approach, which combines cellular components, scaffold, and molecular signals hold great potential in the treatment of secondary lymphedema with the advent of lymphatic graft to reconstruct damaged collecting lymphatic vessel. This review highlights the ideal characteristics of lymphatic graft, the limitation and challenges faced, and the approaches in developing tissue-engineered lymphatic graft. Methods Literature on tissue engineering of lymphatic system and lymphatic tissue biology was reviewed. Results The prime challenge in the design and manufacturing of this graft is producing endothelialized conduit with intraluminal valves. Suitable scaffold material is needed to ensure stability and functionality of the construct. Endothelialization of the construct can be enhanced via biofunctionalization and nanotopography, which mimics extracellular matrix. Nanocomposite polymers with improved performance over existing biomaterials are likely to benefit the development of lymphatic graft. Conclusions With the in-depth understanding of tissue engineering, nanotechnology, and improved knowledge on the biology of lymphatic regeneration, the aspiration to develop successful lymphatic graft is well achievable. PMID:25248852

  6. New developments in clinical aspects of lymphatic disease

    PubMed Central

    Mortimer, Peter S.; Rockson, Stanley G.

    2014-01-01

    The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity — the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn’s disease, obesity, cancer, and cancer-related lymphedema are highlighted. PMID:24590276

  7. Lymphatic imaging: Lymphography, computed tomography and scintigraphy, 2nd ed

    SciTech Connect

    Close, M.E.; Wallace, S.

    1985-01-01

    The latest addition to the Golden's Diagnostic Radiology series deals not only with imaging of the lymphatic system but also with lymphatic anatomy, its pathophysiology, and treatment of disorders. The first two chapters deal with the history of the discovery of the lymphatic system and its normal anatomy. The section on technique contains practical information and discussion of lymphatic physiology and the pathology of lymphomas. Half of the book's 16 chapters are devoted to problems encountered in clinical imaging. The approach is both by anatomy (thorax, neck, abdomen) and pathology (benign disease, lymphoma, solid tumors).

  8. Insights into the pathogenesis of disease in human lymphatic filariasis.

    PubMed

    Nutman, Thomas B

    2013-09-01

    Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ∼40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce lymphatic dilatation. Progressive lymphatic damage and pathology results primarily from the host inflammatory response to the parasites but also perhaps from the host inflammatory response to the parasite's Wolbachia endosymbiont and as a consequence of superimposed bacterial or fungal infections. This review will attempt to shed light on disease pathogenesis in lymphatic filariasis.

  9. Recent advances in the research of lymphatic stomata.

    PubMed

    Wang, Zi-Bin; Li, Meng; Li, Ji-Cheng

    2010-05-01

    Lymphatic stomata are small openings of lymphatic capillaries on the free surface of the mesothelium. The peritoneal cavity, pleural cavity, and pericardial cavity are connected with lymphatic system via these small openings, which have the function of active absorption. The ultrastructure of the lymphatic stomata and their absorption from the body cavities are important clinically, such as ascites elimination, neoplasm metastasis, and inflammatory reaction. The lymphatic stomata play an important role in the physiological and pathological conditions. Our previous study indicated for the first time that nitric oxide (NO) could regulate the opening and absorption of the lymphatic stomata. It could decrease the level of free intracellular calcium [Ca(2+)] through increasing the cyclic guanosine monophosphate (cGMP) level in the rat peritoneal mesothelial cells, thus regulating the lymphatic stomata. This process is related with the NO-cGMP-[Ca(2+)] signal pathway. In this review, we summarize the recent advances in understanding the development and the function of the lymphatic stomata. The ultrastructure and regulations of the lymphatic stomata are also discussed in this review.

  10. Visualization of lymphatic vessel development, growth, and function.

    PubMed

    Pollmann, Cathrin; Hägerling, René; Kiefer, Friedemann

    2014-01-01

    Despite their important physiological and pathophysiological functions, lymphatic endothelial cells and lymphatic vessels remain less well studied compared to the blood vascular system. Lymphatic endothelium differentiates from venous blood vascular endothelium after initial arteriovenous differentiation. Only recently by the use of light sheet microscopy, the precise mechanism of separation of the first lymphatic endothelial progenitors from the cardinal vein has been described as delamination followed by mesenchymal cell migration of lymphatic endothelial cells. Dorsolaterally of the embryonic cardinal vein, lymphatic endothelial cells reaggregate to form the first lumenized lymphatic vessels, the dorsal peripheral longitudinal vessel and the more ventrally positioned primordial thoracic duct. Despite this progress in our understanding of the first lymph vessel formation, intravital observation of lymphatic vessel behavior in the intact organism, during development and in the adult, is prerequisite to a precise understanding of this tissue. Transgenic models and two-photon microscopy, in combination with optical windows, have made live intravital imaging possible: however, new imaging modalities and novel approaches promise gentler, more physiological, and longer intravital imaging of lymphatic vessels.

  11. Ultrasound visualization of the lymphatic vessels in the lower leg.

    PubMed

    Hayashi, Akitatsu; Yamamoto, Takumi; Yoshimatsu, Hidehiko; Hayashi, Nobuko; Furuya, Megumi; Harima, Mitsunobu; Narushima, Mitsunaga; Koshima, Isao

    2015-04-08

    Identification of lymphatic vessels for lymphaticovenular anastomosis (LVA), which is an effective surgical treatment for obstructive lymphedema, is important. Indocyanine green (ICG) lymphography is useful for that purpose, but is not common in many institutions. Although ultrasound is a very common modality, no research has yet underlined the feasibility of the device to detect the lymphatic vessels. First, identification of lymphatic vessels in the lower legs using ultrasound was performed in non-edematous limbs with linear-pattern on ICG lymphography (n = 12). The imaging findings and characteristic of the lymphatic vessels in ultrasonography were investigated on transverse scans. Second, to assess the ultrasound detection technique, ICG was injected to healthy volunteers after identification and marking of the lymphatic vessels using ultrasound (n = 14). Sensitivity and specificity of the examination were calculated. In the first part, the lymphatic vessels were detected by ultrasound in all cases. Characteristic ultrasonography findings of lymphatic vessels included homogeneous, hypoechoic and spicular misshapen images in all cases. In the second part, the overall sensitivity and specificity were 95.5 and 92.9%, respectively. Ultrasonography can identify lymphatic vessels of the lower leg with precision and may aid lymphatic microsurgery for lymphedema. © 2015 Wiley Periodicals, Inc. Microsurgery, 2015. © 2015 Wiley Periodicals, Inc.

  12. The lymphatic phenotype in Turner syndrome: an evaluation of nineteen patients and literature review.

    PubMed

    Atton, Giles; Gordon, Kristiana; Brice, Glen; Keeley, Vaughan; Riches, Katie; Ostergaard, Pia; Mortimer, Peter; Mansour, Sahar

    2015-12-01

    Turner syndrome is a complex disorder caused by an absent or abnormal sex chromosome. It affects 1/2000-1/3000 live-born females. Congenital lymphoedema of the hands, feet and neck region (present in over 60% of patients) is a common and key diagnostic indicator, although is poorly described in the literature. The aim of this study was to analyse the medical records of a cohort of 19 Turner syndrome patients attending three specialist primary lymphoedema clinics, to elucidate the key features of the lymphatic phenotype and provide vital insights into its diagnosis, natural history and management. The majority of patients presented at birth with four-limb lymphoedema, which often resolved in early childhood, but frequently recurred in later life. The swelling was confined to the legs and hands with no facial or genital swelling. There was only one case of suspected systemic involvement (intestinal lymphangiectasia). The lymphoscintigraphy results suggest that the lymphatic phenotype of Turner syndrome may be due to a failure of initial lymphatic (capillary) function.

  13. Near-Infrared Fluorescence Lymphatic Imaging to Reconsider Occlusion Pressure of Superficial Lymphatic Collectors in Upper Extremities of Healthy Volunteers

    PubMed Central

    Vandermeeren, Liesbeth; Vankerckhove, Sophie; Valsamis, Jean-Baptiste; Malloizel-Delaunay, Julie; Moraine, Jean-Jacques; Liebens, Fabienne

    2016-01-01

    Abstract Background: There are very little scientific data on occlusion pressure for superficial lymphatic collectors. Given its importance in determining the transport capacity of lymphatic vessels, it is crucial to know its value. The novel method of near-infrared fluorescence lymphatic imaging (NIRFLI) can be used to visualize lymphatic flow in real time. The goal of this study was to see if this method could be used to measure the lymphatic occlusion pressure. Methods: We observed and recorded lymph flow in the upper limb of healthy volunteers through a transparent cuff using near-infrared fluorescence lymphatic imaging. After obtaining a baseline of the lymph flow without pressure inside the cuff, the cuff was inflated by increments of 10 mm Hg starting at 30 mm Hg. A NIRFLI guided manual lymphatic drainage technique named “Fill & Flush Drainage Method” was performed during the measurement to promote lymph flow. Lymphatic occlusion pressure was determined by observing when lymph flow stopped under the cuff. Results: We measured the lymphatic occlusion pressure on 30 healthy volunteers (11 men and 19 women). Mean lymphatic occlusion pressure in the upper limb was 86 mm Hg (CI ±3.7 mm Hg, α = 0.5%). No significant differences were found between age groups (p = 0.18), gender (p = 0.12), or limb side (p = 0.85). Conclusions: NIRFLI, a transparent sphygmomanometer cuff and the “Fill and Flush” manual lymphatic drainage method were used to measure the lymphatic occlusion pressure in 30 healthy humans. That combination of these techniques allows the visualization of the lymph flow in real time, while ensuring the continuous filling of the lymph collectors during the measurement session, reducing false negative observations. The measured occlusion pressures are much higher than previously described in the medical literature. PMID:27167187

  14. Weibel-Palade bodies and lymphatic endothelium: observations in the lymphatic vessels of normal and inflamed human dental pulps.

    PubMed

    Marchetti, C

    1996-01-01

    The Weibel-Palade bodies, cytoplasmic organelles characterizing endothelial cells, are abundant in lymphatic capillary endothelium of human dental pulp. Their number almost double in the lymphatic vessels of inflamed dental pulps. The data were discussed and compared with others concerning the demonstration of the presence of von Willebrand factor and P-selectin in the Weibel-Palade bodies of lymphatic vessels in mesentery. It is suggested that the increase in the number of Weibel-Palade bodies observed in dental pulp may be connected along with those in the lymphatic vessels to the function that these adhesive molecules play during inflammatory states.

  15. The position- and lymphatic lumen-controlled tissue chambers to study live lymphatic vessels and surrounding tissues ex vivo.

    PubMed

    Maejima, Daisuke; Nagai, Takashi; Bridenbaugh, Eric A; Cromer, Walter E; Gashev, Anatoliy A

    2014-09-01

    Until now, there has been no tool available to provide lymphatic researchers the ability to perform experiments in tissue explants containing lymphatic vessels under tissue position- and lymphatic lumen-controlled conditions. In this article we provide technical details and description of the method of using the newly developed and implemented the position- and lymphatic lumen-controlled tissue chambers to study live lymphatic vessels and surrounding tissues ex vivo. In this study, we, for the first time, performed detailed comparative analysis of the contractile and pumping activity of rat mesenteric lymphatic vessels (MLVs) situated within tissue explants mounted in new tissue chambers and isolated, cannulated, and pressurized rat MLVs maintained in isolated vessel setups. We found no significant differences of the effects of both transmural pressure- and wall shear stress sensitivities of MLVs in tissue chambers and isolated MLVs. We conclude that this new experimental tool, a position- and lymphatic lumen-controlled tissue chamber, allows precise investigation of lymphatic function of MLVs interacting with elements of the tissue microenvironment. This method provides an important new set of experimental tools to investigate lymphatic function.

  16. Leukocyte abnormalities.

    PubMed

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  17. Quantitative Imaging of Lymphatic Function with Liposomal Indocyanine Green

    PubMed Central

    Proulx, Steven T.; Luciani, Paola; Derzsi, Stefanie; Rinderknecht, Matthias; Mumprecht, Viviane; Leroux, Jean-Christophe; Detmar, Michael

    2010-01-01

    Lymphatic vessels play a major role in cancer progression and in postsurgical lymphedema, and several new therapeutic approaches targeting lymphatics are currently being developed. Thus, there is a critical need for quantitative imaging methods to measure lymphatic flow. Indocyanine green (ICG) has been used for optical imaging of the lymphatic system but it is unstable in solution and may rapidly enter venous capillaries after local injection. We developed a novel liposomal formulation of ICG (LP-ICG), resulting in vastly improved stability in solution and an increased fluorescence signal with a shift towards longer wavelength absorption and emission. When injected intradermally to mice, LP-ICG was specifically taken up by lymphatic vessels and allowed improved visualization of deep lymph nodes. In a genetic mouse model of lymphatic dysfunction, injection of LP-ICG showed no enhancement of draining lymph nodes and slower clearance from the injection site. In mice bearing B16 luciferase expressing melanomas expressing vascular endothelial growth factor-C (VEGF-C), sequential near infrared imaging of intradermally-injected LP-ICG enabled quantification of lymphatic flow. Increased flow through draining lymph nodes was observed in mice bearing VEGF-C expressing tumors without metastases while a decreased flow pattern was seen in mice with a higher lymph node tumor burden. This new method likely will facilitate quantitative studies of lymphatic function in preclinical studies and may also have potential for imaging of lymphedema or improved sentinel lymph detection in cancer. PMID:20823159

  18. Lymphatic vessels: new targets for the treatment of inflammatory diseases.

    PubMed

    Dieterich, Lothar C; Seidel, Catharina D; Detmar, Michael

    2014-04-01

    The lymphatic system plays an important role in the physiological control of the tissue fluid balance and in the initiation of immune responses. Recent studies have shown that lymphangiogenesis, the growth of new lymphatic vessels and/or the expansion of existing lymphatic vessels, is a characteristic feature of acute inflammatory reactions and of chronic inflammatory diseases. In these conditions, lymphatic vessel expansion occurs at the tissue level but also within the draining lymph nodes. Surprisingly, activation of lymphatic vessel function by delivery of vascular endothelial growth factor-C exerts anti-inflammatory effects in several models of cutaneous and joint inflammation. These effects are likely mediated by enhanced drainage of extravasated fluid and inflammatory cells, but also by lymphatic vessel-mediated modulation of immune responses. Although some of the underlying mechanisms are just beginning to be identified, lymphatic vessels have emerged as important targets for the development of new therapeutic strategies to treat inflammatory conditions. In this context, it is of great interest that some of the currently used anti-inflammatory drugs also potently activate lymphatic vessels.

  19. Heterogeneity in the lymphatic vascular system and its origin.

    PubMed

    Ulvmar, Maria H; Mäkinen, Taija

    2016-09-01

    Lymphatic vessels have historically been viewed as passive conduits for fluid and immune cells, but this perspective is increasingly being revised as new functions of lymphatic vessels are revealed. Emerging evidence shows that lymphatic endothelium takes an active part in immune regulation both by antigen presentation and expression of immunomodulatory genes. In addition, lymphatic vessels play an important role in uptake of dietary fat and clearance of cholesterol from peripheral tissues, and they have been implicated in obesity and arteriosclerosis. Lymphatic vessels within different organs and in different physiological and pathological processes show a remarkable plasticity and heterogeneity, reflecting their functional specialization. In addition, lymphatic endothelial cells (LECs) of different organs were recently shown to have alternative developmental origins, which may contribute to the development of the diverse lymphatic vessel and endothelial functions seen in the adult. Here, we discuss recent developments in the understanding of heterogeneity within the lymphatic system considering the organ-specific functional and molecular specialization of LECs and their developmental origin. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

  20. Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles

    PubMed Central

    Cai, Shuang; Zhang, Qiuhong; Bagby, Taryn; Forrest, M. Laird

    2011-01-01

    The lymphatic system plays a crucial role in the immune system’s recognition and response to disease, and most solid cancers initially spread from the primary site via the tumor’s surrounding lymphatics before hematological dissemination. Hence, the lymphatic system is an important target for developing new vaccines, cancer treatments, and diagnostic agents. Targeting the lymphatic system by subcutaneous, intestinal, and pulmonary routes has been evaluated and subsequently utilized to improve lymphatic penetration and retention of drug molecules, reduce drug-related systemic toxicities, and enhance bioavailability of poorly soluble and unstable drugs. Lymphatic imaging is an essential tool for the detection and staging of cancer. New nano-based technologies offer improved detection and characterization of the nodal diseases, while new delivery devices can better target and confine treatments to tumors within the nodal space while sparing healthy tissues. This manuscript reviews recent advances in the field of lymphatic drug delivery and imaging and focuses specifically on the development ofliposomes and solid lipid nanoparticles for lymphatic introduction via the subcutaneous, intestinal, and pulmonary routes. PMID:21712055

  1. Isolation and Characterization of Circulating Lymphatic Endothelial Colony Forming Cells

    PubMed Central

    DiMaio, Terri A.; Wentz, Breanna L.; Lagunoff, Michael

    2016-01-01

    Rationale The identification of circulating endothelial progenitor cells has led to speculation regarding their origin as well as their contribution to neovascular development. Two distinct types of endothelium make up the blood and lymphatic vessel system. However, it has yet to be determined whether there are distinct lymphatic-specific circulating endothelial progenitor cells. Objective This study aims to isolate and characterize the cellular properties and global gene expression of lymphatic-specific endothelial progenitor cells. Methods and Results We isolated circulating endothelial colony forming cells (ECFCs) from whole peripheral blood. These cells are endothelial in nature, as defined by their expression of endothelial markers and their ability to undergo capillary morphogenesis in three-dimensional culture. A subset of isolated colonies express markers of lymphatic endothelium, including VEGFR-3 and Prox-1, with low levels of VEGFR-1, a blood endothelial marker, while the bulk of the isolated cells express high VEGFR-1 levels with low VEGFR-3 and Prox-1 expression. The different isolates have differential responses to VEGF-C, a lymphatic endothelial specific cytokine, strongly suggesting that there are lymphatic specific and blood specific ECFCs. Global analysis of gene expression revealed key differences in the regulation of pathways involved in cellular differentiation between blood and lymphatic-specific ECFCs. Conclusion These data indicate that there are two distinguishable circulating ECFC types, blood and lymphatic, which are likely to have discrete functions during neovascularization. PMID:26597759

  2. Aged Lymphatic Vessels and Mast Cells in Perilymphatic Tissues.

    PubMed

    Pal, Sarit; Meininger, Cynthia J; Gashev, Anatoliy A

    2017-05-03

    This review provides a comprehensive summary of research on aging-associated alterations in lymphatic vessels and mast cells in perilymphatic tissues. Aging alters structure (by increasing the size of zones with low muscle cell investiture), ultrastructure (through loss of the glycocalyx), and proteome composition with a concomitant increase in permeability of aged lymphatic vessels. The contractile function of aged lymphatic vessels is depleted with the abolished role of nitric oxide and an increased role of lymphatic-born histamine in flow-dependent regulation of lymphatic phasic contractions and tone. In addition, aging induces oxidative stress in lymphatic vessels and facilitates the spread of pathogens from these vessels into perilymphatic tissues. Aging causes the basal activation of perilymphatic mast cells, which, in turn, restricts recruitment/activation of immune cells in perilymphatic tissues. This aging-associated basal activation of mast cells limits proper functioning of the mast cell/histamine/NF-κB axis that is essential for the regulation of lymphatic vessel transport and barrier functions as well as for both the interaction and trafficking of immune cells near and within lymphatic collecting vessels. Cumulatively, these changes play important roles in the pathogenesis of alterations in inflammation and immunity associated with aging.

  3. Heterogeneity in the lymphatic vascular system and its origin

    PubMed Central

    Ulvmar, Maria H.; Mäkinen, Taija

    2016-01-01

    Lymphatic vessels have historically been viewed as passive conduits for fluid and immune cells, but this perspective is increasingly being revised as new functions of lymphatic vessels are revealed. Emerging evidence shows that lymphatic endothelium takes an active part in immune regulation both by antigen presentation and expression of immunomodulatory genes. In addition, lymphatic vessels play an important role in uptake of dietary fat and clearance of cholesterol from peripheral tissues, and they have been implicated in obesity and arteriosclerosis. Lymphatic vessels within different organs and in different physiological and pathological processes show a remarkable plasticity and heterogeneity, reflecting their functional specialization. In addition, lymphatic endothelial cells (LECs) of different organs were recently shown to have alternative developmental origins, which may contribute to the development of the diverse lymphatic vessel and endothelial functions seen in the adult. Here, we discuss recent developments in the understanding of heterogeneity within the lymphatic system considering the organ-specific functional and molecular specialization of LECs and their developmental origin. PMID:27357637

  4. Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges.

    PubMed

    Maisel, Katharina; Sasso, Maria Stella; Potin, Lambert; Swartz, Melody A

    2017-05-15

    Lymphatic vessels are the primary route of communication from peripheral tissues to the immune system; as such, they represent an important component of local immunity. In addition to their transport functions, new immunomodulatory roles for lymphatic vessels and lymphatic endothelial cells have come to light in recent years, demonstrating that lymphatic vessels help shape immune responses in a variety of ways: promoting tolerance to self-antigens, archiving antigen for later presentation, dampening effector immune responses, and resolving inflammation, among others. In addition to these new biological insights, the growing field of immunoengineering has begun to explore therapeutic approaches to utilize or exploit the lymphatic system for immunotherapy. Copyright © 2017. Published by Elsevier B.V.

  5. How Do Meningeal Lymphatic Vessels Drain the CNS?

    PubMed

    Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan

    2016-09-01

    The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Navigation lymphatic supermicrosurgery for the treatment of cancer-related peripheral lymphedema.

    PubMed

    Yamamoto, Takumi; Yamamoto, Nana; Numahata, Takao; Yokoyama, Ai; Tashiro, Kensuke; Yoshimatsu, Hidehiko; Narushima, Mitsunaga; Koshima, Isao

    2014-02-01

    Lymphatic supermicrosurgery is becoming the treatment of choice for refractory lymphedema. Detection and anastomosis of functional lymphatic vessels are important for lymphatic supermicrosurgery. Navigation lymphatic supermicrosurgery was performed using an operating microscope equipped with an integrated near-infrared illumination system (OPMI Pentero Infrared 800; Carl Zeiss, Oberkochen, Germany). Eight patients with extremity lymphedema who underwent navigation lymphatic supermicrosurgery were evaluated. A total of 21 lymphaticovenular anastomoses were performed on 8 limbs through 14 skin incisions. Lymphatic vessels were enhanced by intraoperative microscopic indocyanine green (ICG) lymphography in 12 of the 14 skin incisions, which resulted in early dissection of lymphatic vessels. All anastomoses showed good anastomosis patency after completion of anastomoses. Postoperative extremity lymphedema index decreased in all limbs. Navigation lymphatic supermicrosurgery, in which lymphatic vessels are visualized with intraoperative microscopic ICG lymphography, allows a lymphatic supermicrosurgeon to find and dissect lymphatic vessels earlier and facilitates successful performance of lymphaticovenular anastomosis.

  7. Localization and proliferation of lymphatic vessels in the tympanic membrane in normal state and regeneration.

    PubMed

    Miyashita, Takenori; Burford, James L; Hong, Young-Kwon; Gevorgyan, Haykanush; Lam, Lisa; Mori, Nozomu; Peti-Peterdi, Janos

    2013-10-25

    We clarified the localization of lymphatic vessels in the tympanic membrane and proliferation of lymphatic vessels during regeneration after perforation of the tympanic membrane by using whole-mount imaging of the tympanic membrane of Prox1 GFP mice. In the pars tensa, lymphatic vessel loops surrounded the malleus handle and annulus tympanicus. Apart from these locations, lymphatic vessel loops were not observed in the pars tensa in the normal tympanic membrane. Lymphatic vessel loops surrounding the malleus handle were connected to the lymphatic vessel loops in the pars flaccida and around the tensor tympani muscle. Many lymphatic vessel loops were detected in the pars flaccida. After perforation of the tympanic membrane, abundant lymphatic regeneration was observed in the pars tensa, and these regenerated lymphatic vessels extended from the lymphatic vessels surrounding the malleus at day 7. These results suggest that site-specific lymphatic vessels play an important role in the tympanic membrane. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Lymphatic albumin clearance from psoriatic skin

    SciTech Connect

    Staberg, B.; Klemp, P.; Aasted, M.; Worm, A.M.; Lund, P.

    1983-12-01

    In nine patients with untreated psoriasis vulgaris, human serum albumin labelled with /sup 125/I or /sup 131/I was injected intradermally in symmetrically located involved and uninvolved skin. The activity of the depots was followed by external detection, and the arrival of labelled albumin in plasma was monitored. In involved psoriatic skin the local mean half-time (T1/2) for tracer disappearance was 20.8 +/- 8.2 (S.D.) hr and in clinically normal skin, 29.1 +/- 9.6 (S.D.) hr. The difference was significant (p less than 0.002). Accordingly, the tracer from involved skin reached higher plasma levels than the tracer from uninvolved skin. However, under slight lymphatic stasis the appearance rate of radiolabelled albumin in plasma from both tissues was minimal during 1 to 2 hours after the injection, indicating that a local direct transvascular drainage of plasma albumin from the interstitium of diseased and normal skin was negligible. We conclude that the previously demonstrated increased extravasation of plasma proteins in involved psoriatic skin is compensated by an increased lymphatic drainage of plasma proteins, and not by an increased local transvascular return.

  9. Experimental chemotherapy of lymphatic filariasis. A review.

    PubMed

    Mak, J W; Navaratnam, V; Ramachandran, C P

    1991-02-01

    An intense global collaborative effort under the leadership of the Steering Committee of the Filariasis Scientific Working Group of the Tropical Diseases Research Programme, World Health Organization, has brought together researchers, pharmaceutical chemists and clinicians in the development and search for antifilarial compounds which are more effective and more convenient to administer than diethylcarbamazine citrate, the current drug of choice for lymphatic filariasis. The Brugia spp.-rodent model has been used extensively for the primary screening and B. pahangi infections in the dog or cat for the secondary screening, of potential filaricides. Recently, the leaf-monkey (Presbytis spp.) infected with subperiodic B. malayi or Wuchereria kalimantani has been used for the tertiary evaluation and pharmacokinetic studies of compounds which have shown effectiveness in the primary and secondary screens. Both P. cristata and P. melalophos are extremely susceptible to subperiodic B. malayi infection, but the former is a better host as a higher peak microfilaremia and adult worm recovery rate were obtained. Although more than 30 potential filaricides have been evaluated in the tertiary screen, only a few compounds have shown some promise against lymphatic filariasis. CGP 20376, a 5-methoxyl-6-dithiocarbamic-S-(2-carboxy-ethyl) ester derivative of benzothiazole, had complete adulticidal and microfilaricidal activities against the parasite at a single oral dose of 20 mg kg-1. However, as the compound or its metabolites caused hepatotoxicity, its clinical use in the present formulation is not recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Lymphatic mapping for upper gastrointestinal malignancies.

    PubMed

    Kitagawa, Yuko; Kitajima, Masaki

    2004-06-01

    Recent studies on lymphatic mapping of upper gastrointestinal (GI) malignancies have provided new insights with regard to the sentinel node (SN) concept in solid tumors. At present, the SN concept seems to be valid not only for breast cancer, but also for esophageal and gastric cancers, which have multidirectional and complicated lymphatic flows. In addition to the staging merits, individualized surgical management has been proposed for upper GI cancer based on the SN concept. Gastric cancer is now a suitable target of SN-guided surgery after breast cancer because of its anatomical situation. Laparoscopic local resection is theoretically feasible for curative treatment of SN-negative early gastric cancer. Because SNs in esophageal cancer are multiple and widespread, complete sampling of SNs is not a minimally invasive procedure, as it is in breast cancer. However, selective and modified lymphadenectomy targeting SNs for clinically N0 esophageal cancer instead of three-field lymph node dissection should become not only feasible but also clinically important. When performing chemoradiotherapy as curative treatment for cT1N0 esophageal cancer, lymphoscintigrams revealing the distribution of SNs in each individual case are useful to tailor the field of irradiation to control occult micrometastases. Although there are several issues to be resolved, this novel procedure has the potential to improve quality control in upper GI cancer.

  11. Role of Hyperplasia of Gingival Lymphatics in Periodontal Inflammation.

    PubMed

    Papadakou, P; Bletsa, A; Yassin, M A; Karlsen, T V; Wiig, H; Berggreen, E

    2017-04-01

    Lymphatic vessels are important for maintenance of tissue fluid homeostasis and afferent antigen transport. In chronic inflammation, lymphangiogenesis takes place and is characterized by lymphatic endothelial cell proliferation and lymphatic hyperplasia. Vascular endothelial growth factor C (VEGFC) is the main known lymphangiogenic growth factor, and its expression is increased in periodontitis, a common chronic infectious disease that results in tissue destruction and alveolar bone loss. The role of lymphangiogenesis during development of periodontitis is unknown. Here, we test if transgenic overexpression of epithelial VEGFC in a murine model is followed by hyperplasia of lymphatic vessels in oral mucosa and if the lymphatic drainage capacity is altered. We also test if lymphatic hyperplasia protects against periodontal disease development. Transgenic keratin 14 (K14)-VEGFC mice had significant hyperplasia of lymphatics in oral mucosa, including gingiva, without changes in blood vessel vasculature. The basal lymph flow was normal but slightly lower than in wild-type mice when oral mucosa was challenged with lipopolysaccharide from Porphyromonas gingivalis. Under normal conditions, K14-VEGFC mice exhibited an increased number of neutrophils in gingiva, demonstrated enhanced phagocyte recruitment in the cervical lymph nodes, and had more alveolar bone when compared with their wild-type littermates. After induction of periodontitis, no strain differences were observed in the periodontal tissues with respect to granulocyte recruitment, bone resorption, angiogenesis, cytokines, and bone-related protein expressions or in draining lymph node immune cell proportions and vascularization. We conclude that overexpression of VEGFC results in hyperplastic lymphatics, which do not enhance lymphatic drainage capacity but facilitate phagocyte transport to draining lymph nodes. Hyperplasia of lymphatics does not protect against development of ligature-induced periodontitis.

  12. Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction

    PubMed Central

    Renaud-Gabardos, Edith; Godet, Anne-Claire; Hantelys, Fransky; Pujol, Francoise; Calise, Denis; Viars, Fanny; Valet, Philippe; Masri, Bernard; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2017-01-01

    Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases. PMID:28614788

  13. Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction.

    PubMed

    Tatin, Florence; Renaud-Gabardos, Edith; Godet, Anne-Claire; Hantelys, Fransky; Pujol, Francoise; Morfoisse, Florent; Calise, Denis; Viars, Fanny; Valet, Philippe; Masri, Bernard; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2017-06-15

    Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases.

  14. Scholars and scientists in the history of the lymphatic system.

    PubMed

    Natale, Gianfranco; Bocci, Guido; Ribatti, Domenico

    2017-09-01

    The discovery of the lymphatic system has a long and fascinating history. The interest in anatomy and physiology of this system paralleled that of the blood cardiocirculatory system and has been maybe obscured by the latter. Paradoxically, if the closed blood system appeared open in Galen's anatomy and physiology, and took a very long time to be correctly described in terms of pulmonary and general circulation by ibn Al-Nafis/Michael Servetus/Realdo Colombo and William Harvey, respectively, the open lymphatic system was incorrectly described as a closed circuit connected with arteries and veins. In ancient times only macroscopic components of the lymphatic system have been described, although misinterpreted, including lymph nodes and lacteals, the latter being easily identified because of their milk-like content. For about 15 centuries the dogmatic acceptance of Galen's notions did not allow a significant progress in medicine. After Vesalius' revolution in anatomical studies, new knowledge was accumulated, and the 17th century was the golden age for the investigation of the lymphatic system with several discoveries: gut lacteals (Gaspare Aselli), cloacal bursa (Hieronimus Fabricius of Acquapendente), reservoir of the chyle (Jean Pecquet), extra-intestinal lymphatic vessels (Thomas Bartholin and Olaus Rudbeck dispute), hepatic lymph circulation (Francis Glisson). In the Enlightenment century Frederik Ruysch described the function of lymphatic valves, and Paolo Mascagni provided a magnificent iconography of the lymphatic network in humans. In recent times, Leonetto Comparini realized three-dimensional reconstructions of the liver lymphatic vessels, and Kari Alitalo discovered the lymphatic growth factor/receptor system. Far from a complete understanding of its anatomy and function, the lymphatic system still needs to be profoundly examined. © 2017 Anatomical Society.

  15. Thymus cell antigen 1 (Thy1, CD90) is expressed by lymphatic vessels and mediates cell adhesion to lymphatic endothelium.

    PubMed

    Jurisic, Giorgia; Iolyeva, Maria; Proulx, Steven T; Halin, Cornelia; Detmar, Michael

    2010-10-15

    The lymphatic vascular system plays an important role in inflammation and cancer progression, although the molecular mechanisms involved are poorly understood. As determined by comparative transcriptional profiling studies of ex vivo isolated mouse intestinal lymphatic endothelial cells versus blood vascular endothelial cells, thymus cell antigen 1 (Thy1, CD90) was expressed at much higher levels in lymphatic endothelial cells than in blood vascular endothelial cells. These findings were confirmed by quantitative PCR, and at the protein level by FACS and immunofluorescence analyses. Thy1 was also strongly expressed by tumor-associated lymphatic vessels, as evaluated in a B16 melanoma footpad model in mice. Blockade of Thy1 inhibited tumor cell adhesion to cultured mouse lymphatic endothelial cells. Importantly, treatment of human dermal microvascular endothelial cells with tumor necrosis factor or phorbol 12-myristate 13-acetate resulted in Thy1 upregulation in podoplanin-expressing lymphatic endothelial cells, but not in podoplanin-negative blood vascular endothelial cells. Moreover, adhesion of human polymorphonuclear and mononuclear leukocytes to human lymphatic endothelial cells was Thy1-dependent. Together, these results identify Thy1 as a novel lymphatic vessel expressed gene and suggest its potential role in the cell adhesion processes required for tumor progression and inflammation. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Rho Kinase Enhances Contractions of Rat Mesenteric Collecting Lymphatics

    PubMed Central

    Kurtz, Kristine H.; Souza-Smith, Flavia M.; Moor, Andrea N.; Breslin, Jerome W.

    2014-01-01

    The mechanisms that control phasic and tonic contractions of lymphatic vessels are poorly understood. We hypothesized that rho kinase ROCK, previously shown to increase calcium (Ca2+) sensitivity in vascular smooth muscle, enhances lymphatic contractile activity in a similar fashion. Contractions of isolated rat mesenteric lymphatic vessels were observed at a luminal pressure of 2 cm H2O in a 37°C bath. The expression of ROCK in isolated rat mesenteric lymphatic vessels was assessed by Western blotting and confocal microscopy. The role of ROCK in contractile function was tested using two specific yet structurally distinct inhibitors: H1152 (0.1–10 μM) and Y-27632 (0.5–50 μM). In addition, lymphatics were transfected with constitutively active (ca)-ROCK protein (2 μg/ml) to assess gain of contractile function. Vessel diameter and the concentration of intracellular free Ca2+ ([Ca2+]i) were simultaneously measured in a subset of isolated lymphatics loaded with the Ca2+-sensing dye fura-2. The results show expression of both the ROCK1 and ROCK2 isoforms in lymphatic vessels. Inhibition of ROCK increased lymphatic end diastolic diameter and end systolic diameter in a concentration-dependent manner. Significant reductions in lymphatic tone and contraction amplitude were observed after treatment 1–10 μM H1152 or 25–50 μM Y-27632. H1152 (10 μM) also significantly reduced contraction frequency. Transient increases in [Ca2+]i preceded each phasic contraction, however this pattern was disrupted by either 10 μM H1152 or 50 μM Y-27632 in the majority of lymphatics studied. The significant decrease in tone caused by H1152 or Y-27632 was not associated with a significant change in the basal [Ca2+]i between transients. Transfection with ca-ROCK protein enhanced lymphatic tone, but was not associated with a significant change in basal [Ca2+]i. Our data suggest that ROCK mediates normal tonic constriction and influences phasic contractions in lymphatics. We propose

  17. Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

    PubMed Central

    Chakraborty, Sanjukta; Zawieja, Scott D.; Wang, Wei; Lee, Yang; Wang, Yuan J.; von der Weid, Pierre-Yves; Zawieja, David C.

    2015-01-01

    Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction. PMID:26453331

  18. Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery.

    PubMed

    Chakraborty, Sanjukta; Zawieja, Scott D; Wang, Wei; Lee, Yang; Wang, Yuan J; von der Weid, Pierre-Yves; Zawieja, David C; Muthuchamy, Mariappan

    2015-12-15

    Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction. Copyright © 2015 the American Physiological Society.

  19. The effect of lymphatic valve morphology on fluid transport

    NASA Astrophysics Data System (ADS)

    Alexeev, Alexander; Ballard, Matthew; Nepiyushchikh, Zhanna; Dixon, Brandon

    2016-11-01

    The lymphatic vasculature is present in nearly all invertebrate tissue, and is essential in the transport of fluid and particles such as immune cells, antigens, proteins and lipids from the tissue to lymph nodes and to the venous circulation. Lymphatic vessels are made of up a series of contractile units that work together in harmony as "micro hearts" to pump fluid against a pressure gradient. Lymphatic valves are critical to this functionality, as they open and close with the oscillating pressure gradients from contractions, thus allowing flow in only one direction and leading to a net pumping effect. We use a hybrid lattice-Boltzmann lattice spring model which captures fluid-solid interactions through two-way coupling between a viscous fluid and lymphatic valves in a section of a lymphatic vessel to study the dynamics of lymphatic valves and their effect on fluid transport. Further, we investigate the effect of variations in valve geometry and material properties on fluid pumping. This work helps to increase our understanding of the mechanisms of lymphatic fluid transport, which has implications in a variety of pathologies, including cancer metastasis, autoimmunity, atherosclerosis and obesity. Support from NSF CMMI 1635133 is gratefully acknowledged.

  20. Interaction of tumor cells and lymphatic vessels in cancer progression.

    PubMed

    Alitalo, A; Detmar, M

    2012-10-18

    Metastatic spread of cancer through the lymphatic system affects hundreds of thousands of patients yearly. Growth of new lymphatic vessels, lymphangiogenesis, is activated in cancer and inflammation, but is largely inactive in normal physiology, and therefore offers therapeutic potential. Key mediators of lymphangiogenesis have been identified in developmental studies. During embryonic development, lymphatic endothelial cells derive from the blood vascular endothelium and differentiate under the guidance of lymphatic-specific regulators, such as the prospero homeobox 1 transcription factor. Vascular endothelial growth factor-C (VEGF-C) and VEGF receptor 3 signaling are essential for the further development of lymphatic vessels and therefore they provide a promising target for inhibition of tumor lymphangiogenesis. Lymphangiogenesis is important for the progression of solid tumors as shown for melanoma and breast cancer. Tumor cells may use chemokine gradients as guidance cues and enter lymphatic vessels through intercellular openings between endothelial cell junctions or, possibly, by inducing larger discontinuities in the endothelial cell layer. Tumor-draining sentinel lymph nodes show enhanced lymphangiogenesis even before cancer metastasis and they may function as a permissive 'lymphovascular niche' for the survival of metastatic cells. Although our current knowledge indicates that the development of anti-lymphangiogenic therapies may be beneficial for the treatment of cancer patients, several open questions remain with regard to the frequency, mechanisms and biological importance of lymphatic metastases.

  1. Lymphatic vessels regulate immune microenvironments in human and murine melanoma.

    PubMed

    Lund, Amanda W; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S; Broggi, Maria A; Spranger, Stefani; Gajewski, Thomas F; Alitalo, Kari; Eikesdal, Hans P; Wiig, Helge; Swartz, Melody A

    2016-09-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.

  2. The lymphatic vasculature revisited-new developments in the zebrafish.

    PubMed

    Padberg, Y; Schulte-Merker, S; van Impel, A

    2017-01-01

    The lymphatic system is lined by endothelial cells and part of the vasculature. It is essential for tissue fluid homeostasis, absorption of dietary fats, and immune surveillance in vertebrates. Misregulation of lymphatic vessel formation and dysfunction of the lymphatic system have been indicated in a number of pathological conditions including lymphedema formation, obesity or chronic inflammatory diseases such as rheumatoid arthritis. In zebrafish, lymphatics were discovered about 10years ago, and the underlying molecular pathways involved in its development have since been studied in detail. Due to its superior live cell imaging possibilities and the broad tool kit for forward and reverse genetics, the zebrafish has become an important model organism to study the development of the lymphatic system during early embryonic development. In the current review, we will focus on the key players during zebrafish lymphangiogenesis and compare the roles of these genes to their mammalian counterparts. In particular, we will focus on novel findings that shed new light on the molecular mechanisms of lymphatic cell fate specification, as well as sprouting and migration of lymphatic precursor cells.

  3. Lymphatic vessel development: fluid flow and valve-forming cells.

    PubMed

    Kume, Tsutomu

    2015-08-03

    Hemodynamic forces regulate many aspects of blood vessel disease and development, including susceptibility to atherosclerosis and remodeling of primary blood vessels into a mature vascular network. Vessels of the lymphatic circulatory system are also subjected to fluid flow-associated forces, but the molecular and cellular mechanisms by which these forces regulate the formation and maintenance of lymphatic vessels remain largely uncharacterized. This issue of the JCI includes two articles that begin to address how fluid flow influences lymphatic vessel development and function. Sweet et al. demonstrate that lymph flow is essential for the remodeling of primary lymphatic vessels, for ensuring the proper distribution of smooth muscle cells (SMCs), and for the development and maturation of lymphatic valves. Kazenwadel et al. show that flow-induced lymphatic valve development is initiated by the upregulation of GATA2, which has been linked to lymphedema in patients with Emberger syndrome. Together, these observations and future studies inspired by these results have potential to lead to the development of strategies for the treatment of lymphatic disorders.

  4. Lymphangion coordination minimally affects mean flow in lymphatic vessels.

    PubMed

    Venugopal, Arun M; Stewart, Randolph H; Laine, Glen A; Dongaonkar, Ranjeet M; Quick, Christopher M

    2007-08-01

    The lymphatic system returns interstitial fluid to the central venous circulation, in part, by the cyclical contraction of a series of "lymphangion pumps" in a lymphatic vessel. The dynamics of individual lymphangions have been well characterized in vitro; their frequencies and strengths of contraction are sensitive to both preload and afterload. However, lymphangion interaction within a lymphatic vessel has been poorly characterized because it is difficult to experimentally alter properties of individual lymphangions and because the afterload of one lymphangion is coupled to the preload of another. To determine the effects of lymphangion interaction on lymph flow, we adapted an existing mathematical model of a lymphangion (characterizing lymphangion contractility, lymph viscosity, and inertia) to create a new lymphatic vessel model consisting of several lymphangions in series. The lymphatic vessel model was validated with focused experiments on bovine mesenteric lymphatic vessels in vitro. The model was then used to predict changes in lymph flow with different time delays between onset of contraction of adjacent lymphangions (coordinated case) and with different relative lymphangion contraction frequencies (noncoordinated case). Coordination of contraction had little impact on mean flow. Furthermore, orthograde and retrograde propagations of contractile waves had similar effects on flow. Model results explain why neither retrograde propagation of contractile waves nor the lack of electrical continuity between lymphangions adversely impacts flow. Because lymphangion coordination minimally affects mean flow in lymphatic vessels, lymphangions have flexibility to independently adapt to local conditions.

  5. Lymphatic vessels regulate immune microenvironments in human and murine melanoma

    PubMed Central

    Lund, Amanda W.; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S.; Broggi, Maria A.; Spranger, Stefani; Gajewski, Thomas F.; Alitalo, Kari; Eikesdal, Hans P.

    2016-01-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment. PMID:27525437

  6. Long-distance transportation of live isolated lymphatic vessels.

    PubMed

    Gashev, Anatoliy A; Davis, Michael J

    2010-12-01

    We performed experiments to test whether isolated lymphatic vessels would remain viable after overnight long-distance shipment. Freshly isolated segments of rat mesenteric lymphatic vessels were placed into tubes filled by chilled D-MEM/F12 supplemented with antibiotics and shipped via overnight by express mail from College Station, TX to Columbia, MO. Standard physiological and pharmacological tests were performed to investigate the influence of the long-distance transport procedure on the spontaneous contractility of isolated, cannulated, and pressurized rat mesenteric lymphatic vessels. The results demonstrate that normal contractile function of isolated lymphatic vessels can be preserved with long-distance shipping and subsequent overnight recovery if the proper precautions are taken. The method of lymphatic vessel transportation described in this report opens up the opportunity to perform in vitro functional tests on lymphatic tissues harvested and initially processed in a remote location. In addition, the described procedures may expand the options for potential sources of fresh human tissue, harvested during surgery or autopsy and allowed to be available to lymphatic researchers in remote locations.

  7. Itching for answers: how histamine relaxes lymphatic vessels.

    PubMed

    Scallan, Joshua P; Davis, Michael J

    2014-10-01

    In the current issue of Microcirculation, studies by Kurtz et al. and Nizamutdinova et al. together provide new evidence supporting a role for histamine as an endothelial-derived molecule that inhibits lymphatic muscle contraction. In particular, Nizamutdinova et al. show that the effects of flow-induced shear stress on lymphatic endothelium are mediated by both nitric oxide and histamine, since only blockade of both prevents contraction strength and frequency from being altered by flow. Separately, Kurtz et al. used confocal microscopy to determine a preferential expression of histamine receptors on the lymphatic endothelium and demonstrated that histamine applied to spontaneously contracting collecting lymphatics inhibits contractions. Previous studies disagreed on whether histamine stimulates or inhibits lymphatic contractions, but also used differing concentrations, species, and preparations. Together these new reports shed light on how histamine acts within the lymphatic vasculature, but also raise important questions about the cell type on which histamine exerts its effects and the signaling pathways involved. This editorial briefly discusses the contribution of each study and its relevance to lymphatic biology. © 2014 John Wiley & Sons Ltd.

  8. Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator

    PubMed Central

    LIERSCH, RUEDIGER; HIRAKAWA, SATOSHI; BERDEL, WOLFGANG E.; MESTERS, ROLF M.; DETMAR, MICHAEL

    2012-01-01

    Research on tumor-induced lymphangiogenesis has predominantly focused on alterations and abnormal growth of peritumoral and intratumoral lymphatic vessels. However, recent evidence indicates that lymphangiogenesis of sentinel lymph nodes might also contribute to cancer progression. In clinical oncology, the sentinel lymph nodes play an important role in diagnosis, staging and management of disease. The prognostic value that may be placed in the analysis of various parameters in tumor-free lymph nodes is still under debate. We, therefore, chose to investigate genetically fluorescent MDA-MB-435/green fluorescent protein human cancer cells transfected to overexpress VEGF-C in a nude mouse model and investigated metastasis, lymph node lymphangiogenesis, lymph node angiogenesis and size of sentinel lymph nodes. The nature of MDA-MB-435, identified as a breast cancer cell line for several decades, has recently been reidentified as being from melanoma origin. Vascular endothelial growth factor-C overexpression induced early metastasis and significantly increased the lymphatic vessel area in sentinel lymph nodes even before the tumor metastasis. At early time-points, expansion of the lymphatic network was observed even though no difference of blood vessel area and lymph node size was detected. These results suggest that primary tumors -via secretion of VEGF-C- can induce hyperplasia of the sentinel lymph node lymphatic vessel network and thereby promote their further spread. In cases of tumor-free lymph nodes the increased lymphatic network of sentinel lymph nodes is a very early premetastatic sign and may provide a new prognostic indicator and target for aggressive diseases. PMID:23076721

  9. Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator.

    PubMed

    Liersch, Ruediger; Hirakawa, Satoshi; Berdel, Wolfgang E; Mesters, Rolf M; Detmar, Michael

    2012-12-01

    Research on tumor-induced lymphangiogenesis has predominantly focused on alterations and abnormal growth of peritumoral and intratumoral lymphatic vessels. However, recent evidence indicates that lymphangiogenesis of sentinel lymph nodes might also contribute to cancer progression. In clinical oncology, the sentinel lymph nodes play an important role in diagnosis, staging and management of disease. The prognostic value that may be placed in the analysis of various parameters in tumor-free lymph nodes is still under debate. We, therefore, chose to investigate genetically fluorescent MDA-MB-435/green fluorescent protein human cancer cells transfected to overexpress VEGF-C in a nude mouse model and investigated metastasis, lymph node lymphangiogenesis, lymph node angiogenesis and size of sentinel lymph nodes. The nature of MDA-MB-435, identified as a breast cancer cell line for several decades, has recently been reidentified as being from melanoma origin. Vascular endothelial growth factor-C overexpression induced early metastasis and significantly increased the lymphatic vessel area in sentinel lymph nodes even before the tumor metastasis. At early time-points, expansion of the lymphatic network was observed even though no difference of blood vessel area and lymph node size was detected. These results suggest that primary tumors -via secretion of VEGF-C- can induce hyperplasia of the sentinel lymph node lymphatic vessel network and thereby promote their further spread. In cases of tumor-free lymph nodes the increased lymphatic network of sentinel lymph nodes is a very early premetastatic sign and may provide a new prognostic indicator and target for aggressive diseases.

  10. Distribution of the lymphatic vessels in the prostatic fascia.

    PubMed

    Soga, Hideo; Takenaka, Atsushi; Murakami, Gen; Haraguchi, Takahiro; Miyake, Hideaki; Tanaka, Kazushi; Fujisawa, Masato

    2011-09-01

    The prostatic fascia-preserving procedure is effective for the early recovery of erectile function after radical prostatectomy; however, the long-term influence of on cancer control was unknown. This study clarified the distribution of lymphatic vessels in the prostatic fascia. The lymphatic vessels were analyzed in 10 prostates obtained from fixed Japanese cadavers (aged, 71-90 years old). Specimens were taken from the apex, the middle part, and the base of the right-hand side of the prostate. Lymphatic vessels were detected by immunohistochemical stain using an antibody specific for the lymphatic endothelial cells (clone D2-40). The lymphatic vessels were counted in the prostate capsule and the prostatic fascia of each section by light microscopy at low power (100×). The median number of lymphatic vessels in the prostatic capsule per prostatic half was 21.0, 14.0, and 21.0 in the apex, middle, and base part of the prostate, respectively. In the prostatic facia the median number of lymphatic vessels per prostatic half was 8.0, 3.0, and 13.0 in the apex, middle, and the base part of the prostate, respectively. In the apex and the middle part the lymphatic vessels in the prostatic fascia were fewer than those in the prostatic capsule. However, in the base part the number of lymphatic vessels in the prostatic fascia was similar to that in the prostatic capsule. The present study suggested the surgeon to pay more attention for the dissection of the fascia at the base of the prostate. Copyright © 2011 Wiley-Liss, Inc.

  11. Can Lymphatic Filariasis Be Eliminated by 2020?

    PubMed

    Rebollo, Maria P; Bockarie, Moses J

    2017-02-01

    Interventions against neglected tropical diseases (NTD), including lymphatic filariasis (LF), scaled up dramatically after the signing of the London Declaration (LD) in 2012. LF is targeted for elimination by 2020, but some countries are considered not on track to meet the 2020 target using the recommended preventive chemotherapy and morbidity management strategies. In this Opinion article we review the prospects for achieving LF elimination by 2020 in the light of the renewed global action against NTDs and the global efforts to achieve the sustainable development goals (SDGs) by 2030. We conclude that LF can be eliminated by 2020 using cross-sectoral and integrated approaches because of the compound effect of the other SDG activities related to poverty reduction and water and sanitation.

  12. Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer

    PubMed Central

    Lund, Amanda W.; Medler, Terry R.; Leachman, Sancy A.; Coussens, Lisa M.

    2015-01-01

    Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, are important contributors to malignancy and potential biomarkers and targets for immunotherapy. PMID:26552413

  13. Lymphosome concept: Anatomical study of the lymphatic system.

    PubMed

    Suami, Hiroo

    2017-01-01

    The gross anatomical study of the lymphatic system in humans and animals has been suspended for almost 100 years. This article introduces the author's technique for investigating the lymphatic system using the concept of the lymphosome. In revisiting the anatomical study of the lymphatic system, our updated knowledge can potentially be utilized either to reassure surgeons about their current procedures in the surgical management of cancers and lymphedema or assist them to refine them. J. Surg. Oncol. 2017;115:13-17. © 2016 Wiley Periodicals, Inc.

  14. A Giant Lymphatic Cyst of the Transverse Colon Mesentery

    PubMed Central

    Batool, Tayyaba; Ahmed, Soofia

    2010-01-01

    Mesenteric cysts are not uncommon in pediatric age group but giant lymphatic cysts of mesentery are reported infrequently. This is a report of six years old female who had vague abdominal pain with distension for two years. Investigations revealed a large cystic mass in abdomen. On exploration a giant lymphatic cyst in the mesentery of transverse colon found. More than 1500 ml of milky fluid was drained. The cyst was unilocular and appeared to be the collection of lymph (chyle) between two leaves of the mesentery of transverse colon. It is postulated that trauma to or malformation of lymphatics at the root of mesentery might have lead to this pathology. PMID:22953250

  15. A giant lymphatic cyst of the transverse colon mesentery.

    PubMed

    Batool, Tayyaba; Ahmed, Soofia; Akhtar, Jamshed

    2010-01-01

    Mesenteric cysts are not uncommon in pediatric age group but giant lymphatic cysts of mesentery are reported infrequently. This is a report of six years old female who had vague abdominal pain with distension for two years. Investigations revealed a large cystic mass in abdomen. On exploration a giant lymphatic cyst in the mesentery of transverse colon found. More than 1500 ml of milky fluid was drained. The cyst was unilocular and appeared to be the collection of lymph (chyle) between two leaves of the mesentery of transverse colon. It is postulated that trauma to or malformation of lymphatics at the root of mesentery might have lead to this pathology.

  16. A Three-Dimensional Lymphatic Endothelial Cell Tube Formation Assay to Identify Novel Kinases Involved in Lymphatic Vessel Remodeling.

    PubMed

    Gambino, T Jessica; Williams, Steven P; Caesar, Carol; Resnick, Daniel; Nowell, Cameron J; Farnsworth, Rae H; Achen, Marc G; Stacker, Steven A; Karnezis, Tara

    2017-01-01

    The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes. The collagen-overlay-based assay was used with primary human adult dermal LECs to investigate a library of 60 tyrosine kinase (TK) and TK-like genes by siRNA knockdown. Nine candidate genes were identified and characterized for their ability to modify key parameters of lymphatic tube formation, including tube length, area, thickness, branching, and number of blind-ended sacs. Four genes-ZAP70, IRAK4, RIPK1, and RIPK2-were identified as high-confidence hits after tertiary deconvolution screens and demonstrate the utility of the assay to define LEC genes critical for the formation of tube structures. This assay facilitates the identification of potential molecular targets for novel drugs designed to modulate the remodeling of lymphatics that is important for the metastatic spread of cancer and other pathologies.

  17. An investigation of the topography of the lymphatic system of the grey kangaroo (Macropus giganteus). 1. The superficial lymphatic system.

    PubMed Central

    Hopwood, P R

    1988-01-01

    The superficial lymphatic system of the grey kangaroo, Macropus giganteus is described. The description is based on dissections of 130 eastern grey kangaroos. The most significant difference found between the superficial lymphatic drainage pattern of kangaroos and that of the domestic species was the existence of large inguino-axillary lymphatic trunks in the kangaroo. Thus in the kangaroo, instead of lymph passing from the inguinal lymphocentre to the lumbar lymphatic trunks as is the situation in the domestic animals, lymph passes from the inguinal lymphocentre to the axillary lymphocentre. Apart from the lymph draining from the head and ventral neck (which passes to the superficial cervical lymphocentre) and lymph which may pass from the superficial lymphatic vessels to deeper lymphatic vessels, all the superficial lymphatic drainage of the kangaroo passes through the axillary lymphocentre. From the viewpoint of the meat inspection of the carcasses of kangaroos taken as game meat animals, pathology of the axillary lymphocentre may reflect disease in a much wider range of body regions than it would in a domestic animal. PMID:3198478

  18. Predictive lymphatic mapping: a method for mapping lymphatic channels in patients with advanced unilateral lymphedema using indocyanine green lymphography.

    PubMed

    Mihara, Makoto; Seki, Yukio; Hara, Hisako; Iida, Takuya; Oka, Aiko; Kikuchi, Kazuki; Narushima, Mitsunaga; Haragi, Makiko; Furniss, Dominic; Hin-Lun, Lawrence; Mitsui, Kito; Murai, Noriyuki; Koshima, Isao

    2014-01-01

    In severe lymphedema, indocyanine green lymphography cannot be used to map lymphatic channels before lymphaticovenular anastomosis (LVA) because linear lymphatics cannot be detected in a severely affected leg. Here, we describe a new method, which we refer to as predictive lymphatic mapping, to predict the location of lymphatics for anastomosis in unilateral lymphedema, thereby improving surgical accuracy and efficiency. The approach consists of marking anatomical landmarks and joining selected landmarks with fixed lines. The distance from these fixed lines to lymphatic channels mapped by indocyanine green lymphography in the unaffected leg is then measured, scaled up based on the difference in circumference between the legs, and transposed to the affected leg. To date, we have used this method in 5 cases of unilateral or asymmetric lymphedema of the lower extremities. In no cases have we failed to find a lymphatic channel suitable for LVA within a 2-cm incision. These results suggest that predictive lymphatic mapping is a useful additional tool for surgeons performing LVA under local anesthesia, which will help to improve the accuracy of incisions and the efficiency of surgery.

  19. Identification of lymphatic vessels and prognostic value of lymphatic microvessel density in lesions of the uterine cervix.

    PubMed

    Saptefraţi, L; Cîmpean, Anca Maria; Ciornîi, A; Ceauşu, Raluca; Eşanu, N; Raica, M

    2009-01-01

    Incomplete characterization of the uterine cervix cancer from molecular point of view represents the main problem for the use of a proper therapy in this disease. Few data are available about D2-40 expression in lymphatic endothelial cells and also in tumor cells from uterine cervix cancer. The aim of the present work was to study the involvement of lymphatics in prognosis and tumor progression of the uterine cervix lesions. We used D2-40 immunostaining to highlight lymphatic vessels from squamous cell metaplasia (n=17), cervical intraepithelial neoplasia (n=11), carcinoma in situ (n=3), microinvasive carcinoma (n=4) and invasive carcinoma (n=19) using Avidin-Biotin technique (LSAB+). Type and distribution of lymphatics in different lesions of the cervix were analyzed. We found significant correlation between lymphatic microvessel density and tumor grade and particular distribution of the lymphatics linked to histopathologic type of the lesions. Also, differences was found in lymphovascular invasion interpretation between routine Hematoxylin and Eosin staining specimens and immunohistochemical ones. Our results showed differences in the distribution and D2-40 expression in lymphatic vessels and tumor cells from the cervix lesions linked to histopathology and tumor grade.

  20. [Diseases of the pulmonary lymphatic system in children].

    PubMed

    Epaud, R; Fauroux, B; Boule, M; Clément, A

    2003-02-01

    Diseases of the lymphatic system in children include a group of exceptional conditions difficult to manage. The anatomy of lymphatic system is complex in the lung. Variable from one subject to another, its complex physiology plays an important role in air-blood exchanges occurring in the lung. In the pulmonary interstitium and in the pleura, the lymphatic system acts like an overflow valve capable of regulating variations in interstitial fluid. The presence or development of dysplasic lymphatics causes leakage, dilatation, and reflux of the lymph through incontinent valves leading to chylothorax and/or fluid overload in the pulmonary interstitium. Symptomatic care is usually proposed, based on a fat-free diet supplemented with light-chain triglycerides and liposoluble vitamins. Other therapeutic options can be proposed. Medical options include cytotoxic agents, somatostatin, and interferon-alpha. Surgery may also be useful, but an assessment of therapeutic efficacy is very difficult due to partial effects and the small number of cases studied.

  1. Roles of transcriptional network during the formation of lymphatic vessels.

    PubMed

    Watabe, Tetsuro

    2012-09-01

    The lymphatic vascular system, also known as the second vascular system in vertebrates, plays crucial roles in various physiological and pathological processes. It participates in the maintenance of normal tissue fluid balance, trafficking of the immune cells and absorption of fatty acids in the gut. Furthermore, lymphatic system is associated with the pathogenesis of a number of diseases, including lymphedema, inflammatory diseases and tumour metastasis. Lymphatic vessels are comprised of lymphatic endothelial cells (LECs), which are differentiated from blood vascular endothelial cells. This review highlights recent advances in our understanding of the transcriptional control of LEC fate determination and reflects on efforts to understand the roles of transcriptional networks during this discrete developmental process.

  2. Monocytes can be induced to express lymphatic phenotypes.

    PubMed

    Changming, W; Xin, L; Hua, T; Shikun, W; Qiong, X; Zhigeng, Z; Xueying, W

    2011-06-01

    Although it has been recently shown that monocytes can transdifferentiate into blood vascular endothelial cells which are involved in angiogenesis, little attention has been paid to their potential to transdifferentiate into lymphatic endothelial cells. Therefore, we examined this question in our study. We first stimulated monocytes with either fibronectin (FN), VEGF-C, TNF-alpha, LPS, or IL-3 for 24h. Then we examined the expression of several markers of lymphatic endothelium and found that the monocytes expressed specific lymphatic endothelial markers, LYVE-1, Podoplanin, and Prox-1, but not common endothelial markers vWF or eNOS. Next, monocytes were incubated in endothelial growth medium with FN and VEGF-C for 6d. These monocytes were also found to express LYVE-1, Podoplanin and Prox-1, but not vWF or eNOS. Our results indicate that monocytes in vitro can be easily induced to present lymphatic phenotypes in an inflammatory environment.

  3. Lymphatic vessel density and function in experimental bladder cancer

    PubMed Central

    Saban, Marcia R; Towner, Rheal; Smith, Nataliya; Abbott, Andrew; Neeman, Michal; Davis, Carole A; Simpson, Cindy; Maier, Julie; Mémet, Sylvie; Wu, Xue-Ru; Saban, Ricardo

    2007-01-01

    Background The lymphatics form a second circulatory system that drains the extracellular fluid and proteins from the tumor microenvironment, and provides an exclusive environment in which immune cells interact and respond to foreign antigen. Both cancer and inflammation are known to induce lymphangiogenesis. However, little is known about bladder lymphatic vessels and their involvement in cancer formation and progression. Methods A double transgenic mouse model was generated by crossing a bladder cancer-induced transgenic, in which SV40 large T antigen was under the control of uroplakin II promoter, with another transgenic mouse harboring a lacZ reporter gene under the control of an NF-κB-responsive promoter (κB-lacZ) exhibiting constitutive activity of β-galactosidase in lymphatic endothelial cells. In this new mouse model (SV40-lacZ), we examined the lymphatic vessel density (LVD) and function (LVF) during bladder cancer progression. LVD was performed in bladder whole mounts and cross-sections by fluorescent immunohistochemistry (IHC) using LYVE-1 antibody. LVF was assessed by real-time in vivo imaging techniques using a contrast agent (biotin-BSA-Gd-DTPA-Cy5.5; Gd-Cy5.5) suitable for both magnetic resonance imaging (MRI) and near infrared fluorescence (NIRF). In addition, IHC of Cy5.5 was used for time-course analysis of co-localization of Gd-Cy5.5 with LYVE-1-positive lymphatics and CD31-positive blood vessels. Results SV40-lacZ mice develop bladder cancer and permitted visualization of lymphatics. A significant increase in LVD was found concomitantly with bladder cancer progression. Double labeling of the bladder cross-sections with LYVE-1 and Ki-67 antibodies indicated cancer-induced lymphangiogenesis. MRI detected mouse bladder cancer, as early as 4 months, and permitted to follow tumor sizes during cancer progression. Using Gd-Cy5.5 as a contrast agent for MRI-guided lymphangiography, we determined a possible reduction of lymphatic flow within the

  4. An Immunological Fingerprint Differentiates Muscular Lymphatics from Arteries and Veins

    PubMed Central

    Bridenbaugh, Eric A.; Wang, Wei; Srimushnam, Maya; Cromer, Walter E.; Zawieja, Scott D.; Schmidt, Susan E.; Jupiter, Daniel C.; Huang, Hung-Chung; Van Buren, Vincent

    2013-01-01

    Abstract The principal function of the lymphatic system is to transport lymph from the interstitium to the nodes and then from the nodes to the blood. In doing so lymphatics play important roles in fluid homeostasis, macromolecular/antigen transport and immune cell trafficking. To better understand the genes that contribute to their unique physiology, we compared the transcriptional profile of muscular lymphatics (prenodal mesenteric microlymphatics and large, postnodal thoracic duct) to axillary and mesenteric arteries and veins isolated from rats. Clustering of the differentially expressed genes demonstrated that the lymph versus blood vessel differences were more profound than between blood vessels, particularly the microvessels. Gene ontology functional category analysis indicated that microlymphatics were enriched in antigen processing/presentation, IgE receptor signaling, catabolic processes, translation and ribosome; while they were diminished in oxygen transport, regulation of cell proliferation, glycolysis and inhibition of adenylate cyclase activity by G-proteins. We evaluated the differentially expressed microarray genes/products by qPCR and/or immunofluorescence. Immunofluorescence documented that multiple MHC class II antigen presentation proteins were highly expressed by an antigen-presenting cell (APC) type found resident within the lymphatic wall. These APCs also expressed CD86, a co-stimulatory protein necessary for T-cell activation. We evaluated the distribution and phenotype of APCs within the pre and postnodal lymphatic network. This study documents a novel population of APCs resident within the walls of muscular, prenodal lymphatics that indicates novel roles in antigen sampling and immune responses. In conclusion, these prenodal lymphatics exhibit a unique profile that distinguishes them from blood vessels and highlights the role of the lymphatic system as an immunovascular system linking the parenchymal interstitium, lymph nodes and the

  5. [The macrophage contribution for maintaining lymphatic vessel in cornea].

    PubMed

    Maruyama, Kazuichi

    2014-11-01

    The presence of antigen-presenting cells and hem- and lymphangiogenesis in the cornea are risk factors for the rejection of corneal transplants. We previously reported that antigen-presenting cells such as macrophages (MPs) play an important role in the induction of lymphatic endothelial cells during inflammation. This prompted us to inquire whether the existence of lymphatic vessels in the cornea is associated with the activation of MPs during inflammation. To investigate this question, we performed suture placement on the cornea to induce inflammation. We found that a large number of MPs were recruited and that lymphatic vessels were formed in response. Next, as C57BL/6 mice have a higher rejection rate after corneal transplantation than BALB/c mice, we compared the corneas of C57BL/6 and BALB/c mice under normal and inflamed conditions. We found that the number of spontaneously formed lymphatic vessels in the C57BL/6 corneas was significantly greater than in the BALB/c corneas, and that there were more activated MPs in the C57BL/6 corneas than in the BALB/c corneas. Additionally, to confirm that activated MPs induced and maintained lymphatic vessels in the cornea, we depleted the number of MPs in C57BL/6 mice via clodronate liposomes. We found that MP depletion reduced the spontaneous formation of lymphatic vessels and reduced inflammation-induced lymphangiogenesis relative to control mice. Finally, we found that mice deficient in MP markers had fewer spontaneously formed lymphatic vessels and less lymphangiogenesis than control C57BL/6 mice. The evidence gathered in this study leads us to conclude that activated MPs appear to play an important role in the formation of new lymphatic vessels and in their maintenance.

  6. Current and Future Lymphatic Imaging Modalities for Tumor Staging

    PubMed Central

    Gao, Kuo; Liu, Tiegang; Tariq, Imran; Sajjad, Ashif; Niu, Meiying; Liu, Guokai; Mehmood, Zahid; Tian, Guihua

    2014-01-01

    Tumor progression is supported by the lymphatic system which should be scanned efficiently for tumor staging as well as the enhanced therapeutic outcomes. Poor resolution and low sensitivity is a limitation of traditional lymphatic imaging modalities; thus new noninvasive approaches like nanocarriers, magnetic resonance imaging, positron-emission tomography, and quantum dots are advantageous. Some newer modalities, which are under development, and their potential uses will also be discussed in this review. PMID:24757671

  7. Sensitivity analysis of near-infrared functional lymphatic imaging

    NASA Astrophysics Data System (ADS)

    Weiler, Michael; Kassis, Timothy; Dixon, J. Brandon

    2012-03-01

    Background - Near-infrared (NIR) imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, offering better spatial and temporal resolution than competing imaging modalities. While NIR lymphatic imaging has begun to be reported in the literature, the technology is still in its infancy and its imaging capabilities have yet to be quantitatively characterized. The objective of this study, therefore, was to characterize the parameters of NIR lymphatic imaging to quantify its capabilities as a diagnostic tool for evaluating lymphatic disease. Methods - An NIR imaging system was developed using a laser diode for excitation, ICG as a fluorescent agent, and a CCD camera to detect emission. A tissue phantom with mock lymphatic vessels of known depths and diameters was used as an alternative to in vivo lymphatic vessels due to the greater degree of control with the phantom. Results and Conclusions - When dissolved in an albumin physiological salt solution (APSS) to mimic interstitial fluid, ICG experiences shifts in the excitation/emission wavelengths such that it is maximally excited at 805nm and produces peak fluorescence at 840nm. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being: 900μM (60g/L) albumin and 193.5μM (150μg/mL) ICG. ICG fluorescence can be detected as deep as 6mm, but spatial resolution deteriorates severely below 3mm, thus skewing vessel geometry measurements. ICG packet travel, a common measure of lymphatic transport, can be detected as deep as 5mm.

  8. Communication between lymphatic and venous systems in mice.

    PubMed

    Shao, Lenan; Takeda, Kazu; Kato, Shigeki; Mori, Shiro; Kodama, Tetsuya

    2015-09-01

    The lymphatic system in mice consists of lymphatic vessels and 22 types of lymph nodes. Metastatic tumor cells in the lymphatic system spread to distant organs through the venous system. However, the communication routes between the lymphatic and venous systems have not been fully elucidated. Here, we identify the communication routes between the lymphatic and venous systems in the axillary and subiliac regions of MXH10/Mo-lpr/lpr inbred mice, which develop systemic swelling of lymph nodes up to 10mm in diameter, allowing investigation of the topography of the lymph nodes and lymphatic vessels. Using a gross anatomy dissection approach, the efferent lymphatic vessels of the proper axillary lymph node were shown to communicate with the subclavian vein. Furthermore, we found that the thoracoepigastric vein, which connects the subclavian vein and inferior vena cava, runs adjacent to the subiliac and proper axillary lymph nodes, and receives venous blood from these lymph nodes routed through small branches. The direction of blood flow in the thoracoepigastric vein occurred in two directions in the intermediate region between the proper axillary lymph node and subiliac lymph node; one to the subclavian vein, the other to the inferior vena cava. This paper reveals the anatomy of the communication between the lymphatic and venous systems in the axillary and subiliac regions of the mouse, and provides new insights relevant to the investigation of the mechanisms of lymph node metastasis and cancer immunology, and the development of diagnostic and treatment methods for lymph node metastasis, including drug delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Morphological and Molecular Characterization of Human Dermal Lymphatic Collectors

    PubMed Central

    Buttler, Kerstin; Ströbel, Philipp; Becker, Jürgen; Aung, Thiha; Felmerer, Gunther; Wilting, Jörg

    2016-01-01

    Millions of patients suffer from lymphedema worldwide. Supporting the contractility of lymphatic collectors is an attractive target for pharmacological therapy of lymphedema. However, lymphatics have mostly been studied in animals, while the cellular and molecular characteristics of human lymphatic collectors are largely unknown. We studied epifascial lymphatic collectors of the thigh, which were isolated for autologous transplantations. Our immunohistological studies identify additional markers for LECs (vimentin, CCBE1). We show and confirm differences between initial and collecting lymphatics concerning the markers ESAM1, D2-40 and LYVE-1. Our transmission electron microscopic studies reveal two types of smooth muscle cells (SMCs) in the media of the collectors with dark and light cytoplasm. We observed vasa vasorum in the media of the largest collectors, as well as interstitial Cajal-like cells, which are highly ramified cells with long processes, caveolae, and lacking a basal lamina. They are in close contact with SMCs, which possess multiple caveolae at the contact sites. Immunohistologically we identified such cells with antibodies against vimentin and PDGFRα, but not CD34 and cKIT. With Next Generation Sequencing we searched for highly expressed genes in the media of lymphatic collectors, and found therapeutic targets, suitable for acceleration of lymphatic contractility, such as neuropeptide Y receptors 1, and 5; tachykinin receptors 1, and 2; purinergic receptors P2RX1, and 6, P2RY12, 13, and 14; 5-hydroxytryptamine receptors HTR2B, and 3C; and adrenoceptors α2A,B,C. Our studies represent the first comprehensive characterization of human epifascial lymphatic collectors, as a prerequisite for diagnosis and therapy. PMID:27764183

  10. Zinc effect on human lymphatic malformation cells in vitro.

    PubMed

    O, Teresa Min-Jung; Lou, Man Si; Ma, Yupo

    2016-01-01

    Lymphatic malformations (LM) are clinically characterized by episodes of inflammatory episodes. Often, an upper respiratory illness or trauma will lead to painful swelling in the distribution of the LM. Zinc is an element involved in numerous aspects of cellular metabolism and is a common dietary supplement and cold remedy. We surmise that zinc may act as a therapeutic anti-inflammatory agent for lymphatic malformations and their cellular components. We investigate the apparent cytotoxic effect of zinc ion on lymphatic malformation cells in vitro. Fresh surgical lymphatic malformation specimens from 10 patients were collected and processed in a laboratory. Tissues were processed and lymphatic malformation cells were isolated and grown. Immunohistochemistry and cell morphology were used to confirm LM cells. HUVEC cells were used as controls. Zinc chloride solution was added to the cells and its effect observed. LM cells were isolated from five of the 10 specimens. Of these, the cells of only one specimen were able to be amplified to confluence. Five specimens were contaminated. Immunohistochemical staining (CD31, D2-40, and LYVE-1) and cell morphology of our specimens were consistent with lymphatic malformation while HUVEC control cells were negative. Zinc has a cytotoxic effect on BEL isolates in vitro with no obvious effect on cell morphology or growth rate of the control HUVEC cells. When compared with the published toxic zinc concentration for most cell types in the literature (100μM total zinc in vitro), our result indicates that LM cells may have a lower tolerance to zinc (10μM total zinc in vitro). Zinc has an apparent morphological effect on lymphatic malformation cells in vitro. Compared with other cell types, LM cells have a lower tolerance to zinc. While this result looks very promising for future therapeutic use of zinc in acute lymphangitis, further studies are necessary, such as finding the IC50 of zinc for lymphatic malformation in vitro and also in

  11. Lymphatic vessels: an emerging actor in atherosclerotic plaque development.

    PubMed

    Kutkut, Issa; Meens, Merlijn J; McKee, Thomas A; Bochaton-Piallat, Marie-Luce; Kwak, Brenda R

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease of large- to medium-sized arteries and is the main underlying cause of death worldwide. The lymphatic vasculature is critical for processes that are intimately linked to atherogenesis such as the immune response and cholesterol metabolism. However, whether lymphatic vessels truly contribute to the pathogenesis of atherosclerosis is less clear despite increasing research efforts in this field. PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications. Current knowledge about lymphatic vessels in the arterial wall came from studies that examined the presence and location of such vessels in human atherosclerotic plaque specimens, as well as in a variety of arteries in animal models for atherosclerosis (e.g. rabbits, dogs, rats and mice). Generally, three experimental approaches have been used to investigate the functional role of plaque-associated lymphatic vessels; experimental lymphostasis was used to investigate lymphatic drainage of the arterial wall, and more recently, studies with genetic interventions and/or surgical transplantation have been performed. Lymphatic vessels seem to be mostly present in the adventitial layer of the arterial walls of animals and humans. They are involved in reverse cholesterol transport from atherosclerotic lesions, and arteries with a dense lymphatic network seem naturally protected against atherosclerosis. Lymphangiogenesis is a process that is an important part of the inflammatory loop in atherosclerosis. However, how augmenting or impeding the distribution of lymphatic vessels impacts disease progression remains to be investigated in future studies. © 2014 Stichting European Society for Clinical Investigation Journal Foundation.

  12. The passive biomechanics of human pelvic collecting lymphatic vessels

    PubMed Central

    Athanasiou, Dimitrios; Jafarnejad, Mohammad; Nixon, Katherine; Duarte, Delfim; Hawkins, Edwin D.; Jamalian, Samira; Cunnea, Paula; Lo Celso, Cristina; Kobayashi, Shunichi; Fotopoulou, Christina; Moore, James E.

    2017-01-01

    The lymphatic system has a major significance in the metastatic pathways in women’s cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport. PMID:28827843

  13. The association of adult Onchocerca volvulus with lymphatic vessels.

    PubMed

    Mackenzie, C D; Huntington, M K; Wanji, S; Lovato, R V; Eversole, R R; Geary, T G

    2010-02-01

    Immunocytochemical examination of onchocercal nodule tissues containing adult Onchocerca volvulus using immuno-markers for blood and lymphatic vessels (vWF, D2-40, podoplanin, Prox-1, and Lyve1) shows a distinct pattern of distribution of these vessels within nodules. Blood vessels were commonly seen associated with organized lymphoid cellular aggregates in the both the outer and inner areas of the nodules. In contrast, the majority of the lymphatic vessel positivity was seen in the central zone in close apposition to the adult parasites, and the remainder usually associated with microfilariae in the outer areas of the nodule. These findings suggest an intimate relationship between adult O. volvulus and lymphatic vessels, including the likely proliferation of lymphatic endothelial cells (lymphangectasia) akin to that seen with other filariae. These findings indicate that adult O. volvulus may migrate via the lymphatic system, and that clinical manifestations of this disease that involve tissue edema may be the result of the location of these worms in the lymphatic system.

  14. Photoacoustic lymphatic imaging with high spatial-temporal resolution

    NASA Astrophysics Data System (ADS)

    Martel, Catherine; Yao, Junjie; Huang, Chih-Hsien; Zou, Jun; Randolph, Gwendalyn J.; Wang, Lihong V.

    2014-11-01

    Despite its critical function in coordinating the egress of inflammatory and immune cells out of tissues and maintaining fluid balance, the causative role of lymphatic network dysfunction in pathological settings is still understudied. Engineered-animal models and better noninvasive high spatial-temporal resolution imaging techniques in both preclinical and clinical studies will help to improve our understanding of different lymphatic-related pathologic disorders. Our aim was to take advantage of our newly optimized noninvasive wide-field fast-scanning photoacoustic (PA) microcopy system to coordinately image the lymphatic vasculature and its flow dynamics, while maintaining high resolution and detection sensitivity. Here, by combining the optical-resolution PA microscopy with a fast-scanning water-immersible microelectromechanical system scanning mirror, we have imaged the lymph dynamics over a large field-of-view, with high spatial resolution and advanced detection sensitivity. Depending on the application, lymphatic vessels (LV) were spectrally or temporally differentiated from blood vessels. Validation experiments were performed on phantoms and in vivo to identify the LV. Lymphatic flow dynamics in nonpathological and pathological conditions were also visualized. These results indicate that our newly developed PA microscopy is a promising tool for lymphatic-related biological research.

  15. The passive biomechanics of human pelvic collecting lymphatic vessels.

    PubMed

    Athanasiou, Dimitrios; Edgar, Lowell T; Jafarnejad, Mohammad; Nixon, Katherine; Duarte, Delfim; Hawkins, Edwin D; Jamalian, Samira; Cunnea, Paula; Lo Celso, Cristina; Kobayashi, Shunichi; Fotopoulou, Christina; Moore, James E

    2017-01-01

    The lymphatic system has a major significance in the metastatic pathways in women's cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport.

  16. Sensitivity analysis of near-infrared functional lymphatic imaging

    NASA Astrophysics Data System (ADS)

    Weiler, Michael; Kassis, Timothy; Dixon, J. Brandon

    2012-06-01

    Near-infrared imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, yet the imaging capabilities of this approach have yet to be quantitatively characterized. We seek to quantify its capabilities as a diagnostic tool for lymphatic disease. Imaging is performed in a tissue phantom for sensitivity analysis and in hairless rats for in vivo testing. To demonstrate the efficacy of this imaging approach to quantifying immediate functional changes in lymphatics, we investigate the effects of a topically applied nitric oxide (NO) donor glyceryl trinitrate ointment. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being 150 μg/mL ICG and 60 g/L albumin. ICG fluorescence can be detected at a concentration of 150 μg/mL as deep as 6 mm with our system, but spatial resolution deteriorates below 3 mm, skewing measurements of vessel geometry. NO treatment slows lymphatic transport, which is reflected in increased transport time, reduced packet frequency, reduced packet velocity, and reduced effective contraction length. NIR imaging may be an alternative to invasive procedures measuring lymphatic function in vivo in real time.

  17. Lymphatics at the crossroads of angiogenesis and lymphangiogenesis

    PubMed Central

    Scavelli, Claudio; Weber, Elisabetta; Aglianò, Margherita; Cirulli, Teresa; Nico, Beatrice; Vacca, Angelo; Ribatti, Domenico

    2004-01-01

    The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies. This review highlights the recent insights and advances into the field of lymphatic vascular research, outlining the most important aspects of the embryo development, structure, specific markers and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms involved in the regulation of lymphangiogenesis are described. PMID:15198686

  18. Quantum dots trace lymphatic drainage from the mouse eye.

    PubMed

    Tam, Alex L C; Gupta, Neeru; Zhang, Zhexue; Yücel, Yeni H

    2011-10-21

    Glaucoma is a leading cause of blindness in the world, often associated with elevated eye pressure. Currently, all glaucoma treatments aim to lower eye pressure by improving fluid exit from the eye. We recently reported the presence of lymphatics in the human eye. The lymphatic circulation is known to drain fluid from organ tissues and, as such, lymphatics may also play a role in draining fluid from the eye. We investigated whether lymphatic drainage from the eye is present in mice by visualizing the trajectory of quantum dots once injected into the eye. Whole-body hyperspectral fluorescence imaging was performed in 17 live mice. In vivo imaging was conducted prior to injection, and 5, 20, 40 and 70 min, and 2, 6 and 24 h after injection. A quantum dot signal was observed in the left neck region at 6 h after tracer injection into the eye. Examination of immunofluorescence-labelled sections using confocal microscopy showed the presence of a quantum dot signal in the left submandibular lymph node. This is the first direct evidence of lymphatic drainage from the mouse eye. The use of quantum dots to image this lymphatic pathway in vivo is a novel tool to stimulate new treatments to reduce eye pressure and prevent blindness from glaucoma.

  19. Quantum dots trace lymphatic drainage from the mouse eye

    NASA Astrophysics Data System (ADS)

    Tam, Alex L. C.; Gupta, Neeru; Zhang, Zhexue; Yücel, Yeni H.

    2011-10-01

    Glaucoma is a leading cause of blindness in the world, often associated with elevated eye pressure. Currently, all glaucoma treatments aim to lower eye pressure by improving fluid exit from the eye. We recently reported the presence of lymphatics in the human eye. The lymphatic circulation is known to drain fluid from organ tissues and, as such, lymphatics may also play a role in draining fluid from the eye. We investigated whether lymphatic drainage from the eye is present in mice by visualizing the trajectory of quantum dots once injected into the eye. Whole-body hyperspectral fluorescence imaging was performed in 17 live mice. In vivo imaging was conducted prior to injection, and 5, 20, 40 and 70 min, and 2, 6 and 24 h after injection. A quantum dot signal was observed in the left neck region at 6 h after tracer injection into the eye. Examination of immunofluorescence-labelled sections using confocal microscopy showed the presence of a quantum dot signal in the left submandibular lymph node. This is the first direct evidence of lymphatic drainage from the mouse eye. The use of quantum dots to image this lymphatic pathway in vivo is a novel tool to stimulate new treatments to reduce eye pressure and prevent blindness from glaucoma.

  20. Sensitivity analysis of near-infrared functional lymphatic imaging

    PubMed Central

    Weiler, Michael; Kassis, Timothy

    2012-01-01

    Abstract. Near-infrared imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, yet the imaging capabilities of this approach have yet to be quantitatively characterized. We seek to quantify its capabilities as a diagnostic tool for lymphatic disease. Imaging is performed in a tissue phantom for sensitivity analysis and in hairless rats for in vivo testing. To demonstrate the efficacy of this imaging approach to quantifying immediate functional changes in lymphatics, we investigate the effects of a topically applied nitric oxide (NO) donor glyceryl trinitrate ointment. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being 150  μg/mL ICG and 60  g/L albumin. ICG fluorescence can be detected at a concentration of 150  μg/mL as deep as 6 mm with our system, but spatial resolution deteriorates below 3 mm, skewing measurements of vessel geometry. NO treatment slows lymphatic transport, which is reflected in increased transport time, reduced packet frequency, reduced packet velocity, and reduced effective contraction length. NIR imaging may be an alternative to invasive procedures measuring lymphatic function in vivo in real time. PMID:22734775

  1. Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer.

    PubMed

    Lund, Amanda W; Medler, Terry R; Leachman, Sancy A; Coussens, Lisa M

    2016-01-01

    Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, and are important contributors to malignancy and potential biomarkers and targets for immunotherapy. The tumor microenvironment and tumor-associated inflammation are now appreciated not only for their role in cancer progression but also for their response to therapy. The lymphatic vasculature is a less-appreciated component of this microenvironment that coordinates local inflammation and immunity and thereby critically shapes local responses. A mechanistic understanding of the complexities of lymphatic vessel function in the unique context of skin provides a model to understand how regional immune dysfunction drives cutaneous malignancies, and as such lymphatic vessels represent a biomarker of cutaneous immunity that may provide insight into cancer prognosis and effective therapy. ©2015 American Association for Cancer Research.

  2. Progression of Inflammatory Bowel Disease to Cancer: Is the Patient Better Off without Lymphatic Vessels or Nodes (or Angiopoietin 2)?

    DTIC Science & Technology

    2012-10-01

    number of functioning lymphatic vessels and impaired lymph drainage (lymphatic vascular insufficiency) in the colon actually protects against...have remained elusive. We proposed that having a reduced number of functioning lymphatic vessels and impaired lymph drainage (lymphatic vascular...Lymphatics, Lymph and the Lymphomyeloid Complex. Academic Press, London, 942 p, 1970. Appendices None Supporting Data None

  3. Chronic High-Fat Diet Impairs Collecting Lymphatic Vessel Function in Mice

    PubMed Central

    Proulx, Steven T.; Ochsenbein, Alexandra M.; Luciani, Paola; Leroux, Jean-Christophe; Wolfrum, Christian; Detmar, Michael

    2014-01-01

    Lymphatic vessels play an essential role in intestinal lipid uptake, and impairment of lymphatic vessel function leads to enhanced adipose tissue accumulation in patients with lymphedema and in genetic mouse models of lymphatic dysfunction. However, the effects of obesity on lymphatic function have been poorly studied. We investigated if and how adipose tissue accumulation influences lymphatic function. Using a lymphatic specific tracer, we performed in vivo near-infrared (NIR) imaging to assess the function of collecting lymphatic vessels in mice fed normal chow or high-fat diet (HFD). Histological and whole mount analyses were performed to investigate the morphological changes in initial and the collecting lymphatic vessels. HFD was associated with impaired collecting lymphatic vessel function, as evidenced by reduced frequency of contractions and diminished response to mechanostimulation. Moreover, we found a significant negative correlation between collecting lymphatic vessel function and body weight. Whole mount analyses showed an enlargement of contractile collecting lymphatic vessels of the hind limb. In K14-VEGF-C mice, HFD resulted in a reduced spreading of the tracer within dermal lymphatic vessels. These findings indicate that adipose tissue expansion due to HFD leads to a functional impairment of the lymphatic vasculature, predominantly in collecting lymphatic vessels. PMID:24714646

  4. Reconstitution of myocardial lymphatic vessels after acute infarction of rat heart.

    PubMed

    Sun, Q N; Wang, Y F; Guo, Z K

    2012-06-01

    We investigated the regeneration of cardiac lymphatic vessels and capillaries in the infarcted myocardiac zones after acute myocardial infarction in rats. The anterior descending artery of the heart was ligated for infarction and both immunohistochemistry and immunofluorescence were used to detect pathological changes of lymphatic vessels in infarcted zone (IZ), infarcted margin zone (MZ) and remote margin zone (RMZ) on days 7, 14, 21, and 28 after surgery. Dynamic variation of lymphatic vessels existed in IZ, MZ and RMZ at different stages after surgery. At day 7, lymphatic vessels and capillaries were not seen in the IZ, very thin lymphatic capillaries were obviously increased in the inner layer of the margin zone, and enlarged and increased lymphatic capillaries were found in the outer layer of margin zone. At 14 days, a few sparsely arranged lymphatic capillaries were observed in the IZ without marked changes in the MZ. At 21 days, constricted regenerating lymphatic capillaries in MZ were decreased, and lymphatic vessels exhibited sprouting towards the IZ. At 28 days, more lymphatic capillaries emerged in the IZ, and the morphology and number of lymphatic vessels and capillaries had returned to normal. There were no marked changes of lymphatic vessels and capillaries in RMZ compared to control myocardium at the 4 time points. This study demonstrates varied remodeling of lymphatic vessels and capillaries in the IZ and MZ after acute myocardial infarction, and these changes in lymphatic vessels likely play an important role for recovery of infarcted myocardiac function.

  5. Integrin-α5β1 is not required for mural cell functions during development of blood vessels but is required for lymphatic-blood vessel separation and lymphovenous valve formation.

    PubMed

    Turner, Christopher J; Badu-Nkansah, Kwabena; Crowley, Denise; van der Flier, Arjan; Hynes, Richard O

    2014-08-15

    Integrin α5β1 is essential for vascular development but it remains unclear precisely where and how it functions. Here, we report that deletion of the gene encoding the integrin-α5 subunit (Itga5) using the Pdgfrb-Cre transgenic mouse line, leads to oedema, haemorrhage and increased levels of embryonic lethality. Unexpectedly, these defects were not caused by loss of α5 from Pdgfrb-Cre expressing mural cells (pericytes and vascular smooth muscle cells), which wrap around the endothelium and stabilise blood vessels, nor by defects in the heart or great vessels, but were due to abnormal development of the lymphatic vasculature. Reminiscent of the pathologies seen in the human lymphatic malformation, fetal cystic hygroma, α5 mutants display defects both in the separation of their blood and lymphatic vasculature and in the formation of the lymphovenous valves. As a consequence, α5-deficient mice develop dilated, blood-filled lymphatic vessels and lymphatic capillaries that are ectopically covered with smooth muscle cells. Analysis of the expression of Pdgfrb during lymphatic development suggests that these defects probably arise from loss of α5β1 integrin in subsets of specialised Prox1(+)Pdgfrb(+) venous endothelial cells that are essential for the separation of the jugular lymph sac from the cardinal vein and formation of the lymphovenous valve leaflets. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Impaired lymphatic function accelerates cancer growth

    PubMed Central

    Steinskog, Eli Sihn Samdal; Sagstad, Solfrid Johanne; Wagner, Marek; Karlsen, Tine Veronica; Yang, Ning; Markhus, Carl Erik; Yndestad, Synnøve; Wiig, Helge; Eikesdal, Hans Petter

    2016-01-01

    Increased lymphangiogenesis is a common feature of cancer development and progression, yet the influence of impaired lymphangiogenesis on tumor growth is elusive. C3HBA breast cancer and KHT-1 sarcoma cell lines were implanted orthotopically in Chy mice, harboring a heterozygous inactivating mutation of vascular endothelial growth factor receptor-3, resulting in impaired dermal lymphangiogenesis. Accelerated tumor growth was observed in both cancer models in Chy mice, coinciding with reduced peritumoral lymphangiogenesis. An impaired lymphatic washout was observed from the peritumoral area in Chy mice with C3HBA tumors, and the number of macrophages was significantly reduced. While fewer macrophages were detected, the fraction of CD163+ M2 macrophages remained constant, causing a shift towards a higher M2/M1 ratio in Chy mice. No difference in adaptive immune cells was observed between wt and Chy mice. Interestingly, levels of pro- and anti-inflammatory macrophage-associated cytokines were reduced in C3HBA tumors, pointing to an impaired innate immune response. However, IL-6 was profoundly elevated in the C3HBA tumor interstitial fluid, and treatment with the anti-IL-6 receptor antibody tocilizumab inhibited breast cancer growth. Collectively, our data indicate that impaired lymphangiogenesis weakens anti-tumor immunity and favors tumor growth at an early stage of cancer development. PMID:27329584

  7. Lymphatic Stomata in the Adult Human Pulmonary Ligament

    PubMed Central

    Miura, Masahiro; Iobe, Hiroaki; Kudo, Tomoo; Shimazu, Yoshihito; Aoba, Takaaki; Okudela, Koji; Nagahama, Kiyotaka; Sakamaki, Kentaro; Yoshida, Maki; Nagao, Toshitaka; Nakaya, Takeo; Kurata, Atsushi; Ohtani, Osamu

    2015-01-01

    Abstract Background: Lymphatic stomata are small lymphatic openings in the serosal membrane that communicate with the serosal cavity. Although these stomata have primarily been studied in experimental mammals, little is known concerning the presence and properties of lymphatic stomata in the adult human pleura. Thus, adult human pleurae were examined for the presence or absence of lymphatic stomata. Methods and Results: A total of 26 pulmonary ligaments (13 left and 13 right) were obtained from 15 adult human autopsy cases and examined using electron and light microscopy. The microscopic studies revealed the presence of apertures fringed with D2-40-positive, CD31-positive, and cytokeratin-negative endothelial cells directly communicating with submesothelial lymphatics in all of the pulmonary ligaments. The apertures' sizes and densities varied from case to case according to the serial tissue section. The medians of these aperture sizes ranged from 2.25 to 8.75 μm in the left pulmonary ligaments and from 2.50 to 12.50 μm in the right pulmonary ligaments. The densities of the apertures ranged from 2 to 9 per mm2 in the left pulmonary ligaments and from 2 to 18 per mm2 in the right pulmonary ligaments. However, no significant differences were found regarding the aperture size (p=0.359) and density (p=0.438) between the left and the right pulmonary ligaments. Conclusions: Our study revealed that apertures exhibit structural adequacy as lymphatic stomata on the surface of the pulmonary ligament, thereby providing evidence that lymphatic stomata are present in the adult human pleura. PMID:25526320

  8. Expression of lymphatic markers during avian and mouse cardiogenesis

    PubMed Central

    Karunamuni, Ganga; Yang, Ke; Doughman, Yong Qiu; Wikenheiser, Jamie; Bader, David; Barnett, Joey; Austin, Anita; Parsons-Wingerter, Patricia; Watanabe, Michiko

    2013-01-01

    The adult heart has been reported to have an extensive lymphatic system, yet the development of this important system during cardiogenesis is still largely unexplored. The nuclear-localized transcription factor Prox-1 identified a sheet of Prox-1-positive cells on the developing aorta and pulmonary trunk in avian and murine embryos just prior to septation of the four heart chambers. The cells coalesced into a branching lymphatic network that spread within the epicardium to cover the heart. These vessels eventually expressed the lymphatic markers LYVE-1, VEGFR-3, and podoplanin. Before the Prox-1-positive cells were detected in the mouse epicardium, LYVE-1, a homologue of the CD44 glycoprotein, was primarily expressed in individual epicardial cells. Similar staining patterns were observed for CD44 in avian embryos. The proximity of these LYVE-1/CD44-positive mesenchymal cells to Prox-1-positive vessels suggests that they may become incorporated into the lymphatics. Unexpectedly, we detected LYVE-1/PECAM/VEGFR-3-positive vessels within the embryonic and adult myocardium which remained Prox-1/podoplanin-negative. Lymphatic markers were surprisingly found in adult rat and embryonic mouse epicardial cell lines, with Prox-1 also exhibiting nuclear-localized expression in primary cultures of embryonic avian epicardial cells. Our data identified three types of cells in the embryonic heart expressing lymphatic markers: (1) Prox-1-positive cells from an extracardiac source that migrate within the serosa of the outflow tract into the epicardium of the developing heart, (2) individual LYVE-1-positive cells in the epicardium that may be incorporated into the Prox-1-positive lymphatic vasculature, and (3) LYVE-1-positive cells/vessels in the myocardium that do not become Prox-1-positive even in the adult heart. PMID:19938109

  9. Immunolocalization of lymphatic vessels in human fetal knee joint tissues.

    PubMed

    Melrose, James; Little, Christopher B

    2010-08-01

    We immunolocalized lymphatic and vascular blood vessels in 12- and 14-week-old human fetal knee joint tissues using a polyclonal antibody to a lymphatic vascular endothelium specific hyaluronan receptor (LYVE-1) and a monoclonal antibody to podoplanin (mAb D2-40). A number of lymphatic vessels were identified in the stratified connective tissues surrounding the cartilaginous knee joint femoral and tibial rudiments. These tissues also contained small vascular vessels with entrapped red blood cells which were imaged using Nomarsky DIC microscopy. Neither vascular nor lymphatic vessels were present in the knee joint cartilaginous rudiments. The menisci in 12-week-old fetal knees were incompletely demarcated from the adjacent tibial and femoral cartilaginous rudiments which was consistent with the ongoing joint cavitation process at the femoral-tibial junction. At 14 weeks of age the menisci were independent structural entities; they contained a major central blood vessel containing red blood cells and numerous communicating vessels at the base of the menisci but no lymphatic vessels. In contrast to the 12-week-old menisci, the 14-week meniscal rudiments contained abundant CD-31 and CD-34 positive but no lymphatic vessels. Isolated 14-week-old meniscal cells also were stained with the CD-31 and CD 34 antibodies; CD-68 +ve cells, also abundant in the 14-week-old menisci, were detectable to a far lesser degree in the 12-week menisci and were totally absent from the femoral and tibial rudiments. The distribution of lymphatic vessels and tissue macrophages in the fetal joint tissues was consistent with their roles in the clearance of metabolic waste and extracellular matrix breakdown products arising from the rapidly remodelling knee joint tissues.

  10. Assessing lymphatic response to treatments in head and neck cancer using near-infrared fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Tan, I.-Chih; Karni, Ron J.; Rasmussen, John C.; Sevick-Muraca, Eva M.

    2014-05-01

    Care for head and neck (HN) cancer could be improved with better mapping of lymphatic drainage pathways in HN region as well as understanding the effect of the cancer treatments on lymphatics. In this study, near-infrared fluorescence imaging is being used to visualize the lymphatics in human subjects diagnosed with HN cancer before and after treatments. Imaging results show the lymphatic architecture and contractile function in HN. Reformation of lymphatics during the course of cancer care was also seen in the longitudinal imaging. This allows us to better understand the lymphatics in HN cancer patients.

  11. [Acute lymphatic leukaemia with eosinophilia in a younger man returning from a travel in the tropics--case report].

    PubMed

    Larsen, Mette Vang; Karstoft, Kristian; Andersen, Mette Klarskov

    2011-05-09

    A 22-year-old man presented with severe back pain and 60% eosinophilia after returning from the tropics. An extensive investigation for parasitic diseases was negative. Over time, his haemoglobin level and thrombocyte count fell, and the spleen and several lymph nodes were enlarged. The patient was diagnosed with acute lymphatic leukaemia with eosinophilia by bone marrow microscopy and flow cytometry. Chromosome analysis detected clonal abnormalities including t(5;14)(q31;q32). He initially responded to chemotherapy, but due to residual disease, he now awaits allogeneic bone marrow transplantation.

  12. New model of macrophage acquisition of the lymphatic endothelial phenotype.

    PubMed

    Hall, Kelly L; Volk-Draper, Lisa D; Flister, Michael J; Ran, Sophia

    2012-01-01

    Macrophage-derived lymphatic endothelial cell progenitors (M-LECPs) contribute to new lymphatic vessel formation, but the mechanisms regulating their differentiation, recruitment, and function are poorly understood. Detailed characterization of M-LECPs is limited by low frequency in vivo and lack of model systems allowing in-depth molecular analyses in vitro. Our goal was to establish a cell culture model to characterize inflammation-induced macrophage-to-LECP differentiation under controlled conditions. Time-course analysis of diaphragms from lipopolysaccharide (LPS)-treated mice revealed rapid mobilization of bone marrow-derived and peritoneal macrophages to the proximity of lymphatic vessels followed by widespread (∼50%) incorporation of M-LECPs into the inflamed lymphatic vasculature. A differentiation shift toward the lymphatic phenotype was found in three LPS-induced subsets of activated macrophages that were positive for VEGFR-3 and many other lymphatic-specific markers. VEGFR-3 was strongly elevated in the early stage of macrophage transition to LECPs but undetectable in M-LECPs prior to vascular integration. Similar transient pattern of VEGFR-3 expression was found in RAW264.7 macrophages activated by LPS in vitro. Activated RAW264.7 cells co-expressed VEGF-C that induced an autocrine signaling loop as indicated by VEGFR-3 phosphorylation inhibited by a soluble receptor. LPS-activated RAW264.7 macrophages also showed a 68% overlap with endogenous CD11b(+)/VEGFR-3(+) LECPs in the expression of lymphatic-specific genes. Moreover, when injected into LPS- but not saline-treated mice, GFP-tagged RAW264.7 cells massively infiltrated the inflamed diaphragm followed by integration into 18% of lymphatic vessels. We present a new model for macrophage-LECP differentiation based on LPS activation of cultured RAW264.7 cells. This system designated here as the "RAW model" mimics fundamental features of endogenous M-LECPs. Unlike native LECPs, this model is

  13. A model to measure lymphatic drainage from the eye.

    PubMed

    Kim, Minhui; Johnston, Miles G; Gupta, Neeru; Moore, Sara; Yücel, Yeni H

    2011-11-01

    Intraocular pressure (IOP) is the most important risk factor for glaucoma development and progression. Most anti-glaucoma treatments aim to lower IOP by enhancing aqueous humor drainage from the eye. Aqueous humor drainage occurs via well-characterized trabecular meshwork (TM) and uveoscleral (UVS) pathways, and recently described ciliary body lymphatics. The relative contribution of the lymphatic pathway to aqueous drainage is not known. We developed a sheep model to quantitatively assess lymphatic drainage along with TM and UVS outflows. This study describes that model and presents our initial findings. Following intracameral injection of (125)I-bovine serum albumin (BSA), lymph was continuously collected via cannulated cervical lymphatic vessels and the thoracic lymphatic duct over either a 3-h or 5-h time period. In the same animals, blood samples were collected from the right jugular vein every 15 min. Lymphatic and TM drainage were quantitatively assessed by measuring (125)I-BSA in lymph and plasma, respectively. Radioactive tracer levels were also measured in UVS and "other" ocular tissue, as well as periocular tissue harvested 3 and 5 h post-injection. Tracer recovered from UVS tissue was used to estimate UVS drainage. The amount of (125)I-BSA recovered from different fluid and tissue compartments was expressed as a percentage of total recovered tracer. Three hours after tracer injection, percentage of tracer recovered in lymph and plasma was 1.64% ± 0.89% and 68.86% ± 9.27%, respectively (n = 8). The percentage of tracer in UVS, other ocular and periocular tissues was 19.87% ± 5.59%, 4.30% ± 3.31% and 5.32% ± 2.46%, respectively. At 5 h (n = 2), lymphatic drainage was increased (6.40% and 4.96% vs. 1.64%). On the other hand, the percentage of tracer recovered from UVS and other ocular tissue had decreased, and the percentage from periocular tissue showed no change. Lymphatic drainage increased steadily over the 3 h post-injection period, while TM

  14. Lymphatic system: a prospective area for advanced targeting of particulate drug carriers.

    PubMed

    Singh, Indu; Swami, Rajan; Khan, Wahid; Sistla, Ramakrishna

    2014-02-01

    The lymphatic system has a critical role in the immune system's recognition and response to disease and it is an additional circulatory system throughout the entire body. Extensive multidisciplinary investigations have been carried out in the area of lymphatic delivery, and lymphatic targeting has attracted a lot of attention for providing preferential chemotherapy and improving bioavailability of drugs that undergo hepatic first-pass metabolism. This review focuses on progress in the field of lymphatic therapeutics and diagnosis. Moreover, the anatomy and physiology of the lymphatic system, particulate drug carriers and different physicochemical parameters of both modified and unmodified particulate drug carriers and their effect on lymphatic targeting are addressed. Particulate drug carriers have encouraged lymphatic targeting, but there are still challenges in targeting drugs and bioactives to specific sites, maintaining desired action and crossing all the physiological barriers. Lymphatic therapy using drug-encapsulated lipid carriers, especially liposomes and solid lipid nanoparticles, emerges as a new technology to provide better penetration into the lymphatics where residual disease exists. Size is the most important criteria when designing nanocarriers for targeting lymphatic vessels as the transportation of these particles into lymphatic vessels is size dependent. By increasing our understanding of lymphatic transport and uptake, and the role of lymphatics in various diseases, we can design new therapeutics for effective disease control.

  15. High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma.

    PubMed

    Seppälä, Miia; Pohjola, Konsta; Laranne, Jussi; Rautiainen, Markus; Huhtala, Heini; Renkonen, Risto; Lemström, Karl; Paavonen, Timo; Toppila-Salmi, Sanna

    2016-12-01

    Tongue cancer has a poor prognosis due to its early metastasis via lymphatic vessels. The present study aimed at evaluating lymphatic vessel density, relative density of lymphatic vessel, and diameter of lymphatic vessels and its predictive role in tongue cancer. Paraffin-embedded tongue and lymph node specimens (n = 113) were stained immunohistochemically with a polyclonal antibody von Willebrand factor, recognizing blood and lymphatic endothelium and with a monoclonal antibody podoplanin, recognizing lymphatic endothelium. The relative density of lymphatic vessels was counted by dividing the mean number of lymphatic vessels per microscopic field (podoplanin) by the mean number of all vessels (vWf) per microscopic field. The high relative density of lymphatic vessels (≥80 %) was associated with poor prognosis in tongue cancer. The relative density of lymphatic vessels predicted poor prognosis in the group of primary tumor size T1-T2 and in the group of non-metastatic cancer. The lymphatic vessel density and diameter of lymphatic vessels were not associated with tongue cancer survival. The relative density of lymphatic vessels might have clinically relevant prognostic impact. Further studies with increased number of patients are needed.

  16. Elimination of Lymphatic Filariasis in The Gambia

    PubMed Central

    Rebollo, Maria P.; Sambou, Sana Malang; Thomas, Brent; Biritwum, Nana-Kwadwo; Jaye, Momodou C.; Kelly-Hope, Louise; Escalada, Alba Gonzalez; Molyneux, David H.; Bockarie, Moses J.

    2015-01-01

    Background The prevalence of Wuchereria bancrofti, which causes lymphatic filariasis (LF) in The Gambia was among the highest in Africa in the 1950s. However, surveys conducted in 1975 and 1976 revealed a dramatic decline in LF endemicity in the absence of mass drug administration (MDA). The decline in prevalence was partly attributed to a significant reduction in mosquito density through the widespread use of insecticidal nets. Based on findings elsewhere that vector control alone can interrupt LF, we asked the question in 2013 whether the rapid scale up in the use of insecticidal nets in The Gambia had interrupted LF transmission. Methodology/Principal Finding We present here the results of three independently designed filariasis surveys conducted over a period of 17 years (1997–2013), and involving over 6000 subjects in 21 districts across all administrative divisions in The Gambia. An immunochromatographic (ICT) test was used to detect W. bancrofti antigen during all three surveys. In 2001, tests performed on stored samples collected between 1997 and 2000, in three divisions, failed to show positive individuals from two divisions that were previously highly endemic for LF, suggesting a decline towards extinction in some areas. Results of the second survey conducted in 2003 showed that LF was no longer endemic in 16 of 21 districts surveyed. The 2013 survey used a WHO recommended LF transmission verification tool involving 3180 6–7 year-olds attending 60 schools across the country. We demonstrated that transmission of W. bancrofti has been interrupted in all 21 districts. Conclusions We conclude that LF transmission may have been interrupted in The Gambia through the extensive use of insecticidal nets for malaria control for decades. The growing evidence for the impact of malaria vector control activities on parasite transmission has been endorsed by WHO through a position statement in 2011 on integrated vector management to control malaria and LF. PMID

  17. Structural and functional features of central nervous system lymphatic vessels.

    PubMed

    Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J; Eccles, Jacob D; Rouhani, Sherin J; Peske, J David; Derecki, Noel C; Castle, David; Mandell, James W; Lee, Kevin S; Harris, Tajie H; Kipnis, Jonathan

    2015-07-16

    One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

  18. Structural and functional features of central nervous system lymphatics

    PubMed Central

    Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J.; Eccles, Jacob D.; Rouhani, Sherin J.; Peske, J. David; Derecki, Noel C.; Castle, David; Mandell, James W.; Kevin, S. Lee; Harris, Tajie H.; Kipnis, Jonathan

    2015-01-01

    One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment1–3, the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood4–6. In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. PMID:26030524

  19. Is tuberculosis a lymphatic disease with a pulmonary portal?

    PubMed

    Behr, Marcel A; Waters, W Ray

    2014-03-01

    Tuberculosis most commonly presents as a pulmonary disease, in which infection, persistence, and induction of transmissible pathology all occur in the lungs. If viewed as a pulmonary disease, enlarged lymph nodes represent reactive adenitis, and extrapulmonary forms of tuberculosis (including lymphatic tuberculosis) are not transmissible, hence representing an evolutionary dead-end for the pathogen. In an alternative theory, Mycobacterium tuberculosis passes asymptomatically through the lungs and rapidly establishes a chronic lymphatic infection. After a period of weeks to decades secondary lung pathology develops, ultimately allowing transmission to occur. Evidence that supports this lymphatic model includes historical descriptions of human tuberculosis from the preantibiotic era, analogy with other mycobacterial infections, observations of tuberculosis in non-human hosts, and experimental models of tuberculosis disease. At a fundamental level, a lymphocentric model proposes that spread of organisms outside the lung parenchyma is essential to induce adaptive immunity, which is crucial for the generation of transmissible pathology. Furthermore, a lymphatic model could explain why the lesion associated with primary infection (Ghon focus) is anatomically separated from the most common site of reactivation disease (the apex). More practically, an alternative perspective that classes tuberculosis as a lymphatic disease might affect strategies for preclinical and clinical assessment of novel diagnostics, drugs, and vaccines.

  20. Immunomodulatory roles of lymphatic vessels in cancer progression.

    PubMed

    Swartz, Melody A

    2014-08-01

    Lymphatic vessels in the tumor microenvironment are known to foster tumor metastasis in many cancers, and they can undergo activation, hyperplasia, and lymphangiogenesis in the tumor microenvironment and in the tumor-draining lymph node. The mechanism underlying this correlation was originally considered as lymphatic vessels providing a physical route for tumor cell dissemination, but recent studies have highlighted new roles of the lymphatic endothelium in regulating host immunity. These include indirectly suppressing T-cell function by secreting immunosuppressive factors and inhibiting dendritic cell (DC) maturation, as well as directly driving T-cell tolerance by antigen presentation in the presence of inhibitory ligands. Furthermore, lymphatic endothelium scavenges and regulates transendothelial transport actively, controlling the sustained delivery of lymph-borne antigens from chronically inflamed tissues to draining lymph nodes where immature DCs, in the absence of danger signals, along with lymph node stromal cells present these antigens to T cells for maintenance of peripheral tolerance to self-antigens, a mechanism that may be hijacked by some tumors. This Masters of Immunology primer aims to present an overview of research in this area and highlight emerging evidence that suggests lymphatic vessels, and lymphangiogenesis, play important immunomodulatory roles in the tumor microenvironment. ©2014 American Association for Cancer Research.

  1. Anatomy and development of the cardiac lymphatic vasculature: Its role in injury and disease.

    PubMed

    Norman, Sophie; Riley, Paul R

    2016-04-01

    Lymphatic vessels are present throughout the entire body in all mammals and function to regulate tissue fluid balance, lipid transport and survey the immune system. Despite the presence of an extensive lymphatic plexus within the heart, until recently the importance of the cardiac lymphatic vasculature and its origins were unknown. Several studies have described the basic anatomy of the developing cardiac lymphatic vasculature and more recently the detailed development of the murine cardiac lymphatics has been documented, with important insight into their cellular sources during embryogenesis. In this review we initially describe the development of systemic lymphatic vasculature, to provide the background for a comparative description of the spatiotemporal development of the cardiac lymphatic vessels, including detail of both canonical, typically venous, and noncanonical (hemogenic endothelium) cellular sources. Subsequently, we address the response of the cardiac lymphatic network to myocardial infarction (heart attack) and the therapeutic potential of targeting cardiac lymphangiogenesis. © 2015 Wiley Periodicals, Inc.

  2. From sewer to saviour - targeting the lymphatic system to promote drug exposure and activity.

    PubMed

    Trevaskis, Natalie L; Kaminskas, Lisa M; Porter, Christopher J H

    2015-11-01

    The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy.

  3. Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature.

    PubMed

    Cha, Young Ryun; Fujita, Misato; Butler, Matthew; Isogai, Sumio; Kochhan, Eva; Siekmann, Arndt F; Weinstein, Brant M

    2012-04-17

    The lymphatic system is crucial for fluid homeostasis, immune responses, and numerous pathological processes. However, the molecular mechanisms responsible for establishing the anatomical form of the lymphatic vascular network remain largely unknown. Here, we show that chemokine signaling provides critical guidance cues directing early trunk lymphatic network assembly and patterning. The chemokine receptors Cxcr4a and Cxcr4b are expressed in lymphatic endothelium, whereas chemokine ligands Cxcl12a and Cxcl12b are expressed in adjacent tissues along which the developing lymphatics align. Loss- and gain-of-function studies in zebrafish demonstrate that chemokine signaling orchestrates the stepwise assembly of the trunk lymphatic network. In addition to providing evidence for a lymphatic vascular guidance mechanism, these results also suggest a molecular basis for the anatomical coalignment of lymphatic and blood vessels.

  4. Down-regulation of polycystin in lymphatic malformations: possible role in the proliferation of lymphatic endothelial cells.

    PubMed

    Ren, Jian-Gang; Xia, Hou-Fu; Yang, Jie-Gang; Zhu, Jun-Yi; Zhang, Wei; Chen, Gang; Zhao, Ji-Hong; Sun, Yan-Fang; Zhao, Yi-Fang

    2017-07-01

    Lymphatic malformations (LMs) are composed of aberrant lymphatic vessels and regarded as benign growths of the lymphatic system. Recent studies have demonstrated that the mutant embryos of PKD1 and PKD2, encoding polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively, result in aberrant lymphatic vessels similar to those observed in LMs. In this study, for the first time, we investigated PC-1 and PC-2 expression and assessed their roles in the development of LMs. Our results demonstrated that PC-1 and PC-2 gene and protein expressions were obviously decreased in LMs compared with normal skin tissues. In addition, the expression of phosphorylated ERK but not total ERK was up-regulated in LMs and negatively correlated with the expression of PC-1 and PC-2. Moreover, up-regulation of Ki67 was detected in LMs and positively correlated with ERK phosphorylation levels. Furthermore, cluster analysis better reflected close correlation between these signals. All of the above results provided strong evidence suggesting that the hyperactivation of the ERK pathway may be caused by down-regulation of PC-1 and PC-2 in LMs, contributing to increased proliferation of lymphatic endothelial cells in LMs. Our present study sheds light on novel potential mechanisms involved in LMs and may help to explore novel treatments for LMs. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. The Lymphatic Endothelial mCLCA1 Antibody Induces Proliferation and Growth of Lymph Node Lymphatic Sinuses

    PubMed Central

    Jordan-Williams, Kimberly L.; Ramanujam, Neela; Farr, Andrew G.

    2016-01-01

    Lymphocyte- and leukocyte-mediated lymph node (LN) lymphatic sinus growth (lymphangiogenesis) is involved in immune responses and in diseases including cancer and arthritis. We previously discovered a 10.1.1 Ab that recognizes the lymphatic endothelial cell (LEC) surface protein mCLCA1, which is an interacting partner for LFA1 and Mac-1 that mediates lymphocyte adhesion to LECs. Here, we show that 10.1.1 Ab treatment specifically induces LEC proliferation, and influences migration and adhesion in vitro. Functional testing by injection of mice with 10.1.1 Ab but not control hamster Abs identified rapid induction of LN LEC proliferation and extensive lymphangiogenesis within 23 h. BrdU pulse-chase analysis demonstrated incorporation of proliferating LYVE-1-positive LEC into the growing medullary lymphatic sinuses. The 10.1.1 Ab-induced LN remodeling involved coordinate increases in LECs and also blood endothelial cells, fibroblastic reticular cells, and double negative stroma, as is observed during the LN response to inflammation. 10.1.1 Ab-induced lymphangiogenesis was restricted to LNs, as mCLCA1-expressing lymphatic vessels of the jejunum and dermis were unaffected by 23 h 10.1.1 Ab treatment. These findings demonstrate that 10.1.1 Ab rapidly and specifically induces proliferation and growth of LN lymphatic sinuses and stroma, suggesting a key role of mCLCA1 in coordinating LN remodeling during immune responses. PMID:27224029

  6. Mechanosensitive β-catenin signaling regulates lymphatic vascular development

    PubMed Central

    Cha, Boksik; Srinivasan, R. Sathish

    2016-01-01

    The Wnt/β-catenin signaling is an evolutionarily conserved pathway that plays a pivotal role in embryonic development and adult homeostasis. However, we have limited information about the involvement of Wnt/β-catenin signaling in the lymphatic vascular system that regulates fluid homeostasis by absorbing interstitial fluid and returning it to blood circulation. In this recent publication we report that canonical Wnt/β-catenin signaling is highly active and critical for the formation of lymphovenus valves (LVVs) and lymphatic valves (LVs). β-catenin directly associates with the regulatory elements of the lymphedema-associated transcription factor, FOXC2 and activates its expression in an oscillatory shear stress (OSS)-dependent manner. The phenotype of β-catenin null embryos was rescued by FOXC2 overexpression. These results suggest that Wnt/β-catenin signaling is a mechanotransducer that links fluid force with lymphatic vascular development. [BMB Reports 2016; 49(8): 403-404] PMID:27418286

  7. Search for lymphatic drainage of the monkey orbit

    SciTech Connect

    McGetrick, J.J.; Wilson, D.G.; Dortzbach, R.K.; Kaufman, P.L.; Lemke, B.N.

    1989-02-01

    Colloid solutions of technetium Tc-99m and india ink injected into the retrobulbar space of the cynomolgus monkey outside the extraocular muscle cone were removed from the orbit by the lymphatic vessels of the conjunctiva and eyelids and were then concentrated within the lymph nodes that drained the conjunctival and eyelid areas. Colloid solutions injected into the retrobulbar space inside the extraocular muscle cone did not reach the conjunctiva and did not collect in any lymph nodes over a 24-hour period. Within the orbit, the injected colloids spread along the planes of the connective-tissue septa. No lymphatic vessels were identified within the orbits posterior to the conjunctiva. Small amounts of india ink left the posterior orbit and ultimately entered the contralateral orbit. This posterior pathway did not lead to lymphatic vessels or lymph nodes and therefore does not appear to represent a prelymphatic pathway.

  8. ACKR2: An Atypical Chemokine Receptor Regulating Lymphatic Biology

    PubMed Central

    Bonavita, Ornella; Mollica Poeta, Valeria; Setten, Elisa; Massara, Matteo; Bonecchi, Raffaella

    2017-01-01

    The lymphatic system plays an important role in the induction of the immune response by transporting antigens, inflammatory mediators, and leukocytes from peripheral tissues to draining lymph nodes. It is emerging that lymphatic endothelial cells (LECs) are playing an active role in this context via the expression of chemokines, inflammatory mediators promoting cell migration, and chemokine receptors. Particularly, LECs express atypical chemokine receptors (ACKRs), which are unable to promote conventional signaling and cell migration while they are involved in the regulation of chemokine availability. Here, we provide a summary of the data on the role of ACKR2 expressed by lymphatics, indicating an essential role for this ACKRs in the regulation of the inflammation and the immune response in different pathological conditions, including infection, allergy, and cancer. PMID:28123388

  9. Lymphatic vessels of the human dental pulp in different conditions.

    PubMed

    Marchetti, C; Poggi, P; Calligaro, A; Casasco, A

    1992-09-01

    The characteristics of the lymphatic vessel endothelial wall have been investigated in human normal and inflamed dental pulps. In normal pulps the endothelial wall is characterized by the presence of micropinocytotic vesicles and intraparietal channels. In the inflamed pulpal tissue, where an increase in interstitial fluid pressure occurs, the distended endothelial wall presents open junctions between endothelial cells and the openings of the intraparietal channels. Moreover the micropinocytotic vesicles disappear. The cytoplasm of the endothelial cells is characterized by the presence of numerous Weibel-Palade bodies, which increase in number in the dilated vessels. In the fibrillar apparatus surrounding the lymphatic vessel wall collagen fibrils are the prevalent component, while elastic fibers are not present. The different morphological properties of the lymphatic vessels are compared and discussed with regard to the variation of the functional conditions of the tissue.

  10. Identification of tumour-reactive lymphatic endothelial cells capable of inducing progression of gastric cancer

    PubMed Central

    Tokumoto, Mao Watanabe; Tanaka, Hiroaki; Tauchi, Yukie; Kasashima, Hiroaki; Kurata, Kento; Yashiro, Masakazu; Sakurai, Katsunobu; Toyokawa, Takahiro; Kubo, Naoshi; Amano, Ryosuke; Kimura, Kenjiro; Muguruma, Kazuya; Maeda, Kiyoshi; Ohira, Masaichi; Hirakawa, Kosei

    2015-01-01

    Background: Tumour cells and stromal cells interact in the tumour microenvironment; moreover, stromal cells can acquire abnormalities that contribute to tumour progression. However, interactions between lymphatic endothelial cells (LECs) and tumour cells are largely unexamined. In this study, we aimed to determine whether tumour-specific LECs inhabit the tumour microenvironment and examine their influence on this microenvironment. Methods: We isolated normal LECs (NLECs) from a non-metastatic lymph node and tumour-associated LECs (TLECs) from cancerous lymph nodes. We examined proliferative and migratory potency, growth factor production, and gene expression of each type of LEC. Moreover, we developed a co-culture system to investigate the interactions between gastric cancer cells and LECs. Results: When compared with NLEC, TLECs had an abnormal shape, high proliferative and migratory abilities, and elevated expression of genes associated with inflammation, cell growth, and cell migration. NLECs co-cultured with gastric cancer cells from the OCUM12 cell line acquired TLEC-like phenotypes. Also, OCUM12 cells co-cultured with TLECs expressed high levels of genes responsible for metastasis. Conclusions: Our results demonstrated that LECs interacted with tumour cells and obtained abnormal phenotypes that could have important roles in tumour progression. PMID:26355233

  11. Topography of Lymphatic Markers in Human Iris and Ciliary Body.

    PubMed

    Kaser-Eichberger, Alexandra; Schrödl, Falk; Trost, Andrea; Strohmaier, Clemens; Bogner, Barbara; Runge, Christian; Motloch, Karolina; Bruckner, Daniela; Laimer, Martin; Schlereth, Simona L; Heindl, Ludwig M; Reitsamer, Herbert A

    2015-07-01

    Reports of lymphatics in the anterior human uvea are contradictory. This might be caused due to a certain topography, which has not been considered yet. Therefore, here we systematically analyze iris and adjacent ciliary body with immunohistochemistry by combining various lymphatic markers. Human iris and ciliary body were obtained from cornea donors and prepared for cryosectioning. Cross sections of tissue blocks at 12/3/6/9 o'clock position and at corresponding intersections (1:30/4:30/7:30/10:30) were processed for immunohistochemistry of LYVE-1, PDPN, PROX1, FOXC2, VEGFR3, and CCL21, and when necessary, these lymphatic markers were combined with CD31, α-smooth muscle-actin, CD68, and 4',6-diamidino-2 phenylindole dihydrochloride (DAPI). Double, triple, and quadruple marker combinations were documented using confocal microscopy. Numerous podoplanin+ cells were mainly located at the anterior border of the iris while LYVE-1+ cells were distributed throughout the nonpigmented part. Both cell populations were PROX1/FOXC2/CCL21/VEGFR3-. Blood vessels, iris smooth muscles, and individual cells were VEGFR3+. While PDPN+ cells were rarely detected posteriorly of the iris root, many LYVE-1+ cells were present within the ciliary body muscle and villi. Within the muscle, occasionally PDPN+ vessel-like structures were detectable, but these were never colocalized with LYVE-1. Similar vessel-like structures were VEGFR3+/PROX1-/CCL21-, but CD31+. Further, ciliary muscle fibers and ciliary epithelium were immunoreactive for VEGFR3/CCL21, but were LYVE-1/PDPN-. A certain topography of structures at the various uvea-positions investigated was not obvious. The majority of LYVE-1+ cells displayed immunoreactivity for CD68. Lymphatic vessels colocalizing for at least two lymphatic markers were not detectable. Therefore, if present, putative lymphatic channels of the anterior uvea might display a different marker panel than generally presumed.

  12. Synthesis of a novel polyamidoamine dendrimer conjugating with alkali blue as a lymphatic tracer and study on the lymphatic targeting in vivo.

    PubMed

    Yang, Rui; Xia, Suxia; Ye, Tiantian; Yao, Jianhua; Zhang, Ruizhi; Wang, Shujun; Wang, Siling

    2016-09-01

    In this study, a novel lymphatic tracer polyamidoamin-alkali blue (PAMAM-AB) was synthesized in order to evaluate the intra-lymphatic targeting ability and lymphatic tropism of PAMAM-AB after subcutaneous administration. UV-Vis, FT-IR, NMR and HPLC characterization were performed to prove the successful synthesis of PAMAM-AB. The calculated AB payload of PAMAM-AB conjugate was seven per dendrimer molecule (27.16% by weight). Hydrolysis stability of PAMAM-AB in vitro was evaluated, which was stable in PBS and human plasma. Lymphatic tracing were studied to determine the blue-stained intensity of PAMAM-AB in right popliteral lymph nodes (PLNs), iliac lymph nodes (ILNs) and para-aortic lymph nodes (PALNs) after subcutaneous administration. The pharmacokinetics and biodistribution of PAMAM-AB in mice were investigated. PLNs, ILNs and PALNs could be obviously blue-stained within 10 min after PAMAM-AB administration, and displayed a more rapid lymphatic absorption, a higher AUC value in lymph nodes and a longer lymph nodes residence time compared with methylene blue solution (MB-S), MB water-in-oil microemulsion (MB-ME), MB multiple microemulsion (MB-MME). Enhanced lymphatic drainage from the injection site and uptake into lymph of PAMAM-AB indicated that PAMAM-AB possesses the double function of lymphatic tracing and lymphatic targeting, and suggested the potential for the development of lymphatic targeting vectors or as a lymphatic tracer in its own right.

  13. Lack of functioning intratumoral lymphatics in colon and pancreas cancer tissue.

    PubMed

    Olszewski, Waldemar L; Stanczyk, Marek; Gewartowska, Magdalena; Domaszewska-Szostek, Anna; Durlik, Marek

    2012-09-01

    There are controversial views as to whether intratumoral or peritumoral lymphatics play a dominant role in the metastatic process. Most clinical observations originate from studies of colon cancer. Colon contains mucosa and submucosa rich in lymphatics and with high lymph formation rate. This seems to be a prerequisite for easy metastasis of cancer cells to regional lymph nodes. However, there are other tissues as pancreas with a rudimentary lymphatic network where cancer metastasis formation is as intensive as in colon cancer. This contradicts the common notion that intratumor lymphatics play major role in metastases. We visualized interstitial space and lymphatics in the central and peripheral regions of colon and pancreas tumors using the color stereoscopic lymphography and simultaneously immunohistochemical performed stainings specific for lymphatic and blood endothelial cells. The density of open and compressed lymphatic and blood vessels was measured in the tumor core and edge. There were very few lymphatics in the colon and pancreas tumor core but numerous minor fluid "lakes" with no visible connection to the peritumoral lymphatics. Lining of "lakes" did not express molecular markers specific for lymphatic endothelial cells. Dense connective tissue surrounding tumor foci did not contain lymphatics. Peritumoral lymphatics were irregularly distributed in both types of tumor and only sporadically contained cells that might be tumor cells. Similar lymphoscintigraphic and histological pictures were seen in colon and pancreas cancer despite of different structure of both tissues. This suggests a uniform reaction of tissues to the growing cancer irrespective of the affected organ.

  14. 38 CFR 4.117 - Schedule of ratings-hemic and lymphatic systems.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... and lymphatic systems. 4.117 Section 4.117 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Hemic and Lymphatic Systems § 4.117 Schedule of ratings—hemic and lymphatic systems. Rating 7700Anemia, hypochromic-microcytic...

  15. 38 CFR 4.117 - Schedule of ratings-hemic and lymphatic systems.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... and lymphatic systems. 4.117 Section 4.117 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Hemic and Lymphatic Systems § 4.117 Schedule of ratings—hemic and lymphatic systems. Rating 7700Anemia, hypochromic-microcytic...

  16. 38 CFR 4.117 - Schedule of ratings-hemic and lymphatic systems.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... and lymphatic systems. 4.117 Section 4.117 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Hemic and Lymphatic Systems § 4.117 Schedule of ratings—hemic and lymphatic systems. Rating 7700Anemia, hypochromic-microcytic...

  17. 38 CFR 4.117 - Schedule of ratings-hemic and lymphatic systems.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... and lymphatic systems. 4.117 Section 4.117 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Hemic and Lymphatic Systems § 4.117 Schedule of ratings—hemic and lymphatic systems. Rating 7700Anemia, hypochromic-microcytic...

  18. 38 CFR 4.117 - Schedule of ratings-hemic and lymphatic systems.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... and lymphatic systems. 4.117 Section 4.117 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Hemic and Lymphatic Systems § 4.117 Schedule of ratings—hemic and lymphatic systems. Rating 7700Anemia, hypochromic-microcytic...

  19. Immunocytochemical localization of lymphatic and venous vessels in colonic polyps and adenomas.

    PubMed

    Tomita, Tatsuo

    2008-07-01

    Histopathological localization of lymphatic vessels has been hindered because of a lack of suitable immunocytochemical markers for lymphatic vessels. Using lymphatic vessels endothelial hyaluronan receptor-1 (LYVE-1) immunocytochemical staining, hyperplastic polyps, tubular adenomas to villous adenomas, were investigated for lymphatic vessels compared with immunostained blood vessels using factor-8. Four cases each of hyperplastic polyps, tubular adenomas to villous adenomas, were routinely fixed in formalin and embedded in paraffin and were immunostained using goat anti-LYVE-1 for lymphatic vessels and rabbit anti-factor-8 for blood vessels. In normal colon and hyperplastic polyps, slender lymphatic vessels were noted in muscularis mucosa, which spread into the base of colonic crypt, whereas round venous vessels, they extend into lamina propria. In tubular adenomas, small lymphatic and venous vessels were noted in broad fibrous stalks. In villous adenomas, smaller lymphatic and venous vessels were noted in fine intervillous stroma. In normal colon and hyperplastic polyps, slender, irregularly shaped lymphatic vessels were present in muscularis mucosa, spreading into the base of the colonic crypt. In tubular adenomas, small lymphatic and venous vessels were noted in fibrous stalks. In villous adenomas, smaller lymphatic and venous vessels were noted in intervillous stroma. There are no increased lymphatic and venous vessels in intermucosal stroma and stalks of adenomas compared with normal colon.

  20. MR lymphangiography for the assessment of the lymphatic system in patients undergoing microsurgical reconstructions of lymphatic vessels.

    PubMed

    Lohrmann, Christian; Felmerer, Gunther; Foeldi, Etelka; Bartholomä, J-P; Langer, Mathias

    2008-05-01

    To assess the morphology of the lymphatic system pre- and postoperatively in patients undergoing microsurgical reconstructions of the lymphatic vessels. 8 lower extremities in 4 consecutive patients with secondary unilateral lymphedema of the lower extremities were examined by MR lymphangiography. 18 mL of gadoteridol and 1 mL of mepivacainhydrochloride 1% were subdivided into 10 portions and injected intracutaneously into the dorsal aspect of each foot at the region of the four interdigital webs and medial to the first proximal phalanx. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For MR lymphangiography a 3D-spoiled gradient-echo sequence was used. For evaluation of the lymphedema a heavily T2-weighted 3D-TSE sequence was performed. In 2 patients the 3D-TSE sequence demonstrated a decrease of the epifascial lymphedema in the postoperative acquisitions, whereby MR lymphangiography displayed an improvement of dermal-back areas and collateral lymphatic vessels. In one patient the epifascial lymphedema of the lower extremity decreased, whereas the diameter of the lymphatic vessels showed a constant diameter of 2 mm. In one patient with a lymphocutaneous fistula at the level of the right groin, the feeding lymphatic vessels and contrast media extravasation could clearly be visualized. The 3D-TSE sequence demonstrated an epi- as well as subfascial lymphedema of the right leg. MR lymphangiography is a safe and accurate diagnostic imaging method for the pre- and postoperative evaluation of the lymphatic circulation in patients undergoing microlymphatic surgery. Due to the minimal-invasiveness and lack of radiation, diagnostic follow-up MR lymphangiography examinations can be performed routinely and with no risk for the patient.

  1. Relationship between high density of peritumoral lymphatic vessels and biological behavior of cervical cancer.

    PubMed

    En-Lin, Song; Wei-Wei, Yu; Xiao-Liang, Xiong; Juan, Xu

    2012-10-01

    To investigate the relationship between lymphangiogenesis and lymphatic metastasis in cervical squamous carcinoma. Eighty cases of invasive cervical squamous cancer were selected as objects of our study. Double immunohistochemical staining with antibodies against lymphatic vessel endothelial hyaluronan receptor 1 and Ki-67 was used to label the lymphatic vessels and mark the proliferative lymphatic vessels in cervical squamous cancer. The peritumoral lymphatic vessel density and intratumoral lymphatic vessel density was assessed. The lymphatic vessels proliferation index was evaluated by calculating Ki-67 proliferation index (PI) to reflect the lymphangiogenesis of cervical squamous cancer. Then the correlation between lymphangiogenesis and clinicopathologic features of cervical squamous cancer was analyzed. The LVD of cervical cancer (15.23 ± 3.6) was clearly higher than that of the adjacent normal cervical subepithelial tissues (9.9 ± 2.5, P < 0.001). The peritumoral lymphatic vessel density of cervical cancer (18.75 ± 4.3) was significantly higher than the intratumoral lymphatic vessel density of cervical cancer (11.71 ± 4.9, P < 0.001). Lymphatic PI (LPI) of cervical cancer (0.258 ± 0.07) was higher than that of the adjacent normal cervical subepithelial tissues (0.068 ± 0.08, P < 0.001). The peritumoral lymphatic vessel PI of cervical cancer (0.324 ± 0.06) was notably higher than the intratumoral lymphatic vessel PI of cervical cancer (0.232 ± 0.06, P < 0.001). Peritumoral lymphatic vessel density and peritumoral lymphatic vessel were clearly associated with the lymph node metastasis (P = 0.001 and P = 0.002, respectively) and lymphovascular space invasion (P = 0.024 and P = 0.01, respectively). The high density of peritumoral lymphatic vessels is a potential predictor of more aggressive phenotype of cervical squamous cancer.

  2. Assessment of The Lymphatic System of the Genitalia Using Magnetic Resonance Lymphography Before and After Treatment of Male Genital Lymphedema

    PubMed Central

    Lu, Qing; Jiang, Zhaohua; Zhao, Zizhou; Wu, Lianming; Wu, Guangyu; Suo, Shiteng; Xu, Jianrong

    2016-01-01

    Abstract Treatment for chronic male genital lymphedema (GL) is limited. No standard treatment or validated instrument to assess GL is available. The aim of this study was to explore whether magnetic resonance lymphography (MRL) could be used to assess GL, select proper treatment for patients, and monitor postoperative progress. This is a retrospective analysis of a prospectively acquired cohort of men with GL presenting for MRL over a 7-year period. Thirty-six of 47 eligible men were included. All men were offered preoperative and postoperative MRL and assigned a morphology and function classification. Men with mild, moderate, and severe nodal dysfunction underwent complex decongestive physiotherapy (CDP), lymphoveneous microsurgery, and surgical excision, respectively. The volume reductions in the genitalia of patients with mild and moderate nodal dysfunction were recorded and compared using Student t test. The abnormal superficial and deep lymphatic vessels in the lymphedematous genitalia were detected by MRL, and inguinal lymph node dysfunction was classified by MRL. Seven patients with mild dysfunction who underwent CDP showed a more significant mean volume reduction in the genitalia than did 9 patients with moderate dysfunction. Three patients with hyperplasia and moderate dysfunction who underwent microsurgical operations and 17 patients with hypoplasia and moderate or severe nodal dysfunction who underwent surgical excision had excellent cosmetic results with no lymphedema at the 3- to 5-year follow-up. MRL can be used to assess morphological and functional lymphatic abnormalities in GL, preoperatively select appropriate treatment, and postoperatively evaluate treatment outcomes. PMID:27227943

  3. The Socioeconomic Impact of Lymphatic Filariasis in Tropical Countries

    ERIC Educational Resources Information Center

    Nwoke, Bertram Ekejiuba Bright; Nwoke, Eunice Anyalewechi; Dozie, Ikechukwu Nosike Simplicius

    2007-01-01

    Lymphatic filariasis (LF) is an endemic parasitic disease and a major cause of acute and chronic morbidity and incapacitation with devastating public health and socio-economic consequences. It exacerbates poor conditions of afflicted persons and endemic communities through reduced or lost labour supply and productivity. Stigmatisation and…

  4. Lymphatic mapping and sentinel node location with magnetite nanoparticles

    NASA Astrophysics Data System (ADS)

    Jung, Chu W.; Rogers, James M.; Groman, Ernest V.

    1999-04-01

    Subcutaneously administered magnetite nanoparticles were used to locate sentinel lymph nodes in normal rats. Nanoparticles sequestered in brachial and axillary lymph nodes produced magnetic susceptibility artifacts in gradient recall echo magnetic resonance images. The artifact sizes enabled the determination of nanoparticle nodal uptake rates and lymphatic drainage patterns. These studies were confirmed by use of 59Fe labeled magnetite nanoparticles.

  5. Antifilarial compounds in the treatment and control of lymphatic filariasis.

    PubMed

    Mak, J W

    2004-12-01

    Diethylcarbamazine citrate (DEC) has been used for treatment and control of lymphatic filariasis since the 1950s. Although this remarkable drug is still useful and modified strategies in its usage have been developed, a number of newer antifilarial compounds are now available. Numerous field trials evaluating their efficacy in the control of lymphatic filariasis have been conducted. In particular, ivermectin (IVM), albendazole (ALB), and DEC have been tested singly and in combinations and the results of such field studies should be evaluated. While most of the studies were based on efficacy in the clearance of microfilaraemia, a few clinical trials evaluated the adulticidal activity of these compounds. Some antibiotics are effective in killing Wolbachia bacteria symbionts of filarial worms, but their role in the chemotherapy of lymphatic filariasis is still undefined. This review of randomised controlled field studies and randomised controlled clinical trials with these compounds will summarise the findings and give recommendations on their appropriate use for the control and treatment of lymphatic filariasis.

  6. Lymphatic vessels in the development of tissue and organ rejection.

    PubMed

    Hos, Deniz; Cursiefen, Claus

    2014-01-01

    The lymphatic vascular system-amongst other tasks-is critically involved in the regulation of adaptive immune responses as it provides an important route for APC trafficking to secondary lymphatic organs. In this context, the cornea, which is the transparent and physiologically avascular "windscreen" of the eye, has served as an excellent in vivo model to study the role of the blood and lymphatic vasculature in mediating allogenic immune responses after transplantation. Especially the mouse model of high-risk corneal transplantation, where corneal avascularity is abolished by a severe inflammatory stimulus prior to keratoplasty, allows for comparison to other transplantations performed in primarily vascularized tissues and solid organs. Using this model, we recently demonstrated that especially lymphatic vessels, but not blood vessels, define the high-risk status of vascularized corneas and that anti(lymph)angiogenic treatment significantly promotes corneal allograft survival. Since evidence for lymphangiogenesis and its potential association with graft rejection is nowadays also present in solid organ transplantation, studies are currently addressing the potential benefits of anti(lymph)angiogenic treatment as a novel therapeutic concept also in solid organ grafting with promising initial results.

  7. Utility of a microwave surgical instrument in sealing lymphatic vessels.

    PubMed

    Takebayashi, Katsushi; Shiomi, Hisanori; Naka, Shigeyuki; Murayama, Hiroyuki; Murakami, Koichiro; Akabori, Hiroya; Yamaguchi, Tsuyoshi; Shimizu, Tomoharu; Murata, Satoshi; Yamamoto, Hiroshi; Kurumi, Yoshimasa; Tani, Tohru

    2013-08-01

    This study assessed the ability of a novel microwave coagulation surgical instrument (MWCX) to seal lymphatic vessels when compared with LigaSure (Valleylab, Boulder, CO), the Harmonic Scalpel (HS; Ethicon Endo-Surgery, Cincinnati, OH), and electric cautery. The burst pressure of pig inguinal lymphatic vessels was assessed after the sealing of vessels with each surgical instrument. The rate of lymphorrhea from pig mesenteric lymphatic vessels was also investigated using indocyanine green and visualized with the Photodynamic Eye system (Hamamatsu Hotoniks, Hamamatsu, Japan). Burst pressures were higher with MWCX (average, 300 mm Hg), LigaSure (average, 290 mm Hg), and HS (average, 253 mm Hg) when compared with electric cautery (average, 152.3 mm Hg; vs MWCX: P = .002, vs LigaSure: P = .002, vs HS: P = .004). The rate of lymphorrhea was significantly lower with LigaSure (13.3%), HS (18.8%), and MWCX (13.3%) when compared with electric cautery (77.3%; vs LigaSure: P < .001, vs HS: P < .001, vs MWCX: P < .001). MWCX was equivalent to LigaSure and HS in terms of the ability to seal lymphatic vessels. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. The Socioeconomic Impact of Lymphatic Filariasis in Tropical Countries

    ERIC Educational Resources Information Center

    Nwoke, Bertram Ekejiuba Bright; Nwoke, Eunice Anyalewechi; Dozie, Ikechukwu Nosike Simplicius

    2007-01-01

    Lymphatic filariasis (LF) is an endemic parasitic disease and a major cause of acute and chronic morbidity and incapacitation with devastating public health and socio-economic consequences. It exacerbates poor conditions of afflicted persons and endemic communities through reduced or lost labour supply and productivity. Stigmatisation and…

  9. Integrated morbidity management for lymphatic filariasis and podoconiosis, Ethiopia.

    PubMed

    Deribe, Kebede; Kebede, Biruck; Tamiru, Mossie; Mengistu, Belete; Kebede, Fikreab; Martindale, Sarah; Sime, Heven; Mulugeta, Abate; Kebede, Biruk; Sileshi, Mesfin; Mengiste, Asrat; McPherson, Scott; Fentaye, Amha

    2017-09-01

    Lymphatic filariasis and podoconiosis are the major causes of tropical lymphoedema in Ethiopia. The diseases require a similar provision of care, but until recently the Ethiopian health system did not integrate the morbidity management. To establish health-care services for integrated lymphoedema morbidity management, the health ministry and partners used existing governmental structures. Integrated disease mapping was done in 659 out of the 817 districts, to identify endemic districts. To inform resource allocation, trained health extension workers carried out integrated disease burden assessments in 56 districts with a high clinical burden. To ensure standard provision of care, the health ministry developed an integrated lymphatic filariasis and podoconiosis morbidity management guideline, containing a treatment algorithm and a defined package of care. Experienced professionals on lymphoedema management trained government-employed health workers on integrated morbidity management. To monitor the integration, an indicator on the number of lymphoedema-treated patients was included in the national health management information system. In 2014, only 24% (87) of the 363 health facilities surveyed provided lymphatic filariasis services, while 12% (44) provided podoconiosis services. To date, 542 health workers from 53 health centres in 24 districts have been trained on integrated morbidity management. Between July 2013 and June 2016, the national health management information system has recorded 46 487 treated patients from 189 districts. In Ethiopia, an integrated approach for lymphatic filariasis and podoconiosis morbidity management was feasible. The processes used could be applicable in other settings where these diseases are co-endemic.

  10. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-β1-mediated tissue fibrosis

    PubMed Central

    Avraham, Tomer; Yan, Alan; Zampell, Jamie C.; Daluvoy, Sanjay V.; Haimovitz-Friedman, Adriana; Cordeiro, Andrew P.

    2010-01-01

    Although radiation therapy is a major risk factor for the development of lymphedema following lymphadenectomy, the mechanisms responsible for this effect remain unknown. The purpose of this study was therefore to determine the effects of radiation on lymphatic endothelial cells (LECs) and lymphatic function. The tails of wild-type or acid sphingomyelinase (ASM)-deficient mice were treated with 0, 15, or 30 Gy of radiation and then analyzed for LEC apoptosis and lymphatic function at various time points. To analyze the effects of radiation fibrosis on lymphatic function, we determined the effects of transforming growth factor (TGF)-β1 blockade after radiation in vivo. Finally, we determined the effects of radiation and exogenous TGF-β1 on LECs in vitro. Radiation caused mild edema that resolved after 12–24 wk. Interestingly, despite resolution of tail edema, irradiated animals displayed persistent lymphatic dysfunction. Radiation caused loss of capillary lymphatics and was associated with a dose-dependent increase in LEC apoptosis. ASM−/− mice had significantly less LEC apoptosis; however, this finding did not translate to improved lymphatic function at later time points. Short-term blockade of TGF-β1 function after radiation markedly decreased tissue fibrosis and significantly improved lymphatic function but did not alter LEC apoptosis. Radiation therapy decreases lymphatic reserve by causing depletion of lymphatic vessels and LECs as well as promoting soft tissue fibrosis. Short-term inhibition of TGF-β1 activity following radiation improves lymphatic function and is associated with decreased soft tissue fibrosis. ASM deficiency confers LEC protection from radiation-induced apoptosis but does not prevent lymphatic dysfunction. PMID:20519446

  11. Monoclonal Antibodies in the Lymphatics: Selective Delivery to Lymph Node Metastases of a Solid Tumor

    NASA Astrophysics Data System (ADS)

    Weinstein, John N.; Steller, Michael A.; Keenan, Andrew M.; Covell, David G.; Key, Marc E.; Sieber, Susan M.; Oldham, Robert K.; Hwang, Kou M.; Parker, Robert J.

    1983-10-01

    After subcutaneous injection, monoclonal antibodies directed against a tumor can enter local lymphatic vessels, pass to the draining lymph nodes, and bind to metastases there. Lymphatic delivery of antibody to early metastases is more efficient than intravenous administration, and the lymphatic route can be used to image smaller metastatic deposits. Perhaps more important, the lymphatic route minimizes binding of antibodies to circulating tumor antigens and to cross-reactive antigens present on normal tissues. Antibodies inappropriate for intravenous use because of binding to normal tissues may therefore be useful against lymph node metastases when injected subcutaneously or directly into lymphatic vessels.

  12. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development.

    PubMed

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-07-01

    Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).

  13. Intestinal and peri-tumoral lymphatic endothelial cells are resistant to radiation-induced apoptosis

    SciTech Connect

    Sung, Hoon Ki; Morisada, Tohru; Cho, Chung-Hyun; Oike, Yuichi; Lee, Jayhun; Sung, Eon Ki; Chung, Jae Hoon; Suda, Toshio; Koh, Gou Young . E-mail: gykoh@kaist.ac.kr

    2006-06-30

    Radiation therapy is a widely used cancer treatment, but it is unable to completely block cancer metastasis. The lymphatic vasculature serves as the primary route for metastatic spread, but little is known about how lymphatic endothelial cells respond to radiation. Here, we show that lymphatic endothelial cells in the small intestine and peri-tumor areas are highly resistant to radiation injury, while blood vessel endothelial cells in the small intestine are relatively sensitive. Our results suggest the need for alternative therapeutic modalities that can block lymphatic endothelial cell survival, and thus disrupt the integrity of lymphatic vessels in peri-tumor areas.

  14. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

    PubMed Central

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W.; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-01-01

    ABSTRACT Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT). PMID:27622039

  15. [THE STRUCTURE OF LYMPHATIC CAPILLARIES OF THE CILIARY BODY OF THE HUMAN EYE].

    PubMed

    Borodin, Yu I; Bgatova, N P; Chernykh, V V; Trunov, A N; Pozhidayeva, A A; Konenkov, V I

    2015-01-01

    Using light microscopy, immunohistochemistry and electron microscopy, the structural organization of interstitial spaces and vessels of the ciliary body of the human eye (n = 5) were studied. The ciliary body was found to contain wide interstitial spaces--tissue clefts bound by collagen fibers and fibroblasts. Organ-specific lymphatic capillaries were also demonstrated in the ciliary body. According to the present findings and the lymphatic region concept, the first 2 elements of the lymphatic region of the eye were described: tissue clefts--prelymphatics and lymphatic capillaries of the ciliary body. The third element of the lymphatic region are the lymph nodes of the head and neck.

  16. Expression of Lymphatic Markers in the Adult Rat Spinal Cord.

    PubMed

    Kaser-Eichberger, Alexandra; Schroedl, Falk; Bieler, Lara; Trost, Andrea; Bogner, Barbara; Runge, Christian; Tempfer, Herbert; Zaunmair, Pia; Kreutzer, Christina; Traweger, Andreas; Reitsamer, Herbert A; Couillard-Despres, Sebastien

    2016-01-01

    Under physiological conditions, lymphatic vessels are thought to be absent from the central nervous system (CNS), although they are widely distributed within the rest of the body. Recent work in the eye, i.e., another organ regarded as alymphatic, revealed numerous cells expressing lymphatic markers. As the latter can be involved in the response to pathological conditions, we addressed the presence of cells expressing lymphatic markers within the spinal cord by immunohistochemistry. Spinal cord of young adult Fisher rats was scrutinized for the co-expression of the lymphatic markers PROX1 and LYVE-1 with the cell type markers Iba1, CD68, PGP9.5, OLIG2. Rat skin served as positive control for the lymphatic markers. PROX1-immunoreactivity was detected in many nuclei throughout the spinal cord white and gray matter. These nuclei showed no association with LYVE-1. Expression of LYVE-1 could only be detected in cells at the spinal cord surface and in cells closely associated with blood vessels. These cells were found to co-express Iba1, a macrophage and microglia marker. Further, double labeling experiments using CD68, another marker found in microglia and macrophages, also displayed co-localization in the Iba1+ cells located at the spinal cord surface and those apposed to blood vessels. On the other hand, PROX1-expressing cells found in the parenchyma were lacking Iba1 or PGP9.5, but a significant fraction of those cells showed co-expression of the oligodendrocyte lineage marker OLIG2. Intriguingly, following spinal cord injury, LYVE-1-expressing cells assembled and reorganized into putative pre-vessel structures. As expected, the rat skin used as positive controls revealed classical lymphatic vessels, displaying PROX1+ nuclei surrounded by LYVE-1-immunoreactivity. Classical lymphatics were not detected in adult rat spinal cord. Nevertheless, numerous cells expressing either LYVE-1 or PROX1 were identified. Based on their localization and overlapping expression with

  17. Expression of Lymphatic Markers in the Adult Rat Spinal Cord

    PubMed Central

    Kaser-Eichberger, Alexandra; Schroedl, Falk; Bieler, Lara; Trost, Andrea; Bogner, Barbara; Runge, Christian; Tempfer, Herbert; Zaunmair, Pia; Kreutzer, Christina; Traweger, Andreas; Reitsamer, Herbert A.; Couillard-Despres, Sebastien

    2016-01-01

    Under physiological conditions, lymphatic vessels are thought to be absent from the central nervous system (CNS), although they are widely distributed within the rest of the body. Recent work in the eye, i.e., another organ regarded as alymphatic, revealed numerous cells expressing lymphatic markers. As the latter can be involved in the response to pathological conditions, we addressed the presence of cells expressing lymphatic markers within the spinal cord by immunohistochemistry. Spinal cord of young adult Fisher rats was scrutinized for the co-expression of the lymphatic markers PROX1 and LYVE-1 with the cell type markers Iba1, CD68, PGP9.5, OLIG2. Rat skin served as positive control for the lymphatic markers. PROX1-immunoreactivity was detected in many nuclei throughout the spinal cord white and gray matter. These nuclei showed no association with LYVE-1. Expression of LYVE-1 could only be detected in cells at the spinal cord surface and in cells closely associated with blood vessels. These cells were found to co-express Iba1, a macrophage and microglia marker. Further, double labeling experiments using CD68, another marker found in microglia and macrophages, also displayed co-localization in the Iba1+ cells located at the spinal cord surface and those apposed to blood vessels. On the other hand, PROX1-expressing cells found in the parenchyma were lacking Iba1 or PGP9.5, but a significant fraction of those cells showed co-expression of the oligodendrocyte lineage marker OLIG2. Intriguingly, following spinal cord injury, LYVE-1-expressing cells assembled and reorganized into putative pre-vessel structures. As expected, the rat skin used as positive controls revealed classical lymphatic vessels, displaying PROX1+ nuclei surrounded by LYVE-1-immunoreactivity. Classical lymphatics were not detected in adult rat spinal cord. Nevertheless, numerous cells expressing either LYVE-1 or PROX1 were identified. Based on their localization and overlapping expression with

  18. Study on enhanced lymphatic exposure of polyamidoamin-alkali blue dendrimer for paclitaxel delivery and influence of the osmotic pressure on the lymphatic targeting.

    PubMed

    Yang, Rui; Mao, Yuling; Ye, Tiantian; Xia, Suxia; Wang, Shujun; Wang, Siling

    2016-09-01

    In this study, paclitaxel (PTX)-loaded polyamidoamin-alkali blue (PTX-P-AB) was prepared in order to investigate the intralymphatic targeting ability and anti-cancer effect after subcutaneous (s.c.) administration. The physicochemical properties and in vitro drug release were evaluated. The lymphatic drainage and lymph nodes (LNs) uptake were examined by pharmacokinetics and distribution recovery of PTX in plasma, LNs, injection site (IS) and tissues after s.c. injection in healthy mice and in tumor-bearing mice. The osmotic pressure of PTX-P-AB affecting the lymphatic targeting was studied. The anti-tumor activity of PTX-P-AB was investigated in mice bearing S180 metastatic tumors. Results showed that PTX-P-AB with suitable and stable physicochemical properties could be used for in vivo lymphatic studies, and displayed the more rapid lymphatic absorption, the higher AUC value in LNs, the longer LNs residence time and the higher metastasis-inhibiting rate compared with Taxol®. Enhanced lymphatic drainage from the IS and uptake into lymph by increasing the osmotic pressure of PTX-P-AB indicated that PTX-P-AB possesses the double function of lymphatic tracing and lymphatic targeting, and suggested the potential for the development of lymphatic targeting vectors and the lymphatic tracer for treatment and diagnosis.

  19. The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems

    PubMed Central

    Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A.J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John

    2014-01-01

    Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the

  20. The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems.

    PubMed

    Wu, Min; Frieboes, Hermann B; Chaplain, Mark A J; McDougall, Steven R; Cristini, Vittorio; Lowengrub, John S

    2014-08-21

    Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response

  1. Lymphatic Contribution to the Cellular Niche in Heterotopic Ossification

    PubMed Central

    Loder, Shawn; Agarwal, Shailesh; Sorkin, Michael; Breuler, Chris; Li, John; Peterson, Joshua; Hsieh, Hsiao Hsin Sung; Wang, Stewart; Mehrara, Babak; Levi, Benjamin

    2016-01-01

    Objective The objective of this study was to determine the contribution of lymphatic tissue to heterotopic ossification. Background Heterotopic ossification (HO) is the pathologic development of ectopic bone within soft tissues often following severe trauma. Characterization of the tissue niche supporting HO is critical to identifying therapies directed against this condition. Lymphangiogenesis is up-regulated during incidents of trauma, thereby co-incident with the niche supportive of HO. We hypothesized that lymphatic tissues play a critical role in HO formation. Methods Mice underwent hindlimb Achilles’ tendon transection and dorsal burn injury(burn/tenotomy) to induce HO. The popliteal and inguinal lymph nodes were excised ipsilateral to the tenotomy site. Flow cytometry and immunostaining were used to quantify and localize lymphoendothelium. MicroCT was used to quantify HO. Results Enrichment of mature lymphatic tissues was noted 2 weeks after injury at the tendon transection sites when compared with the contralateral, intact tendon based on LYVE1+ tubules (10.9% v. 0.8%, p<0.05). Excision of the inguinal and popliteal nodes with draining popliteal lymphatic vessel significantly decreased the presence of mature lymphoendothelium 2 weeks after injury (10.9% v. 3.3%, p<0.05). Bone-cartilage-stromal progenitor cells (CD105+/AlphaV+/Tie2−/CD45−/CD90−/BP1−) were also significantly decreased after lymph node excision (10.2% v. 0.5%, p<0.05). A significant decrease was noted in the volume of de novo HO present within the soft tissues (0.12 mm^3 v. 0.02 mm^3). Conclusions These findings suggest that lymphatic vessels are intimately linked with the formation de novo bone within soft tissues following trauma, and their presence may facilitate bone formation. PMID:26779981

  2. Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors.

    PubMed

    Shin, Masahiro; Male, Ira; Beane, Timothy J; Villefranc, Jacques A; Kok, Fatma O; Zhu, Lihua J; Lawson, Nathan D

    2016-10-15

    Vascular endothelial growth factor C (Vegfc) activates its receptor, Flt4, to induce lymphatic development. However, the signals that act downstream of Flt4 in this context in vivo remain unclear. To understand Flt4 signaling better, we generated zebrafish bearing a deletion in the Flt4 cytoplasmic domain that eliminates tyrosines Y1226 and 1227. Embryos bearing this deletion failed to initiate sprouting or differentiation of trunk lymphatic vessels and did not form a thoracic duct. Deletion of Y1226/7 prevented ERK phosphorylation in lymphatic progenitors, and ERK inhibition blocked trunk lymphatic sprouting and differentiation. Conversely, endothelial autonomous ERK activation rescued lymphatic sprouting and differentiation in flt4 mutants. Interestingly, embryos bearing the Y1226/7 deletion formed a functional facial lymphatic network enabling them to develop normally to adulthood. By contrast, flt4 null larvae displayed hypoplastic facial lymphatics and severe lymphedema. Thus, facial lymphatic vessels appear to be the first functional lymphatic network in the zebrafish, whereas the thoracic duct is initially dispensable for lymphatic function. Moreover, distinct signaling pathways downstream of Flt4 govern lymphatic morphogenesis and differentiation in different anatomical locations. © 2016. Published by The Company of Biologists Ltd.

  3. Molecular and functional analyses of the contractile apparatus in lymphatic muscle

    NASA Technical Reports Server (NTRS)

    Muthuchamy, Mariappan; Gashev, Anatoliy; Boswell, Niven; Dawson, Nancy; Zawieja, David; Delp, Z. (Principal Investigator)

    2003-01-01

    Lymphatics are necessary for the generation and regulation of lymph flow. Lymphatics use phasic contractions and extrinsic compressions to generate flow; tonic contractions alter resistance. Lymphatic muscle exhibits important differences from typical vascular smooth muscle. In this study, the thoracic duct exhibited significant functional differences from mesenteric lymphatics. To understand the molecular basis for these differences, we examined the profiles of contractile proteins and their messages in mesenteric lymphatics, thoracic duct, and arterioles. Results demonstrated that mesenteric lymphatics express only SMB smooth muscle myosin heavy chain (SM-MHC), whereas thoracic duct and arterioles expressed both SMA and SMB isoforms. Both SM1 and SM2 isoforms of SM-MHC were detected in arterioles and mesenteric and thoracic lymphatics. In addition, the fetal cardiac/skeletal slow-twitch muscle-specific beta-MHC message was detected only in mesenteric lymphatics. All four actin messages, cardiac alpha-actin, vascular alpha-actin, enteric gamma-actin, and skeletal alpha-actin, were present in both mesenteric lymphatics and arterioles. However, in thoracic duct, predominantly cardiac alpha-actin and vascular alpha-actin were found. Western blot and immunohistochemical analyses corroborated the mRNA studies. However, in arterioles only vascular alpha-actin protein was detected. These data indicate that lymphatics display genotypic and phenotypic characteristics of vascular, cardiac, and visceral myocytes, which are needed to fulfill the unique roles of the lymphatic system.

  4. Decline of lymphatic vessel density and function in murine skin during aging.

    PubMed

    Karaman, Sinem; Buschle, Dorina; Luciani, Paola; Leroux, Jean-Christophe; Detmar, Michael; Proulx, Steven T

    2015-10-01

    Lymphatic vessels play important roles in the pathogenesis of many conditions that have an increased prevalence in the elderly population. However, the effects of the aging process on the lymphatic system are still relatively unknown. We have applied non-invasive imaging and whole-mount staining techniques to assess the lymphatic vessel function and morphology in three different age groups of mice: 2 months (young), 7 months (middle-aged), and 18 months (aged). We first developed and validated a new method to quantify lymphatic clearance from mouse ear skin, using a lymphatic-specific near-infrared tracer. Using this method, we found that there is a prominent decrease in lymphatic vessel function during aging since the lymphatic clearance was significantly delayed in aged mice. This loss of function correlated with a decreased lymphatic vessel density and a reduced lymphatic network complexity in the skin of aged mice as compared to younger controls. The blood vascular leakage in the skin was slightly increased in the aged mice, indicating that the decreased lymphatic function was not caused by a reduced capillary filtration in aged skin. The decreased function of lymphatic vessels with aging might have implications for the pathogenesis of a number of aging-related diseases.

  5. Primary and Secondary Lymphatic Valve Development: Molecular, Functional and Mechanical Insights

    PubMed Central

    Bazigou, Eleni; Wilson, John T.; Moore, James E.

    2015-01-01

    Fluid homeostasis in vertebrates critically relies on the lymphatic system forming a hierarchical network of lymphatic capillaries and collecting lymphatics, for the efficient drainage and transport of extravasated fluid back to the cardiovascular system. Blind–ended lymphatic capillaries employ specialized junctions and anchoring filaments to encourage a unidirectional flow of the interstitial fluid into the initial lymphatic vessels, whereas collecting lymphatics are responsible for the active propulsion of the lymph to the venous circulation via the combined action of lymphatic muscle cells and intraluminal valves. Here we describe recent findings on molecular and physical factors regulating the development and maturation of these two types of valves and examine their role in tissue-fluid homeostasis. PMID:25086182

  6. Efficient Assessment of Developmental, Surgical and Pathological Lymphangiogenesis Using a Lymphatic Reporter Mouse and Its Embryonic Stem Cells

    PubMed Central

    Jung, Wonhyuek; Seong, Young Jin; Park, Eunkyung; Bramos, Athanasios; Kim, Kyu Eui; Lee, Sunju; Daghlian, George; Seo, Jung In; Choi, Inho; Choi, In-Seon; Koh, Chester J.; Kobielak, Agnieszka; Ying, Qi-Long; Johnson, Maxwell; Gardner, Daniel; Wong, Alex K.; Choi, Dongwon; Hong, Young-Kwon

    2016-01-01

    Several lymphatic reporter mouse lines have recently been developed to significantly improve imaging of lymphatic vessels. Nonetheless, the usage of direct visualization of lymphatic vessels has not been fully explored and documented. Here, we characterized a new Prox1-tdTomato transgenic lymphatic reporter mouse line, and demonstrated how this animal tool enables the researchers to efficiently assess developmental, surgical and pathological lymphangiogenesis by direct visualization of lymphatic vessels. Moreover, we have derived embryonic stem cells from this reporter line, and successfully differentiated them into lymphatic vessels in vivo. In conclusion, these experimental tools and techniques will help advance lymphatic research. PMID:27280889

  7. Efficacy of B cell Depletion Therapy on Joint Flare is Associated with Increased Lymphatic Flow

    PubMed Central

    Li, Jie; Ju, Yawen; Bouta, Echoe M.; Xing, Lianping; Wood, Ronald W.; Kuzin, Igor; Bottaro, Andrea; Ritchlin, Christopher T.; Schwarz, Edward M.

    2012-01-01

    Objective B cell depletion therapy (BCDT) ameliorates rheumatoid arthritis by mechanisms that are incompletely understood. Arthritic flare in tumor necrosis factor transgenic (TNF-Tg) mice is associated with efferent lymph node (LN) “collapse,” triggered by B cell translocation into lymphatic spaces and decreased lymphatic drainage. We examined whether BCDT efficacy is associated with restoration of lymphatic drainage due to removal of obstructing nodal B cells. Methods We developed contrast-enhancement (CE) MRI imaging, near-infrared indocyanine green (NIR-ICG) imaging, and intravital immunofluorescent imaging to longitudinally assess synovitis, lymphatic flow, and cell migration in lymphatic vessels in TNF-Tg mice. We tested to see if BCDT efficacy is associated with restoration of lymphatic draining and cell egress from arthritic joints. Results Unlike active lymphatics to normal and pre-arthritic knees, afferent lymphatic vessels to collapsed LNs in inflamed knees do not pulse. Intravital immunofluorescent imaging demonstrated that CD11b+ monocytes/macrophages in lymphatic vessels afferent to expanding LN travel at high velocity (186 ± 37 micrometer/sec), while these cells are stationary in lymphatic vessels afferent to collapsed PLN. BCDT of flaring TNF-Tg mice significantly decreased knee synovial volume by 50% from the baseline level, and significantly increased lymphatic clearance versus placebo (p<0.05). This increased lymphatic drainage restored macrophages egress from inflamed joints without recovery of the lymphatic pulse. Conclusion These results support a novel mechanism in which BCDT of flaring joints lessens inflammation by increasing lymphatic drainage and subsequent migration of cells and cytokines from the synovial space. PMID:23002006

  8. Unusual vanishing interstitial lymphatic "pearls" in a patient presenting with extensive interstitial and mediastinal MDCT features of acute cardiogenic failure related to bradycardia and mitral regurgitation.

    PubMed

    Coulier, Bruno; El Khoury, Elie; Deprez, Fabrice C; Ghaye, Benoît; Van den Broeck, Stephane; Tourmous, Hussein

    2014-12-01

    Thoracic multidetector computed tomography-MDCT-was simultaneously performed during emergency abdominal CT in a patient presenting with abdominal pain and acute cardiogenic edema related to sick sinus syndrome and mitral prolapse with regurgitation. A constellation of severe but completely reversible interstitial and mediastinal features was found comprising pleural effusions, diffuse alveolar ground glass, thickening of the bronchial walls and septal lines, hazy infiltration of the mediastinal fat, and enlarged lymphatic nodes. Multiple atypical hypodense nodular "pearls" were also found. These oval shape or fusiform pearls were distributed along the thickened septal lines and disappeared completely after treatment. The hypothesis of transient lymphatic ectasia or lakes is proposed for these never previously described abnormalities.

  9. Supermicrosurgical deep lymphatic vessel-to-venous anastomosis for a breast cancer-related arm lymphedema with severe sclerosis of superficial lymphatic vessels.

    PubMed

    Yamamoto, Takumi; Yamamoto, Nana; Hayashi, Akitatsu; Koshima, Isao

    2017-02-01

    Lymphatic supermicrosurgery or supermicrosurgical lymphaticovenular anastomosis (LVA) is becoming popular for the treatment of compression-refractory upper extremity lymphedema (UEL) with its effectiveness and minimally invasiveness. In conventional LVA, superficial lymphatic vessels are used for anastomosis, but its treatment efficacy would be minimum when superficial lymphatic vessels are severely sclerotic. Theoretically, deep lymphatic vessels can be used for LVA, but no clinical case has been reported regarding deep lymphatic vessel-to-venous anastomosis (D-LVA). We report a breast cancer-related UEL case treated with D-LVA, in which a less-sclerotic deep lymphatic vessel was useful for anastomosis but superficial lymphatic vessels were not due to severe sclerosis. A 62-year-old female suffered from an 18-year history of compression-refractory right UEL after right breast cancer treatments, and underwent LVA under local infiltration anesthesia. Because superficial lymphatic vessels found in surgical fields were all severely sclerotic, a deep lymphatic vessel was dissected at the cubital fossa. A 0.50-mm deep lymphatic vessel running along the brachial artery was supermicrosurgically anastomosed to a nearby 0.40-mm vein. At postoperative 12 months, her right UEL index decreased from 134 to 118, and she could reduce compression frequency from every day to 1-2 days per week to maintain the reduced lymphedematous volume. D-LVA may be a useful option for the treatment of compression-refractory UEL, when superficial lymphatic vessels are severely sclerotic. © 2015 Wiley Periodicals, Inc. Microsurgery 37:156-159, 2017. © 2015 Wiley Periodicals, Inc.

  10. Absence of lymphatic vessels in the developing human sclera.

    PubMed

    Schlereth, Simona L; Neuser, Barbara; Herwig, Martina C; Müller, Annette M; Koch, Konrad R; Reitsamer, Herbert A; Schrödl, Falk; Cursiefen, Claus; Heindl, Ludwig M

    2014-08-01

    The adult sclera is free of lymphatic vessels, but contains a net of blood vessels. Whether and when this selectively lymphangiogenic privilege is achieved during embryologic development is not known yet. Therefore, we investigated the developing human sclera for blood- and lymphatic vessels in 34 abortions/stillborns (12-38 weeks of gestation). The probes were subdivided into three groups (group 1: 12-18 weeks of gestation, n = 10; group 2: 19-23 weeks of gestation, n = 13; group 3: 24-38 weeks of gestation, n = 11), and prepared for paraffin sections followed by immunohistochemistry against CD31 to detect blood vessels, and against lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1)/podoplanin to detect lymphatic vessels. We could show, that in the human episclera distinct CD31 + blood vessels are present as early as week of gestation 13. Their amount increased during pregnancy, whereas stromal CD31 + blood vessels were elevated in early pregnancy and regressed with ongoing pregnancy. In the lamina fusca CD31 + blood vessels were absent at any time point investigated. Single LYVE1 + cells were identified primarily in the episclera; their amount decreased significantly with increasing gestational ages (group 1 compared to group 3: p < 0.01). However, LYVE1+/podoplanin + lymphatic vessels were not detectable in the sclera at any gestational ages analyzed. In contrast to the conjunctiva where LYVE1+/podoplanin + lymphatic vessels were detectable as early as week 17, the amount of LYVE1 + cells in the sclera was highest in early pregnancy (group 1), with a significant decrease during continuing pregnancy (p < 0.001). These findings are the first evidence for a fetal lymphangiogenic privilege of the sclera and show, that the fetal human sclera contains CD31 + blood vessels, but is primarily alymphatic. Our findings suggest a strong expression of selectively antilymphangiogenic factors, making the developing sclera a potential model to

  11. Real-time Intraoperative Fluorescent Lymphography: A New Technique for Lymphatic Sparing Surgery.

    PubMed

    Ietto, G; Amico, F; Soldini, G; Chiappa, C; Franchin, M; Iovino, D; Romanzi, A; Saredi, G; Cassinotti, E; Boni, L; Tozzi, M; Carcano, G

    2016-11-01

    Many surgical procedures can produce persistent lymphorrhea, lymphoceles, and lymphedema after lymph node and lymph vessel damage. Appropriate visualization of the lymphatic system is challenging. Indocyanine green (ICG) is a well-known nontoxic dye for lymphatic flow evaluation. ICG fluorescence-guided lymphography has emerged as a promising technique for intraoperative lymphatic mapping. Our goal was to develop a high spatial resolution, real-time intraoperative imaging technique to avoid or recognize early deep lymphatic vessel damage. We intraoperatively performed ICG fluorescence-guided lymphography during a kidney transplant. ICG was injected in the subcutaneous tissue of the patient's groin in the Scarpa's triangle. A dedicated laparoscopic high-definition camera system was used. Soon after ICG injection, the lymphatic vessels were identified in the abdominal retroperitoneal compartment as fluorescent linear structures running side by side to the iliac vessels. Surgical dissection was therefore performed, avoiding iatrogenic damage to major lymphatic structures. Another ICG injection at the end of the procedure confirmed that the lymphatic vessels were intact without lymph spread. Intraoperative lymphatic mapping with an ICG fluorescence-sensitive camera system is a safe and feasible procedure. ICG real-time fluorescence lymphography can be used to avoid or recognize early deep lymphatic vessel damage and reduce postoperative complications related to the lymphatic system. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Progressive loss of lymphatic vessels in skin of patients with systemic sclerosis.

    PubMed

    Manetti, Mirko; Milia, Anna Franca; Guiducci, Serena; Romano, Eloisa; Matucci-Cerinic, Marco; Ibba-Manneschi, Lidia

    2011-02-01

    Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular and fibrotic changes in the skin and internal organs. The role of blood vessel dysfunction in the pathogenesis of SSc has been extensively investigated, but few studies have addressed the involvement of the lymphatic vascular system. Our aim was to evaluate dermal lymphatic vessels in patients with SSc according to different phases of skin involvement. Skin biopsies were obtained from the forearm of 25 SSc patients (10 early/15 late-stage disease) and 13 healthy controls. Skin sections were immunostained for podoplanin (D2-40), which is selectively expressed in lymphatic endothelial cells, and examined by confocal laser scanning microscopy. Lymphatic vessels were counted in the papillary and reticular dermis. Data were analyzed using Student's t test. The number of lymphatic vessels was significantly reduced in the papillary and reticular dermis of SSc patients compared with controls. In early SSc, lymphatic vessel counts were not different from controls in the papillary dermis, and showed a trend toward a reduction in the reticular dermis. In late SSc, a significant reduction in lymphatic vessels compared with controls was found in both the papillary and reticular dermis. The number of lymphatic vessels in the papillary dermis of late SSc was significantly lower than in early SSc. In SSc, lymphatic microangiopathy is linked to the progression of skin involvement. The progressive disappearance of lymphatic vessels may have a critical pathogenetic role in the progression of SSc from an early edematous phase to overt fibrosis.

  13. Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels.

    PubMed

    Lee, Ji Yoon; Hong, Seok-Ho; Shin, Minsang; Heo, Hye-Ryeon; Jang, In Ho

    2016-09-16

    The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. LyP-1-conjugated doxorubicin-loaded liposomes suppress lymphatic metastasis by inhibiting lymph node metastases and destroying tumor lymphatics

    NASA Astrophysics Data System (ADS)

    Yan, Zhiqiang; Zhan, Changyou; Wen, Ziyi; Feng, Linglin; Wang, Fei; Liu, Yu; Yang, Xiangkun; Dong, Qing; Liu, Min; Lu, Weiyue

    2011-10-01

    Lymphatic metastasis can be greatly promoted by metastases growth and lymphangiogenesis in lymph nodes (LNs). LyP-1, a cyclic peptide, is able to specifically bind with tumor cells and tumor lymphatics in metastatic LNs. This work aimed to use LyP-1-conjugated liposomes (L-LS) loaded with doxorubicin (DOX) (L-LS/DOX) to suppress lymphatic metastasis by inhibiting both metastases and tumor lymphatics in LNs. L-LS were prepared and exhibited sizes around 90 nm and spherical morphology as characterized by transmission electron microscopy. The in vitro cellular studies showed that LyP-1 modification obviously increased liposome uptake by MDA-MB-435 tumor cells and enhanced the cytotoxicity of liposomal DOX. A popliteal and iliac LN metastases model was successfully established by subcutaneous inoculation of tumor cells to nude mice. The immunofluorescence staining analysis indicated that LyP-1 modification enabled specific binding of liposome with tumor lymphatics and enhanced the destroying effect of liposomal DOX on tumor lymphatics. The in vivo fluorescence imaging and pharmacodynamic studies showed that LyP-1 modification increased liposome uptake by metastatic LNs and that L-LS/DOX significantly decreased metastatic LN growth and LN metastasis rate. These results suggested that L-LS/DOX were an effective delivery system for suppressing lymphatic metastasis by simultaneously inhibiting LN metastases and tumor lymphatics.

  15. Quantitative study of the topographic distribution of conjunctival lymphatic vessels in the monkey.

    PubMed

    Guo, Wenyi; Zhu, Yuanfang; Yu, Paula K; Yu, Xiaobo; Sun, Xinghuai; Cringle, Stephen J; Su, Er-Ning; Yu, Dao-Yi

    2012-01-01

    The purpose of this study was to quantify the topographic distribution of bulbar conjunctival microlymphatic vessels in the monkey. Sixteen eyes from 8 rhesus monkeys were used. Full thickness pieces of globe wall were excised from each quadrant. Cryosections were stained for 5'-nucleotidase, an enzyme histochemical staining for lymphatic vessels, or vascular endothelial growth factor receptor-3, an immunohistochemical marker for the identification of lymphatic endothelial cells, and then counterstained by hematoxylin. The remaining bulbar conjunctiva was dissected and flat mounted. The tissue was then processed with 5'-nucleotidase and alkaline phosphatase, an enzyme histochemical stain with higher activity in blood vessels. Microscope images were further analysed by image processing. The density of lymphatics, diameter of lymphatic vessels, and the size of the drainage zone of each blind end of the initial lymphatics were studied. Conjunctival lymphatics consisted of initial lymphatics and pre-collectors. The initial lymphatics with blind ends were predominately distributed just under the epithelium. The density of these lymphatics (∼50%) and the drainage zone area (∼0.81 mm(2)) was similar in each quadrant, with no difference in the limbus and fornix regions. The average diameter of lymphatic vessels in each quadrant ranged from 82 to 111 μm, and was greater in the superior and nasal regions. Larger calibre pre-collectors with valve-like structures were mostly located sub Tenon's membrane and predominantly located in the region mid-way between the limbus and fornix. There was a marked depth difference in initial lymphatic distribution, with the initial lymphatics mostly confined to the region between Tenon's membrane and the conjunctival epithelium. Detailed knowledge of the topographic distribution of conjunctival lymphatics have significant relevance to a better understanding of immunology, drug delivery, glaucoma filtration surgery, and tumour

  16. Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis.

    PubMed

    Christianson, Dawn R; Dobroff, Andrey S; Proneth, Bettina; Zurita, Amado J; Salameh, Ahmad; Dondossola, Eleonora; Makino, Jun; Bologa, Cristian G; Smith, Tracey L; Yao, Virginia J; Calderone, Tiffany L; O'Connell, David J; Oprea, Tudor I; Kataoka, Kazunori; Cahill, Dolores J; Gershenwald, Jeffrey E; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2015-02-24

    Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial-melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell-cell interactions at the lymphatic-tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.

  17. Abnormal Head Position

    MedlinePlus

    ... an ocular cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal ... cause permanent tightening of neck muscles that can lead to chronic neck ache or headache. An abnormal ...

  18. Skeletal limb abnormalities

    MedlinePlus

    ... medlineplus.gov/ency/article/003170.htm Skeletal limb abnormalities To use the sharing features on this page, please enable JavaScript. Skeletal limb abnormalities refers to a variety of bone structure problems ...

  19. Tooth - abnormal colors

    MedlinePlus

    ... medlineplus.gov/ency/article/003065.htm Tooth - abnormal colors To use the sharing features on this page, please enable JavaScript. Abnormal tooth color is any color other than white to yellowish- ...

  20. Urine - abnormal color

    MedlinePlus

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  1. Lymphoscintigraphic studies of lymphatic drainage from the testes

    SciTech Connect

    Yeh, S.D.; Morse, M.J.; Grando, R.; Kleinert, E.L.; Whitmore, W.F. Jr.

    1986-12-01

    Two colloidal radiopharmaceuticals, Au-198 and Tc-99m antimony, were used to evaluate the lymphatic drainage of the testis in experimental animals and humans. One to 24 hours after direct intratesticular injection of Au-198 colloid in dogs and 4-6 hours after injection of Tc-99m antimony colloid in men, distribution within retroperitoneal lymph nodes was demonstrated. Uptake within the para-aortic lymph nodes primarily draining the testis was decreased following proximal ligation of the spermatic vessels in dogs. Testicular lymphoscintigraphy successfully demonstrated an intact spermatic cord lymphatic communication to the para-aortic nodes in five of six patients with chronic lower-extremity lymphedema. When the intact testicle and spermatic cord were transposed to the thigh in a patient with chronic lymphedema of the lower extremity, percutaneous pedal lymphoscintigraphy successfully demonstrated uptake within the para-aortic lymph nodes draining the ipsilateral testis.

  2. Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration

    PubMed Central

    Brinkman, C. Colin; Iwami, Daiki; Hritzo, Molly K.; Xiong, Yanbao; Ahmad, Sarwat; Simon, Thomas; Hippen, Keli L.; Blazar, Bruce R.; Bromberg, Jonathan S.

    2016-01-01

    Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LTαβ rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NFκB signalling via LTβR. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression. PMID:27323847

  3. Imaging blood vessels and lymphatic vessels in the zebrafish.

    PubMed

    Jung, H M; Isogai, S; Kamei, M; Castranova, D; Gore, A V; Weinstein, B M

    2016-01-01

    Blood vessels supply tissues and organs with oxygen, nutrients, cellular, and humoral factors, while lymphatic vessels regulate tissue fluid homeostasis, immune trafficking, and dietary fat absorption. Understanding the mechanisms of vascular morphogenesis has become a subject of intense clinical interest because of the close association of both types of vessels with pathogenesis of a broad spectrum of human diseases. The zebrafish provides a powerful animal model to study vascular morphogenesis because of their small, accessible, and transparent embryos. These unique features of zebrafish embryos permit sophisticated high-resolution live imaging of even deeply localized vessels during embryonic development and even in adult tissues. In this chapter, we summarize various methods for blood and lymphatic vessel imaging in zebrafish, including nonvital resin injection-based or dye injection-based vessel visualization, and alkaline phosphatase staining. We also provide protocols for vital imaging of vessels using microangiography or transgenic fluorescent reporter zebrafish lines. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Pediatric lymphatic malformations: evolving understanding and therapeutic options.

    PubMed

    Defnet, Ann M; Bagrodia, Naina; Hernandez, Sonia L; Gwilliam, Natalie; Kandel, Jessica J

    2016-05-01

    Multimodal treatment of lymphatic malformations continues to expand as new information about the biology and genetics of these lesions is discovered, along with knowledge gained from clinical practice. A patient-centered approach, ideally provided by a multidisciplinary medical and surgical team, should guide timing and modality of treatment. Current treatment options include observation, surgery, sclerotherapy, radiofrequency ablation, and laser therapy. New medical and surgical therapies are emerging, and include sildenafil, propranolol, sirolimus, and vascularized lymph node transfer. The primary focus of management is to support and optimize these patients' quality of life. Researchers continue to study lymphatic malformations with the goal of increasing therapeutic options and developing effective clinical pathways for these complicated lesions.

  5. Core content for training in venous and lymphatic medicine

    PubMed Central

    Min, Robert J; Comerota, Anthony J; Meissner, Mark H; Carman, Teresa L; Rathbun, Suman W; Jaff, Michael R; Wakefield, Thomas W; Feied, Craig F

    2014-01-01

    The major venous societies in the United States share a common mission to improve the standards of medical practitioners, the educational goals for teaching and training programs in venous disease, and the quality of patient care related to the treatment of venous disorders. With these important goals in mind, a task force made up of experts from the specialties of dermatology, interventional radiology, phlebology, vascular medicine, and vascular surgery was formed to develop a consensus document describing the Core Content for venous and lymphatic medicine and to develop a core educational content outline for training. This outline describes the areas of knowledge considered essential for practice in the field, which encompasses the study, diagnosis, and treatment of patients with acute and chronic venous and lymphatic disorders. The American Venous Forum and the American College of Phlebology have endorsed the Core Content. PMID:25059735

  6. Lymphatic filariasis in India: epidemiology and control measures.

    PubMed

    Raju, Khk; Jambulingam, P; Sabesan, S; Vanamail, P

    2010-01-01

    Lymphatic filariasis caused by Wuchereria bancrofti and Brugia malayi is an important public health problem in India. Both parasites produce essentially similar clinical presentations in man, related mainly to the pathology of the lymphatic system. Filariasis is endemic in 17 States and six Union Territories, with about 553 million people at risk of infection. The Government of India has accorded a high priority for elimination of this infection through mass chemotherapy programme (annual, single dose of Diethylcarbamazine citrate, i.e. DEC - 6 mg/kg of bodyweight, plus Albendazole repeated four to six times). This campaign has become a part of the National Vector-Borne Disease Control Programme in 2003 under the National Health Policy 2002 and aims to eliminate filariasis by 2015. We discuss here the epidemiology and current control strategy for filariasis; highlighting key issues, challenges and options in the implementation of the programme, and suggesting measures for mid-course corrections in the elimination strategy.

  7. Insufficient Lymph Drainage Causes Abnormal Lipid Accumulation and Vein Wall Degeneration

    PubMed Central

    Tanaka, Hiroki; Yamamoto, Naoto; Suzuki, Minoru; Mano, Yuuki; Sano, Masaki; Zaima, Nobuhiro; Sasaki, Takeshi; Setou, Mitsutoshi

    2016-01-01

    Objective: Previously, we analyzed human varicose veins (VV) using imaging mass spectrometry (IMS) and detected the abnormal accumulation of lipid molecules in the walls of VV, possibly due to insufficient lipid drainage by the lymphatic vessels. In this study, we created an animal model of lymphatic insufficiency to investigate the effects of insufficient lymph drainage on vein walls. Methods: In rats, the lymphatic collecting vessels surrounding the femoral vein were ligated on one side (the model tissue), which caused the local retention of lymphatic fluid in the perivascular tissue. The equivalent contralateral tissue was used as a control. A histological study of the femoral vein and the surrounding perivascular tissue was conducted. IMS was used to analyze the distribution of lipid molecules in the perivascular tissue. Results: Fourteen days after the procedure, the lymphatic vessels in the model tissue were significantly dilated. Furthermore, IMS revealed that the composition of the lipid molecules in the perivascular regions of the model tissue had altered. Compared with the control tissue, the model tissue exhibited marked perivascular accumulation of lysophosphatidylcholine (1-acyl 16:0), phosphatidylcholine (16:0/20:4), and triglycerides (52:2). Interestingly, the walls of the femoral veins running through the model tissue were 3.4-fold thicker than those of the femoral veins running through the control tissue. The number of tumor necrosis factor α-positive adipocytes was increased in the perivascular regions of the model tissue. Conclusion: The findings of this study indicated that the accumulation of lymphatic fluid due to insufficient lymph drainage changes the structure of vein walls, and such changes might be associated with chronic venous insufficiency. (This is a translation of Jpn J Phlebol 2015; 26: 227–235.) PMID:28018498

  8. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... PROBLEMS Abnormal Uterine Bleeding • What is a normal menstrual cycle? • When is bleeding abnormal? • At what ages is ... treat abnormal bleeding? •Glossary What is a normal menstrual cycle? The normal length of the menstrual cycle is ...

  9. Imported lymphatic filariasis in an Indian immigrant to iran.

    PubMed

    Kia, Eshrat Beigom; Sharifdini, Meysam; Hajjaran, Homa; Shahbazi, Ali Ehsan; Sayyad Talaie, Zahra

    2014-03-01

    Lymphatic filariasis (LF), a nematode disease transmitted by arthropod vectors, is repeatedly reported in immigrant population. This disease is not endemic in Iran; however, different species of mosquitoes, capable of transmission of parasite microfilaria, are distributed in the country. Hereby, incidental detection of an imported case of LF due to Wuchereria bancrofti in an Indian worker in Iran is reported. Identification of the case was performed based on morphological and morphometrical characteristics of microfilaria and PCR sequencing.

  10. [Clinical analysis of two cases with diffuse pulmonary lymphatic disease].

    PubMed

    Liu, J R; Shen, W B; Wen, Z; An, R; Zhou, C J; Zhao, S Y

    2016-05-01

    To analyze the clinical characteristics and diagnosis of 2 cases with diffuse pulmonary lymphatic disease. Clinical manifestations of the children were retrospectively analyzed. Two patients were both from Beijing Children Hospital in 2013 and 2014.Diffuse pulmonary lymphatic disease was diagnosed by pathology of pleura in case 1 and by lymphoscintigraphy in case 2. The first patient was a male aged 10-year-5-month who presented with a history of pleural effusion for 2 years. Examination revealed chylothorax and pericardial effusion. After pleural decortications and ligation of thoracic duct was performed, he still had recurrent chylothorax. Pathology of pleura revealed lymphangioma. Physical examination showed diminished breath sound and heart sounds. A bronchoscope revealed too much white viscous secretions. Thorax ultrasound revealed lymphangioma in bilateral lower thoracic cavity and post inferior mediastinum. Chest computed tomography showed diffuse thickening of the interlobular septa and bronchovascular bundle in both lungs, many punctate calcification in the lower field. Abdomen ultrasound revealed a small quantity seroperitoneum. Lymphoscintigraphy revealed radioactivity enhancement in bilateral thoracic cavity. The second patient was a female aged 6 years and 9 months, who presented with a history of recurrent cough for 2 years and 9 months. Physical examination showed normal result. Pulmonary function showed mixed ventilation function disturbance. A bronchoscopy showed extensive viscous secretions. Mediastinum, heart and abdomen were normal on ultrasound. Chest computed tomography showed diffuse thickening of the interlobular septa and bronchovascular bundle in both lungs and bilateral pleural thickening. Lymphoscintigraphy revealed diffuse lymphangiectasis in both lungs. Both patients received a diagnosis of diffuse pulmonary lymphatic disease. Case 1 who had died was diagnosed with diffuse pulmonary lymphangiomatosis. Case 2 had no exacerbation after 9

  11. Clinical features of mesenteric lymphatic malformation in children.

    PubMed

    Kim, Soo-Hong; Kim, Hyun-Young; Lee, Cheol; Min, Hye Sook; Jung, Sung-Eun

    2016-04-01

    Mesenteric lymphatic malformations (MLs) are a heterogeneous group of benign diseases of the lymphatic system that present with cystic dilated lymphatics of the mesentery. MLs are rare and represent less than 5% of all lymphatic malformations. The aims of this study were to analyze the characteristics of MLs in children and to suggest a modified classification. We investigated 25 patients who underwent ML surgery. The clinical data and pathological findings were reviewed retrospectively. We divided the patients into 4 groups according to the operative findings. Group 1 included patients with MLs involving the intestinal walls. Group 2 included patients with pedicle-type MLs with no relationship to the mesenteric vessels. Group 3 patients presented with MLs located in the mesenteric boundaries near the mesenteric vessels. Group 4 patients had multicentric and diffusely infiltrated MLs. The male-to-female ratio was 11:14, and the median age at diagnosis was 5years of age. The most common symptom was abdominal pain. The jejunal mesentery was the most frequently involved site in this study. Five patients showed the macrocystic type and 20 patients showed the mixed cystic type. With the exception of one patient with a large mixed cystic-type ML who underwent incomplete mass excision, 24 patients underwent complete mass excision. The group 1 patients (n=14) underwent mass excision performed with segmental resection of the bowel. The group 2 patients (n=3) only underwent mass excision surgery. The patients in group 3 (n=7) underwent mass excision with segmental resection of the intestine because ML excision altered the blood supply of the adjacent intestines. The group 4 patients (n=1) presented with MLs involving the entire mesentery and underwent incomplete excision. The relationships between MLs and the neighboring organs determine the surgical strategy, and the size and location of MLs affect the operative methods. The modified classification based on these findings

  12. How regenerating lymphatics function: lessons from lizard tails.

    PubMed

    Blacker, Helen A; Tsopelas, Chris; Orgeig, Sandra; Daniels, Christopher B; Chatterton, Barry E

    2007-01-01

    Rational treatment of lymphoedema may be improved in the future with a better understanding of the physiological processes involved in the regeneration of new lymphatic vessels (lymphangiogenesis). Many lizard species undergo tail autotomy as a predator escape response and subsequently regenerate nonlymphoedematous tails. Such species may offer novel models for examining lymphangiogenesis. In this lymphoscintigraphic evaluation, three radioactive tracers were employed, (99m)Tc-antimony trisulphide colloid (approximately 10 nm diameter), (99m)Tc-tin fluoride colloid (approximately 2,000 nm; (99m)Tc-TFC), and (99m)Tc-diethylenetriaminepentaacetic acid (soluble; (99m)Tc-DTPA), to examine lymphatic function in regenerating tails of the Australian marbled gecko, Christinus marmoratus. Rate of local clearance and velocity of migration were determined in geckos with original tails and at 6, 9, 12, and >24 weeks after autotomy. In original-tailed geckos, the smaller radiocolloid was cleared to a greater extent and had a faster lymph velocity than in geckos with regenerated tails. The same parameters measured for larger particles were greater in early regeneration than later. (99m)Tc-TFC did not migrate from the injection site in fully regenerated and original gecko tails, which indicates that larger particles are increasingly impeded as tail regeneration progresses. Soluble (99m)Tc-DTPA diffused from the injection site extremely rapidly via venous capillaries in all tails, confirming that the slower clearance of the colloids is solely via the lymphatics. Differences in clearance and lymph velocity between differently sized colloids throughout tail regeneration may be influenced by changes in surrounding tissue structure density and the lymphatic vessel porosity. c 2006 Wiley-Liss, Inc.

  13. Lymph node biophysical remodeling is associated with melanoma lymphatic drainage.

    PubMed

    Rohner, Nathan Andrew; McClain, Jacob; Tuell, Sara Lydia; Warner, Alex; Smith, Blair; Yun, Youngho; Mohan, Abhinav; Sushnitha, Manuela; Thomas, Susan Napier

    2015-11-01

    Tissue remodeling is a characteristic of many solid tumor malignancies including melanoma. By virtue of tumor lymphatic transport, remodeling pathways active within the local tumor microenvironment have the potential to be operational within lymph nodes (LNs) draining the tumor interstitium. Here, we show that lymphatic drainage from murine B16 melanomas in syngeneic, immune-competent C57Bl/6 mice is associated with LN enlargement as well as nonuniform increases in bulk tissue elasticity and viscoelasticity, as measured by the response of whole LNs to compression. These remodeling responses, which quickly manifest in tumor-draining lymph nodes (TDLNs) after tumor inoculation and before apparent metastasis, were accompanied by changes in matrix composition, including up to 3-fold increases in the abundance of soluble collagen and hyaluronic acid. Intranodal pressures were also significantly increased in TDLNs (+1 cmH2O) relative to both non-tumor-draining LNs (-1 cmH2O) and LNs from naive animals (-1 to 2 cmH2O). These data suggest that the reorganization of matrix structure, composition, and fluid microenvironment within LNs associated with tumor lymphatic drainage parallels remodeling seen in primary malignancies and has the potential to regulate the adhesion, proliferation, and signaling function of LN-resident cells involved in directing melanoma disease progression.

  14. Synchronization and Random Triggering of Lymphatic Vessel Contractions

    PubMed Central

    Baish, James W.; Kunert, Christian; Padera, Timothy P.; Munn, Lance L.

    2016-01-01

    The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump-the heart–to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal check valves. Due to the large number and spatial distribution of such pumps, high-level coordination would be unwieldy. This leads to the question of how each segment of lymphatic vessel responds to local signals that can contribute to the coordination of pumping on a network basis. Beginning with elementary fluid mechanics and known cellular behaviors, we show that two complementary oscillators emerge from i) mechanical stretch with calcium ion transport and ii) fluid shear stress induced nitric oxide production (NO). Using numerical simulation and linear stability analysis we show that the newly identified shear-NO oscillator shares similarities with the well-known Van der Pol oscillator, but has unique characteristics. Depending on the operating conditions, the shear-NO process may i) be inherently stable, ii) oscillate spontaneously in response to random disturbances or iii) synchronize with weak periodic stimuli. When the complementary shear-driven and stretch-driven oscillators interact, either may dominate, producing a rich family of behaviors similar to those observed in vivo. PMID:27935958

  15. Synchronization and Random Triggering of Lymphatic Vessel Contractions.

    PubMed

    Baish, James W; Kunert, Christian; Padera, Timothy P; Munn, Lance L

    2016-12-01

    The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump-the heart-to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal check valves. Due to the large number and spatial distribution of such pumps, high-level coordination would be unwieldy. This leads to the question of how each segment of lymphatic vessel responds to local signals that can contribute to the coordination of pumping on a network basis. Beginning with elementary fluid mechanics and known cellular behaviors, we show that two complementary oscillators emerge from i) mechanical stretch with calcium ion transport and ii) fluid shear stress induced nitric oxide production (NO). Using numerical simulation and linear stability analysis we show that the newly identified shear-NO oscillator shares similarities with the well-known Van der Pol oscillator, but has unique characteristics. Depending on the operating conditions, the shear-NO process may i) be inherently stable, ii) oscillate spontaneously in response to random disturbances or iii) synchronize with weak periodic stimuli. When the complementary shear-driven and stretch-driven oscillators interact, either may dominate, producing a rich family of behaviors similar to those observed in vivo.

  16. Visualisation and stereological assessment of blood and lymphatic vessels.

    PubMed

    Lokmic, Zerina; Mitchell, Geraldine M

    2011-06-01

    The physiological processes involved in tissue development and regeneration also include the parallel formation of blood and lymphatic vessel circulations which involves their growth, maturation and remodelling. Both vascular systems are also frequently involved in the development and progression of pathological conditions in tissues and organs. The blood vascular system circulates oxygenated blood and nutrients at appropriate physiological levels for tissue survival, and efficiently removes all waste products including carbon dioxide. This continuous network consists of the heart, aorta, arteries, arterioles, capillaries, post-capillary venules, venules, veins and vena cava. This system exists in an interstitial environment together with the lymphatic vascular system, including lymph nodes, which aids maintenance of body fluid balance and immune surveillance. To understand the process of vascular development, vascular network stability, remodelling and/or regression in any research model under any experimental conditions, it is necessary to clearly and unequivocally identify and quantify all elements of the vascular network. By utilising stereological methods in combination with cellular markers for different vascular cell components, it is possible to estimate parameters such as surface density and surface area of blood vessels, length density and length of blood vessels as well as absolute vascular volume. This review examines the current strategies used to visualise blood vessels and lymphatic vessels in two- and three-dimensions and the basic principles of vascular stereology used to quantify vascular network parameters.

  17. Regional differences in pleural lymphatic albumin concentration in sheep

    SciTech Connect

    Albertine, K.H.; Schultz, E.L.; Wiener-Kronish, J.P.; Staub, N.C.

    1987-01-01

    We used quantitative reflectance autoradiography to compare the concentration of albumin in visceral pleural lymphatics at the cranial and caudal ends of the sheep's lung in the vertical (60 degrees head-up) and horizontal (supine) positions. Twelve to fourteen hours after injecting 125I-albumin intravenously we placed four anesthetized sheep in the vertical position to establish a microvascular hydrostatic pressure gradient along the vertical height of the lung. We placed two anesthetized sheep in the horizontal position. Four hours later, we fixed the left lung and removed visceral pleural tissue blocks from the cranial and caudal ends, separated by a 15-cm distance, along the costovertebral margin. We measured the silver grain density in the pleural lymphatic autoradiograms by dark-field reflectance microspectrophotometry. In the vertical position, the lymph albumin concentration at the cranial end (top) of the lung averaged 2.5 +/- 0.4 g/dl compared with the caudal end (bottom), which averaged 1.8 +/- 0.3 g/dl. The difference (42% greater at the top than the bottom) is significant (P less than 0.05). The computed gradient in perimicrovascular interstitial albumin osmotic pressure was 0.26 +/- 0.13 cmH2O/cm lung height. There were no differences between the cranial and caudal lymphatic groups in the two horizontal sheep. We conclude that in the sheep lung there is a gradient in perimicrovascular albumin concentration due to the vertical gradient in microvascular hydrostatic pressure.

  18. Scarpa Fascia Preservation in Abdominoplasty: Does It Preserve the Lymphatics?

    PubMed

    Tourani, Saam S; Taylor, G Ian; Ashton, Mark W

    2015-08-01

    The course of the cutaneous lymphatic collectors of the abdominal wall in relation to the Scarpa fascia is unclear in the literature. Preserving the Scarpa fascia in the lower abdomen to reduce the seroma rate following abdominoplasty has been suggested based on the assumption that the lower abdominal lymphatics run deep to this layer along their entire course. Using the previously described technique, the superficial lymphatic drainage of eight hemiabdomen specimens from four fresh human cadavers was investigated. The upper and lower abdominal collectors originated at the umbilical and midline watershed areas in a subdermal plane by the union of precollectors draining the dermis. In the lower abdomen, the depth of the collectors gradually increased in the subcutaneous fat as they coursed toward the groin. They eventually pierced the Scarpa fascia before draining into the superficial inguinal nodes located deep to this layer. The transition from the supra- to the infra-Scarpa fascia plane occurred within 2 to 3 cm of the inguinal ligament in 95 percent of the collectors. In the four cadavers studied, preserving the Scarpa fascia during abdominoplasty would not preserve the lower abdominal collectors.

  19. Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis

    PubMed Central

    Lerner, Thomas R.; de Souza Carvalho-Wodarz, Cristiane; Repnik, Urska; Russell, Matthew R.G.; Borel, Sophie; Diedrich, Collin R.; Rohde, Manfred; Wainwright, Helen; Collinson, Lucy M.; Wilkinson, Robert J.; Griffiths, Gareth; Gutierrez, Maximiliano G.

    2016-01-01

    In extrapulmonary tuberculosis, the most common site of infection is within the lymphatic system, and there is growing recognition that lymphatic endothelial cells (LECs) are involved in immune function. Here, we identified LECs, which line the lymphatic vessels, as a niche for Mycobacterium tuberculosis in the lymph nodes of patients with tuberculosis. In cultured primary human LECs (hLECs), we determined that M. tuberculosis replicates both in the cytosol and within autophagosomes, but the bacteria failed to replicate when the virulence locus RD1 was deleted. Activation by IFN-γ induced a cell-autonomous response in hLECs via autophagy and NO production that restricted M. tuberculosis growth. Thus, depending on the activation status of LECs, autophagy can both promote and restrict replication. Together, these findings reveal a previously unrecognized role for hLECs and autophagy in tuberculosis pathogenesis and suggest that hLECs are a potential niche for M. tuberculosis that allows establishment of persistent infection in lymph nodes. PMID:26901813

  20. Fluorescein sodium fluorescence microscope-integrated lymphangiography for lymphatic supermicrosurgery.

    PubMed

    Ayestaray, Benoit; Bekara, Farid

    2015-07-01

    Microscope-integrated lymphangiography is a useful method in the field of lymphatic supermicrosurgery. Fluorescence based on indocyanine green (ICG) is the most commonly used. Fluorescein sodium is a fluorescent tracer used for retinal and neurosurgical angiography but not yet for lymphatic supermicrosurgery. In this report, we present a case in which the fluorescein sodium fluorescence microscope-integrated lymphangiography was used for assessment of lymphatic drainage pathway and patency in a patient treated for secondary lymphedema by lymphaticovenular anastomoses. Fluorescein sodium fluorescence microscope-integrated lymphangiography was evaluated in a 67-year-old female presented for a Campisi clinical stage IV lymphedema of the upper limb. Transcutaneous guidance and vascular fluorescence were assessed. A comparison with ICG fluorescence was made intraoperatively. Two lymphaticovenular anastomoses were performed and their patency were checked by lymphangiography. Transcutaneous signal was found higher with fluorescein sodium fluorescence. Intraluminal visualization was possible with fluorescein sodium coloration during lymphaticovenular anastomoses. No adverse reaction occurred. The circumferential differential reduction rate of affected limb was 8.1% 3 months after lymphaticovenular anastomoses. The use of fluorescence microscope-integrated lymphangiography with fluorescein sodium may be superior to ICG fluorescence in assistance of lymphaticovenular anastomoses.

  1. Effect of hepatoma H22 on lymphatic endothelium in vitro

    PubMed Central

    Yu, Hua; Zhou, Hong-Zhi; Wang, Chun-Mei; Gu, Xiao-Ming; Pan, Bo-Rong

    2004-01-01

    AIM: To determine the effect of metastatic hepatoma cells on lymphangioma-derived endothelium, and to establish in vitro model systems for assessing metastasis-related response of lymphatic endothelium. METHODS: Benign lymphangioma, induced by intraperitoneal injection of the incomplete Freund’s adjuvant in BALB/c mice, was embedded in fibrin gel or digested and then cultured in the conditioned medium derived from hepatoma H22. Light and electron microscopy, and the transwell migration assay were used to determine the effect of H22 on tissue or cell culture. Expressions of Flt-4, c-Fos, proliferating cell nuclear antigen (PCNA), and inducible nitric oxide synthase (iNOS) in cultured cells, and content of nitric oxide in culture medium were also examined. RESULTS: The embedded lymphangioma pieces gave rise to array of capillaries, while separated cells from lymphangioma grew to a cobblestone-like monolayer. H22 activated growth and migration of the capillaries and cells, induced expressions of Flt-4, c-Fos, PCNA and iNOS in cultured cells, and significantly increased the content of NO in the culture medium. CONCLUSION: Lymphangioma-derived cells keep the differentiated phenotypes of lymphatic endothelium, and the models established in this study are feasible for in vitro study of metastasis-related response of lymphatic endothelium. PMID:15526361

  2. Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis.

    PubMed

    Lerner, Thomas R; de Souza Carvalho-Wodarz, Cristiane; Repnik, Urska; Russell, Matthew R G; Borel, Sophie; Diedrich, Collin R; Rohde, Manfred; Wainwright, Helen; Collinson, Lucy M; Wilkinson, Robert J; Griffiths, Gareth; Gutierrez, Maximiliano G

    2016-03-01

    In extrapulmonary tuberculosis, the most common site of infection is within the lymphatic system, and there is growing recognition that lymphatic endothelial cells (LECs) are involved in immune function. Here, we identified LECs, which line the lymphatic vessels, as a niche for Mycobacterium tuberculosis in the lymph nodes of patients with tuberculosis. In cultured primary human LECs (hLECs), we determined that M. tuberculosis replicates both in the cytosol and within autophagosomes, but the bacteria failed to replicate when the virulence locus RD1 was deleted. Activation by IFN-γ induced a cell-autonomous response in hLECs via autophagy and NO production that restricted M. tuberculosis growth. Thus, depending on the activation status of LECs, autophagy can both promote and restrict replication. Together, these findings reveal a previously unrecognized role for hLECs and autophagy in tuberculosis pathogenesis and suggest that hLECs are a potential niche for M. tuberculosis that allows establishment of persistent infection in lymph nodes.

  3. A brief perspective on the diverging theories of lymphatic targeting with colloids

    PubMed Central

    Siram, Karthik; Marslin, Gregory; Raghavan, Chellan Vijaya; Balakumar, Krishnamoorthy; Rahman, Habibur; Franklin, Gregory

    2016-01-01

    For targeted delivery of colloids to the lymphatic system, the colloids should efficiently reach and remain in the lymphatics for a considerable period of time. As per the current knowledge, diffusion and phagocytosis are the two mechanisms through which colloids reach the lymphatic system. Several parameters including particle size and charge have been shown to affect the direct uptake of colloids by the lymphatic system. Although many researchers attached ligands on the surface of colloids to promote phagocytosis-mediated lymphatic delivery, another school of thought suggests avoidance of phagocytosis by use of carriers like polyethylene glycol (PEG)ylated colloids to impart stealth attributes and evade phagocytosis. In this perspective, we weigh up the paradoxical theories and approaches available in the literature to draw conclusions on the conditions favorable for achieving efficient lymphatic targeting of colloids. PMID:27366065

  4. A brief perspective on the diverging theories of lymphatic targeting with colloids.

    PubMed

    Siram, Karthik; Marslin, Gregory; Raghavan, Chellan Vijaya; Balakumar, Krishnamoorthy; Rahman, Habibur; Franklin, Gregory

    2016-01-01

    For targeted delivery of colloids to the lymphatic system, the colloids should efficiently reach and remain in the lymphatics for a considerable period of time. As per the current knowledge, diffusion and phagocytosis are the two mechanisms through which colloids reach the lymphatic system. Several parameters including particle size and charge have been shown to affect the direct uptake of colloids by the lymphatic system. Although many researchers attached ligands on the surface of colloids to promote phagocytosis-mediated lymphatic delivery, another school of thought suggests avoidance of phagocytosis by use of carriers like polyethylene glycol (PEG)ylated colloids to impart stealth attributes and evade phagocytosis. In this perspective, we weigh up the paradoxical theories and approaches available in the literature to draw conclusions on the conditions favorable for achieving efficient lymphatic targeting of colloids.

  5. Myeloid cells pave the way for lymphatic system development and maintenance.

    PubMed

    Ivanov, Stoyan; Randolph, Gwendalyn J

    2017-04-01

    The maintenance of tissue homeostasis is indispensable for health. In particular, removal of toxic compounds from cells and organs is a vital process for the organism. The lymphatic vasculature works in order to ensure the efficient removal of tissue waste. Forbidden over the last decade when more attention was paid to the blood vasculature, studies on the lymphatic vasculature have gained momentum during the last couple of years. The lymphatic vasculature naturally runs parallel to the blood vasculature and their synergistic work is critical for maintaining tissue homeostasis. Diminished lymphatic function results in accumulation of body fluids in tissues and gives rise to edema. Recently, it became obvious that immune cells including myeloid cells and lymphocytes are able to interact with and control the development and function of the lymphatic vasculature. In this review, we will focus on the interaction between myeloid cells, including macrophages, monocytes, and dendritic cells, with lymphatic vessels.

  6. Immunohistochemical study of the lymphatic vessels in major salivary glands of the rat.

    PubMed

    Aiyama, Shigeo; Kikuchi, Kenichiro; Takada, Kiyomi; Ikeda, Rie; Sato, Sumie; Kuroki, Jyunya

    2011-02-01

    This study was designed to examine whether lymphatic vessels are present in the lobules of major salivary glands in the rat. Immunostaining with an antibody against podoplanin, a lymphatic endothelial cell marker, was performed on sections of the submandibular, sublingual and parotid glands. Light microscopy demonstrated podoplanin-positive lymphatic vessels around the interlobular ducts and the interlobular arteries and veins in the interlobular connective tissue in all of the major salivary glands. No podoplanin-positive lymphatic vessels were found in the lobules. Electron microscopy also demonstrated lymphatic endothelial cells showing podoplanin expression only in the interlobular connective tissue. These findings suggest that the lymphatic system of the rat major salivary glands originates in the interlobular connective tissue, and not in the lobules.

  7. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI.

    PubMed

    Absinta, Martina; Ha, Seung-Kwon; Nair, Govind; Sati, Pascal; Luciano, Nicholas J; Palisoc, Maryknoll; Louveau, Antoine; Zaghloul, Kareem A; Pittaluga, Stefania; Kipnis, Jonathan; Reich, Daniel S

    2017-10-03

    Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.

  8. The lymphatic vascular system in liver diseases: its role in ascites formation.

    PubMed

    Chung, Chuhan; Iwakiri, Yasuko

    2013-06-01

    The lymphatic system is part of the circulatory system and plays a key role in normal vascular function. Its failure plays a crucial role in the development and maintenance of various diseases including liver diseases. Lymphangiogenesis (the growth of lymphatic vessels) and changes in the properties of lymphatic vessels are associated with pathogenesis of tumor metastases, ascites formation, liver fibrosis/cirrhosis and portal hypertension. Despite its significant role in liver diseases and its importance as a potential therapeutic target for those diseases, the lymphatic vascular system of the liver is poorly understood. Therefore, how the lymphatic vascular system in general and lymphangiogenesis in particular are mechanistically related to the pathogenesis and maintenance of liver diseases are largely unknown. This article summarizes: 1) the lymphatic vascular system; 2) its role in liver tumors, liver fibrosis/cirrhosis and portal hypertension; and 3) its role in ascites formation.

  9. [Advances in the research of the peritoneal lymphatic stomata in human].

    PubMed

    Li, H; Li, J

    2000-12-01

    Peritoneal lymphatic stomata are small openings of the subperitoneal lymphatic vessels on the free surface of the mesothelium. The peritoneal cavity is connected with lymphatic system via these small openings which are considered to be the main passage-way that can absorb matter from the peritoneal cavity. The lymphatic stomata are claimed to be involved in many clinic procedures, such as ascites elimination; ultrafiltration failure on the continuous ambulatory peritoneal dialysis; metastasis of tumor cells from the peritoneal cavity, and so on. It was reported that the cellular factor-NO(i.e. endothelium-derived relaxing factor, EDRF) can enhance the patency of the stomata and lymphatic absorption of the stomata by stimulating guanylate way, then increasing the concentration of the cGMP, decreasing the concentration of the [Ca2+] and as a result diastole the lymphatic stomata. Some traditional Chinese medicines, which can enhance absorption of ascites, have a regulative function on the stomata by enhancing the NO concentration.

  10. Near-Infrared Fluorescence Lymphatic Imaging of a Toddler With Congenital Lymphedema.

    PubMed

    Greives, Matthew R; Aldrich, Melissa B; Sevick-Muraca, Eva M; Rasmussen, John C

    2017-03-29

    Primary lymphedema in the pediatric population remains poorly diagnosed and misunderstood due to a lack of information on the causation and underlying anatomy of the lymphatic system. Consequently, therapeutic protocols for pediatric patients remain sparse and with little evidence to support them. In an effort to better understand the causation of primary pediatric lymphedema and to better inform clinical care, we report the use of near-infrared fluorescence lymphatic imaging on the extremities of an alert, 21-month-old boy who presented with unilateral right arm and hand lymphedema at birth. The imaging results indicated an intact, apparently normal lymphatic anatomy with no obvious malformation, but with decreased lymphatic contractile function of the affected upper extremity relative to the contralateral and lower extremities. We hypothesized that the lack of contraction of the lymphatic vessels rather than an anatomic malformation was the source of the unilateral extremity swelling, and that compression and manual lymphatic drainage could be effective treatments.

  11. Intracellular uptake of macromolecules by brain lymphatic endothelial cells during zebrafish embryonic development.

    PubMed

    van Lessen, Max; Shibata-Germanos, Shannon; van Impel, Andreas; Hawkins, Thomas A; Rihel, Jason; Schulte-Merker, Stefan

    2017-05-12

    The lymphatic system controls fluid homeostasis and the clearance of macromolecules from interstitial compartments. In mammals brain lymphatics were only recently discovered, with significant implications for physiology and disease. We examined zebrafish for the presence of brain lymphatics and found loosely connected endothelial cells with lymphatic molecular signature covering parts of the brain without forming endothelial tubular structures. These brain lymphatic endothelial cells (BLECs) derive from venous endothelium, are distinct from macrophages, and are sensitive to loss of Vegfc. BLECs endocytose macromolecules in a selective manner, which can be blocked by injection of mannose receptor ligands. This first report on brain lymphatic endothelial cells in a vertebrate embryo identifies cells with unique features, including the uptake of macromolecules at a single cell level. Future studies will address whether this represents an uptake mechanism that is conserved in mammals and how these cells affect functions of the embryonic and adult brain.

  12. Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis.

    PubMed

    Tammela, Tuomas; Saaristo, Anne; Holopainen, Tanja; Ylä-Herttuala, Seppo; Andersson, Leif C; Virolainen, Susanna; Immonen, Ilkka; Alitalo, Kari

    2011-02-09

    The dissemination of tumor cells to sites far from the primary tumor (metastasis) is the principal cause of death in cancer patients. Tumor-associated lymphatic vessels are a key conduit for metastatic tumor cells, which typically first colonize the lymph nodes. Although the primary tumor and affected lymph nodes can be removed during surgery, tumor cells inside lymphatic vessels are left behind. Here, we show that in-transit tumor cells inside lymphatic vessels in mice bearing mouse melanomas or human lung tumors give rise to metastases. Using photodynamic therapy with the benzoporphyrin derivative verteporfin, we selectively destroyed lymphatic vessels in mice and pigs. Destruction of tumor-associated lymphatic vessels also eradicated intralymphatic tumor cells and prevented metastasis of mouse melanoma cells and subsequent relapse. Photodynamic therapy, when combined with anti-lymphangiogenic therapy, prevented further tumor invasion of lymphatic vessels. These findings highlight the potential of targeting in-transit tumor cells in patients.

  13. Lymphatic filariasis in Papua New Guinea: prospects for elimination.

    PubMed

    Bockarie, Moses J; Kazura, James W

    2003-02-01

    Lymphatic filariasis is a significant public health problem in several Pacific island countries. Papua New Guinea is one of the most populous countries in this region, and 39% of its residents are estimated to be infected with Wuchereria bancrofti. The Ministries of Health of the 22 islands and territories in the Pacific region are committed to taking action against lymphatic filariasis. Accordingly, a regional collaborative effort aimed at the control of filariasis has been organized under the auspices of a program referred to as PacELF. The main objective of PacELF is to eliminate filariasis as public health problem in the Pacific region by the year 2010, 10 years before global elimination of this infectious disease has been targeted. This contribution describes the epidemiology and ecological features of filariasis and prospects for its elimination in Papua New Guinea. The frequencies of microfilaremia, chronic lymphatic disease, and acute filarial morbidity in Papua New Guinea are higher than in many other endemic countries of the Pacific, Africa, and South America. All possible combinations of these three manifestations of filariasis exist. They occur independently of each other, and there is no association between chronic lymphatic disease and microfilarial status. Anopheles punctulatus mosquitoes are the main vectors throughout the country. Transmission intensity is heterogeneous and a major determinant of local patent infection and morbidity rates. Annual transmission potential and annual infective biting rates are positively associated with the village-specific microfilarial rate, mean intensity of microfilaremia, and prevalence of leg edema. Children and adults have similar worm burdens, assessed by circulating filarial antigen levels, in areas of high transmission, whereas worm burdens increase with age in areas of lower transmission. Intensity of exposure to infective third-stage larvae (L3) is significantly correlated with filarial antigen

  14. Significantly high lymphatic vessel density in cutaneous metastasizing melanoma

    PubMed Central

    Špirić, Z; Erić, M; Eri, Ž; Skrobić, M

    2015-01-01

    Background Cutaneous melanoma has the propensity to early metastatic spread via the lymphatic vessels. Recent studies have found a positive correlation between an increased number of tumor-associated lymphatics and lymph node metastasis. The aim of this study was to determine whether there was a difference in the lymphatic vessel density (LVD) when cutaneous metastasizing melanomas were compared with nonmetastasizing melanomas and nevi. Methods Ninety-five melanoma specimens (45 with lymph node metastasis, 50 nonmetastasizing) and 22 nevi specimens (7 compound, 5 intradermal, 4 blue, and 6 dysplastic) were investigated by immunostaining for the lymphatic endothelial marker D2-40. The quantification of lymphatics was conducted by computer-assisted morphometric analysis. Metastasizing and nonmetastasizing melanoma specimens were matched according to their thickness into three classes ≤2.0 mm, 2.01 – 4.0 mm, >4.0 mm. Results Metastasizing melanomas thick 2.01–4.0 mm and thicker than 4.0 mm, showed a significantly higher intratumoral and peritumoral LVD compared with nonmetastasizing melanomas (2.01–4.0 mm, p =0.006 and p =0.032, respectively; >4.0 mm, p =0.045 and p =0.026, respectively). No significant difference in intratumoral and peritumoral LVD was found between metastasizing and nonmetastasizing melanomas of thickness ≤2.0 mm. Metastasizing melanomas showed a significantly higher intratumoral LVD compared with compound, intradermal, blue and dysplastic nevi p <0.001, p =0.002, p =0.002 and p <0.001, respectively), and significantly higher peritumoral LVD compared with compound nevi (p=0.039). Total average LVD was significantly higher in metastasizing melanomas than in nonmetastasizing melanomas (p <0.001), compound, intradermal, blue and dysplastic nevi (p <0.001, p <0.001, p =0.001 and p <0.001, respectively). Conclusions This study shows higher LVD in metastasizing melanomas compared with nonmetastasizing melanomas and nevi. In melanomas with

  15. Increased lymphatic vessels in patients with encapsulating peritoneal sclerosis.

    PubMed

    Yaginuma, Tatsuhiro; Yamamoto, Izumi; Yamamoto, Hiroyasu; Mitome, Jun; Tanno, Yudo; Yokoyama, Keitaro; Hayashi, Takenori; Kobayashi, Tetsuya; Watanabe, Michiaki; Yamaguchi, Yutaka; Hosoya, Tatsuo

    2012-01-01

    The angiogenic response is partly involved in the progression of encapsulating peritoneal sclerosis (EPS). However, the details of the angiogenic response, especially for lymphatic vessels in patients with EPS, remain unclear. In addition, because of technical limitations, morphology studies reported to date have examined only the parietal peritoneum. The morphologies of parietal and visceral lymphatic vessels in patients with EPS both need to be analyzed. We examined peritoneal samples from 18 patients with EPS who underwent enterolysis of the visceral peritoneum and compared them with samples from 17 autopsy cases (controls). To examine the angiogenic response, we performed immunohistochemistry for the endothelial markers CD34 (blood vessels) and podoplanin (lymphatic vessels) and for the cell proliferation marker Ki-67. Immunogold electron microscopy analysis for podoplanin was also performed. In 7 of 18 cases, we compared differences in the angiogenic response of the parietal and visceral peritoneal membranes. Angiogenic responses were more frequent in the compact zone than in regenerated layers. The number of capillaries positive for anti-CD34 and anti-podoplanin monoclonal antibodies per unit area of visceral peritoneal tissue was, respectively, 41.1 ± 29.3/mm(2) in EPS patients and 2.7 ± 4.4/mm(2) in controls (p ≤ 0.01) and 48.1 ± 43.9/mm(2) in EPS patients and 4.1 ± 5.4/mm(2) in controls (p ≤ 0.01). The percentage of capillaries positive for anti-Ki-67, CD34, and podoplanin was 4.6% in EPS patients (p ≤ 0.01) and 0.8% in controls (p = 0.09). The immunogold electron microscopy analysis revealed that podoplanin was localized to endothelial cells with anchoring filaments, a specific feature of lymphatic vessels. Furthermore, compared with parietal peritoneal membrane, visceral peritoneal membrane had a more prominent podoplanin-positive capillary profile, but not a prominent CD34-positive capillary profile. In addition, fibroblast-like cells double

  16. Basement membrane protein distribution in LYVE-1-immunoreactive lymphatic vessels of normal tissues and ovarian carcinomas.

    PubMed

    Vainionpää, Noora; Bützow, Ralf; Hukkanen, Mika; Jackson, David G; Pihlajaniemi, Taina; Sakai, Lynn Y; Virtanen, Ismo

    2007-05-01

    The endothelial cells of blood vessels assemble basement membranes that play a role in vessel formation, maintenance and function, and in the migration of inflammatory cells. However, little is known about the distribution of basement membrane constituents in lymphatic vessels. We studied the distribution of basement membrane proteins in lymphatic vessels of normal human skin, digestive tract, ovary and, as an example of tumours with abundant lymphatics, ovarian carcinomas. Basement membrane proteins were localized by immunohistochemistry with monoclonal antibodies, whereas lymphatic capillaries were detected with antibodies to the lymphatic vessel endothelial hyaluronan receptor-1, LYVE-1. In skin and ovary, fibrillar immunoreactivity for the laminin alpha4, beta1, beta2 and gamma1 chains, type IV and XVIII collagens and nidogen-1 was found in the basement membrane region of the lymphatic endothelium, whereas also heterogeneous reactivity for the laminin alpha5 chain was detected in the digestive tract. Among ovarian carcinomas, intratumoural lymphatic vessels were found especially in endometrioid carcinomas. In addition to the laminin alpha4, beta1, beta2 and gamma1 chains, type IV and XVIII collagens and nidogen-1, carcinoma lymphatics showed immunoreactivity for the laminin alpha5 chain and Lutheran glycoprotein, a receptor for the laminin alpha5 chain. In normal lymphatic capillaries, the presence of primarily alpha4 chain laminins may therefore compromise the formation of endothelial basement membrane, as these truncated laminins lack one of the three arms required for efficient network assembly. The localization of basement membrane proteins adjacent to lymphatic endothelia suggests a role for these proteins in lymphatic vessels. The distribution of the laminin alpha5 chain and Lutheran glycoprotein proposes a difference between normal and carcinoma lymphatic capillaries.

  17. Infrared fluorescence imaging of lymphatic regeneration in nonhuman primate facial vascularized composite allografts.

    PubMed

    Mundinger, Gerhard S; Narushima, Mitsunaga; Hui-Chou, Helen G; Jones, Luke S; Ha, Jinny S; Shipley, Steven T; Drachenberg, Cinthia B; Dorafshar, Amir H; Koshima, Isao; Bartlett, Stephen T; Barth, Rolf N; Rodriguez, Eduardo D

    2012-03-01

    Clinical vascularized composite allografts (VCA), although performed with good success, have been characterized by rejection episodes and postoperative graft edema. We investigated lymphatic donor-recipient reconstitution and lymphatic regeneration in a nonhuman primate facial VCA model. Heterotopic partial face (n = 9) VCAs were performed in cynomolgus macaques. Grafts were monitored for rejection episodes and response to immunosuppressive therapies as previously described. Donor and recipient lymphatic channels were evaluated using a near-infrared handheld dual-channel light-emitting diode camera system capable of detecting fluorescence from indocyanine green injections. Graft lymphatic channels were serially evaluated from postoperative day 0 to 364. Preoperative imaging demonstrated superficial lymphatic anatomy similar to human anatomy. Initial resolution of facial allograft swelling coincided with superficial donor-recipient lymphatic channel reconstitution. Reconstitution occurred despite early acute rejection episodes in 2 animals. However, lymphatic channels demonstrated persistent functional and anatomic pathology, and graft edema never fully resolved. No differences in lymphatic channels were noted between grafts that developed transplant vasculopathy (n = 3) and those that did not (n = 6). Dynamic changes in patterns of lymphatic drainage were noted in 4 animals following withdrawal of immunosuppression. Donor-recipient lymphatic channel regeneration following VCA did not result in resolution of edema. Technical causes of graft edema may be overcome with alternative surgical techniques, allowing for direct investigation of the immunologic relationship between VCA graft edema and rejection responses. Mechanisms and timing of dynamic donor-recipient lymphatic channel relationships can be evaluated using fluorescent imaging systems to better define the immunologic role of lymphatic channels in VCA engraftment and rejection responses, which may have direct

  18. [The lens of the eye and its relation to the lymphatic system].

    PubMed

    Fabian, G

    1986-12-01

    On the basis of well-tried methods of investigation with vital dyes (patent blue violet and Japanese ink) and in combination with the drug (Conjunctisan A), the natural pathways of resorption through the lymphatics of the eye in the mouse, were displayed and this permitted the transport mechanisms to be followed. It was possible gradually to understand the morphology of the lymphatic drainage and, in this way evidence was produced regarding the relationships of the lymphatic system and the regional lymph nodes.

  19. Response of lymphatics of canine hind limb to sympathetic nerve stimulation.

    PubMed

    Browse, N L

    1968-07-01

    1. The changes in lymphatic pressure in a limb whose circulation was temporarily arrested with a pneumatic cuff have been studied.2. Stimulation of the lumbar sympathetic chain caused an increase in lymphatic pressure. It has been shown that this is a primary not a secondary phenomenon, due to an active lymphomotor mechanism.3. The increase of lymphatic tone is proportional to the rate of stimulation; peak values are reached between 5 and 9 impulses/sec.

  20. Endogenous TNFα orchestrates the trafficking of neutrophils into and within lymphatic vessels during acute inflammation

    PubMed Central

    Arokiasamy, Samantha; Zakian, Christian; Dilliway, Jessica; Wang, Wen; Nourshargh, Sussan; Voisin, Mathieu-Benoit

    2017-01-01

    Neutrophils are recognised to play a pivotal role at the interface between innate and acquired immunities following their recruitment to inflamed tissues and lymphoid organs. While neutrophil trafficking through blood vessels has been extensively studied, the molecular mechanisms regulating their migration into the lymphatic system are still poorly understood. Here, we have analysed neutrophil-lymphatic vessel interactions in real time and in vivo using intravital confocal microscopy applied to inflamed cremaster muscles. We show that antigen sensitisation of the tissues induces a rapid but transient entry of tissue-infiltrated neutrophils into lymphatic vessels and subsequent crawling along the luminal side of the lymphatic endothelium. Interestingly, using mice deficient in both TNF receptors p55 and p75, chimeric animals and anti-TNFα antibody blockade we demonstrate that tissue-release of TNFα governs both neutrophil migration through the lymphatic endothelium and luminal crawling. Mechanistically, we show that TNFα primes directly the neutrophils to enter the lymphatic vessels in a strictly CCR7-dependent manner; and induces ICAM-1 up-regulation on lymphatic vessels, allowing neutrophils to crawl along the lumen of the lymphatic endothelium in an ICAM-1/MAC-1-dependent manner. Collectively, our findings demonstrate a new role for TNFα as a key regulator of neutrophil trafficking into and within lymphatic system in vivo. PMID:28287124

  1. Current views on the function of the lymphatic vasculature in health and disease

    PubMed Central

    Wang, Yingdi; Oliver, Guillermo

    2010-01-01

    The lymphatic vascular system is essential for lipid absorption, fluid homeostasis, and immune surveillance. Until recently, lymphatic vessel dysfunction had been associated with symptomatic pathologic conditions such as lymphedema. Work in the last few years had led to a better understanding of the functional roles of this vascular system in health and disease. Furthermore, recent work has also unraveled additional functional roles of the lymphatic vasculature in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension. In this review, we summarize the functional roles of the lymphatic vasculature in health and disease. PMID:20889712

  2. Airway response to sirolimus therapy for the treatment of complex pediatric lymphatic malformations.

    PubMed

    Alemi, A Sean; Rosbe, Kristina W; Chan, Dylan K; Meyer, Anna K

    2015-12-01

    Head and neck lymphatic malformations can create airway management challenges requiring tracheotomy. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), may inhibit growth of lymphatic malformations. We describe two patients born with large lymphatic malformations with improved airway symptoms following sirolimus therapy. Patient #1 underwent tracheotomy and multi-modal therapy including sirolimus with reduction in airway involvement but regrowth after discontinuation of sirolimus. Patient #2 also experienced a significant response to sirolimus allowing for extubation and discharge without tracheotomy. Early initiation of sirolimus therapy should be considered as a means to avoid tracheotomy in complex head and neck lymphatic malformations.

  3. A tale of two models: mouse and zebrafish as complementary models for lymphatic studies.

    PubMed

    Kim, Jun-Dae; Jin, Suk-Won

    2014-07-01

    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.

  4. Endogenous TNFα orchestrates the trafficking of neutrophils into and within lymphatic vessels during acute inflammation.

    PubMed

    Arokiasamy, Samantha; Zakian, Christian; Dilliway, Jessica; Wang, Wen; Nourshargh, Sussan; Voisin, Mathieu-Benoit

    2017-03-13

    Neutrophils are recognised to play a pivotal role at the interface between innate and acquired immunities following their recruitment to inflamed tissues and lymphoid organs. While neutrophil trafficking through blood vessels has been extensively studied, the molecular mechanisms regulating their migration into the lymphatic system are still poorly understood. Here, we have analysed neutrophil-lymphatic vessel interactions in real time and in vivo using intravital confocal microscopy applied to inflamed cremaster muscles. We show that antigen sensitisation of the tissues induces a rapid but transient entry of tissue-infiltrated neutrophils into lymphatic vessels and subsequent crawling along the luminal side of the lymphatic endothelium. Interestingly, using mice deficient in both TNF receptors p55 and p75, chimeric animals and anti-TNFα antibody blockade we demonstrate that tissue-release of TNFα governs both neutrophil migration through the lymphatic endothelium and luminal crawling. Mechanistically, we show that TNFα primes directly the neutrophils to enter the lymphatic vessels in a strictly CCR7-dependent manner; and induces ICAM-1 up-regulation on lymphatic vessels, allowing neutrophils to crawl along the lumen of the lymphatic endothelium in an ICAM-1/MAC-1-dependent manner. Collectively, our findings demonstrate a new role for TNFα as a key regulator of neutrophil trafficking into and within lymphatic system in vivo.

  5. A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

    PubMed Central

    Kim, Jun-Dae; Jin, Suk-Won

    2014-01-01

    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. PMID:24854860

  6. A New Technique to Map the Lymphatic Distribution and Alignment of the Penis.

    PubMed

    Long, Liu Yan; Qiang, Pan Fu; Ling, Tao; Wei, Zhang Yan; Long, Zhang Yu; Shan, Meng; Rong, Li Shi; Li, Li Hong

    2015-08-01

    The present study was to examine the distribution of lymphatic vessels in the penis of normal adult males, which could provide an anatomical basis for improvement of incisions in penile lengthening surgery, and may also help to prevent postoperative refractory edema. Thirteen normal adult male volunteers were recruited for this study. Contrast agent was injected subcutaneously in the foreskin of the penis, and after two minutes magnetic resonance lymphangiography (MRL) was performed. The acquired magnetic resonance images were analyzed to determine the changes in the number and diameter of lymphatic vessels in different parts of the penis. Maximum intensity projections (MIP) and materializes interactive medical image control system (MIMICS) were applied to analyze the overall distribution of lymphatic vessels in the penis. Magnetic resonance imaging (MRI) showed that the lymphatic vessels were in conspicuous contrast with surrounding tissues and could be clearly identified. Penile lymphatic vessels were clearly visible in the root of the penis. At the junction of the penis and the abdominal wall, all lymphatic vessels were found to be concentrated in the dorsal part of the penis. MIP two-dimensional reconstruction showed that the overall distribution of relatively large lymphatic vessels in the dorsal and ventral parts of the penis could be seen clearly on bilateral 45° position, but not inside the abdominal wall because some of lymphatic vessels were overlapped by other tissues in the abdomen. MIMICS three-dimensional reconstruction was able to reveal the overall spatial distribution of lymphatic vessels in the penis from any angle. The reconstruction results showed that there were 1-2 main lymphatic vessels on the root of dorsal penis, which coursed along the cavernous to the first physiological curvature of the penis. Lymphatic vessels merged on both sides of the ventral penis. At the root of the penis, lymphatic vessels gradually coursed to the dorsal surface

  7. [Lymphatic system of the tongue and its role in glositis of odontogenic origin].

    PubMed

    Chkhikvishvili, M Dzh

    2005-02-01

    In aged persons reduction of diameter of tongue lymphatic capillaries precedes thinning of the Kaarl net. In the process of tongue inflammation, lymphogenic way of inclusion in 6|6 and 8|8 teeth lower area should be stuck out with existence of alleged "Integration Centers". Lymphatic knots and lymphatic ducts are in prevailed placed in corresponding tissues of lower-chin and lower teeth. Lymphatic-muscular system and its anatomical links and age-related changeability raise the special interest during odontogenic infections with tongue inflammation.

  8. Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling.

    PubMed

    Williams, Steven P; Odell, Adam F; Karnezis, Tara; Farnsworth, Rae H; Gould, Cathryn M; Li, Jason; Paquet-Fifield, Sophie; Harris, Nicole C; Walter, Anne; Gregory, Julia L; Lamont, Sara F; Liu, Ruofei; Takano, Elena A; Nowell, Cameron J; Bower, Neil I; Resnick, Daniel; Smyth, Gordon K; Coultas, Leigh; Hogan, Benjamin M; Fox, Stephen B; Mueller, Scott N; Simpson, Kaylene J; Achen, Marc G; Stacker, Steven A

    2017-10-03

    Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that LGALS1, which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  9. Advanced drug delivery to the lymphatic system: lipid-based nanoformulations

    PubMed Central

    Khan, Arshad Ali; Mudassir, Jahanzeb; Mohtar, Noratiqah; Darwis, Yusrida

    2013-01-01

    The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipid-based nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes

  10. Investigation of the lymphatic stream of the stomach in gastric cancer with solitary lymph node metastasis.

    PubMed

    Tokunaga, Masanori; Ohyama, Shigekazu; Hiki, Naoki; Fukunaga, Tetsu; Yamada, Kazuhiko; Sano, Takeshi; Yamaguchi, Toshiharu

    2009-06-01

    Understanding the lymphatic drainage route in gastric cancer is crucial for complete lymph node retrieval from sites susceptible to metastasis. However, the lymphatic stream of the stomach is complex and remains incompletely characterized. Patients with small (<4 cm) serosa-negative gastric cancer with solitary lymph node metastasis treated at the Cancer Institute Hospital were included in this study. A total of 135 patients were classified according to the location of the solitary lymph node metastasis into the left gastric artery (LGA) group, the right gastroepiploic artery (RGEA) group, the right gastric artery (RGA) group, or the splenic artery (SA) group. The location of the primary tumors was investigated to aid the mapping of the lymphatic stream of the stomach. Lymphatic flow in LGA (65 patients) and in RGEA (57 patients) are main lymphatic drainage routes of the stomach. The lymphatic area overlapped in the lower third of the stomach in LGA and RGEA, and the lymphatic flow associated with gastric cancer located within this overlapped area can be multidirectional. Skip metastases were observed in 13 patients (10%), and all skip metastases were observed in the suprapancreatic area (station 7, 8a, 9, or 11p). The lymphatic stream of the stomach is complicated and multidirectional. Understanding and mapping the complex lymphatic streams of the stomach will allow surgeons to perform more effective lymph node dissection during gastric cancer surgery.

  11. Bioengineering dermo-epidermal skin grafts with blood and lymphatic capillaries.

    PubMed

    Marino, Daniela; Luginbühl, Joachim; Scola, Simonetta; Meuli, Martin; Reichmann, Ernst

    2014-01-29

    The first bioengineered, autologous, dermo-epidermal skin grafts are presently undergoing clinical trials; hence, it is reasonable to envisage the next clinical step at the forefront of plastic and burn surgery, which is the generation of autologous skin grafts that contain vascular plexuses, preformed in vitro. As the importance of the blood, and particularly the lymphatic vascular system, is increasingly recognized, it is attractive to engineer both human blood and lymphatic vessels in one tissue or organ graft. We show here that functional lymphatic capillaries can be generated using three-dimensional hydrogels. Like normal lymphatics, these capillaries branch, form lumen, and take up fluid in vitro and in vivo after transplantation onto immunocompromised rodents. Formation of lymphatic capillaries could be modulated by both lymphangiogenic and anti-lymphangiogenic stimuli, demonstrating the potential usefulness of this system for in vitro testing. Blood and lymphatic endothelial cells never intermixed during vessel development, nor did blood and lymphatic capillaries anastomose under the described circumstances. After transplantation of the engineered grafts, the human lymphatic capillaries anastomosed to the nude rat's lymphatic plexus and supported fluid drainage. Successful preclinical results suggest that these skin grafts could be applied on patients suffering from severe skin defects.

  12. The Lymphatic Anatomy of the Lower Eyelid and Conjunctiva and Correlation with Postoperative Chemosis and Edema.

    PubMed

    Shoukath, Sajna; Taylor, G Ian; Mendelson, Bryan C; Corlett, Russell J; Shayan, Ramin; Tourani, Saam S; Ashton, Mark W

    2017-03-01

    There are minimal data in the literature regarding the lymphatic drainage of the conjunctiva and lower eyelid and the relationship with postoperative chemosis and edema. Injection, microdissection, and histologic and radiologic studies were conducted on 12 hemifacial fresh cadaver specimens. Indocyanine green lymphography was conducted in five volunteers. Histology identified lymphatic vessels superficial and deep to the orbicularis oculi. Cadaveric dissection, injection, and radiographic studies identified interconnecting superficial and deep facial lymphatic systems and a conjunctival lymphatic network draining through the tarsal plate to the deep lymphatic system. The superficial lymphatic collectors traveled in subcutaneous fat within the lateral orbital and nasolabial fat compartments. The lateral deep lymphatic collectors traveled beneath orbicularis oculi, then through the superficial orbicularis retaining ligament, and into the sub-orbicularis oculi fat in the roof of the prezygomatic space. These vessels descended to preperiosteal fat at the level of zygomaticocutaneous ligaments to travel adjacent to the facial nerve into preauricular nodes. Indocyanine green lymphography identified correlating draining pathways laterally to the parotid nodes and medially to submandibular nodes. The authors have found that the lower eyelid and conjunctiva are drained by interconnecting superficial and deep lymphatic systems of the face. The superficial system is vulnerable to damage in incisions and dissection in the infraorbital area. The deep system is vulnerable to damage in dissection around the orbicularis retaining ligament and the zygomaticocutaneous ligaments. The authors suggest that concurrent damage to both the superficial and deep lymphatic systems, especially laterally, may be responsible for postoperative chemosis and edema.

  13. Supermicrosurgical anastomosis of superficial lymphatic vessel to deep lymphatic vessel for a patient with cellulitis-induced chronic localized leg lymphedema.

    PubMed

    Yamamoto, Takumi; Koshima, Isao

    2015-01-01

    Supermicrosurgical lymphaticovenular anastomosis (LVA) has been reported to be useful for the treatment of obstructive lymphedema. However, LVA has a potential risk of anastomosis site thrombosis. It is more physiological to use a lymphatic vessel as a recipient vessel of lymphatic bypass surgery, because there is no chance for blood to contact the anastomosis site. We report a chronic localized lower leg lymphedema case treated with supermicrosurgical superficial-to-deep lymphaticolymphatic anastomosis (LLA). A 66-year-old male with a 60-year history of cellulitis-induced left lower leg lymphedema suffered from very frequent episodes of cellulitis and underwent LLA under local infiltration anesthesia. LLA was performed at the dorsum of the left foot. A dilated superficial lymphatic vessel was found in the fat layer, and a nondilated intact deep lymphatic vessel was found along the dorsalis pedis artery below the deep fascia. The superficial lymphatic vessel was supermicrosurgically anastomosed to the deep lymphatic vessel in a side-to-end fashion. After the surgery, the patient had no episodes of cellulitis, and the left lower leg lymphedematous volume decreased. Superficial-to-deep LLA may be a useful option for the treatment of secondary lymphedema due to obstruction of only the superficial lymphatic system.

  14. Observations on the prenatal development of human lymphatic vessels with focus on basic structural elements of lymph flow.

    PubMed

    Petrenko, Valerii M; Gashev, Anatoliy A

    2008-01-01

    The prenatal development of human lymphatic systems has not attracted enough attention by lymphatic researchers in the past. Yet clearly these critical, early events determine the fate and function of the human lymphatic system. The main focus of these studies was to investigate the embryonic development of human lymphangions including lymphatic valves and muscle cells, to better understand the prenatal formation of basic structural elements of lymph flow. This review in most of its parts is a short summary of the findings. It provides important information necessary for understanding the development and functioning of the human lymphatic system. The structural basis of the active lymph transport system--the lymphatic muscle cells and lymphatic valves--which is absolutely necessary for all functions of lymphatic system, is already formed during the first half of the prenatal development in humans. During the second half of this development maturation of this system is already underway. The enlargement of lymphatic muscle cells together with increases in their quantity leads to formation of the multi-layered lymphatic vessel wall, able to develop contractions strong enough to propel lymph downstream of the lymphatic channels against gravity in bipedal humans. The development of the competent valves in lymphatic vessels occurs at the same time creating the ground for effective net, unidirectional lymph flow. The data summarized here represents some of the first systematic studies of the prenatal development of lymphatic muscle cells and valves in humans.

  15. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD

    PubMed Central

    2013-01-01

    Background De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking. Methods Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6. Results The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p < 0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p < 0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0

  16. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD.

    PubMed

    Mori, Michiko; Andersson, Cecilia K; Graham, Gerard J; Löfdahl, Claes-Göran; Erjefält, Jonas S

    2013-06-11

    De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking. Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6. The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p < 0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p < 0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0.05), as well as the alveolar

  17. Apolipoprotein A-I Modulates Atherosclerosis Through Lymphatic Vessel-Dependent Mechanisms in Mice.

    PubMed

    Milasan, Andreea; Jean, Gabriel; Dallaire, François; Tardif, Jean-Claude; Merhi, Yahye; Sorci-Thomas, Mary; Martel, Catherine

    2017-09-22

    Subcutaneously injected lipid-free apoA-I (apolipoprotein A-I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high-density lipoprotein-cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis-related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA-I. Atherosclerotic Ldlr(-/-) mice treated with low-dose lipid-free apoA-I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr(-/-) mice when compared with albumin-control mice. Treatment of human lymphatic endothelial cells with apoA-I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge-like manner, a mechanism that could strengthen endothelial cell-cell junctions and limit atherosclerosis-associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA-I-treated Ldlr(-/-) mice revealed that apoA-I decreased ex vivo platelet aggregation. This suggests that in vivo apoA-I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function. Altogether, we bring forward a new pleiotropic role for apoA-I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  18. The lymphatic system in the dorsal skinfold chamber of the Syrian golden hamster in vivo.

    PubMed

    Schacht, Vivien; Berens von Rautenfeld, Dirk; Abels, Christoph

    2004-05-01

    The lymphatic network contributes to maintaining tissue homeostasis and immunological function by transporting fluid, plasma protein and cells from peripheral tissue via the lymph nodes into the blood vascular system. In contrast to the blood circulatory system, little is known about the lymphatic system. In particular, suitable animal models are lacking. Therefore, the dorsal skinfold chamber model was used to investigate the existence of a lymphatic system. To analyze the lymphatic network Syrian golden hamsters (n=12) fitted with titanium chambers were used. FITC-dextran of different concentrations (5% or 25%) and different molecular weights (4, 40 or 150 kDa) was used to contrast lymphatic vessels and measure initial lymph flow velocity. Intravital fluorescence microscopy enabled the quantification of diameter, velocity and branching order. Histology and electron microscopy supported the in vivo findings. Immediately after intradermal injection of FITC-dextran the lymphatics including valves were visible. The diameters of the lymphatic vessels (n=189) ranged from 133+/-5.4 microm (branching order 1) to 26+/-4.0 microm (branching order 5). Using different molecular weights of FITC-dextran, no significant differences in velocity were measured (327+/-157 microm/s with 4 kDa, 391+/-126 microm/s with 40 kDa, and 378+/-175 microm/s with 150 kDa). Blood and lymphatic vessels could not be differentiated clearly by H&E staining. However, endothelial cells of vessels with an irregularly shaped lumen containing no erythrocytes in cross section showed a weaker signal for CD31 staining as compared to endothelial cells of vessels containing erythrocytes. Moreover, transmission electron microscopy identified the dye-containing vessels as lymphatics after intradermal injection of Berlin Blue. In conclusion, a lymphatic network was characterized in the dorsal skinfold chamber model of the Syrian golden hamster. Thus, this well-established animal model for intravital microscopy

  19. Dynamic imaging of lymphatic vessels and lymph nodes using a bimodal nanoparticulate contrast agent.

    PubMed

    Mounzer, Rawad; Shkarin, Pavel; Papademetris, Xenophon; Constable, Todd; Ruddle, Nancy H; Fahmy, Tarek M

    2007-01-01

    Evaluation of lymphedema and lymph node metastasis in humans has relied primarily on invasive or radioactive modalities. While noninvasive technologies such as magnetic resonance imaging (MRI) offer the potential for true three-dimensional imaging of lymphatic structures, invasive modalities, such as optical fluorescence microscopy, provide higher resolution and clearer delineation of both lymph nodes and lymphatic vessels. Thus, contrast agents that image lymphatic vessels and lymph nodes by both fluorescence and MRI may further enhance our understanding of the structure and function of the lymphatic system. Recent applications of bimodal (fluorescence and MR) contrast agents in mice have not achieved clear visualization of lymphatic vessels and nodes. Here the authors describe the development of a nanoparticulate contrast agent that is taken up by lymphatic vessels to draining lymph nodes and detected by both modalities. A unique nanoparticulate contrast agent composed of a polyamidoamine dendrimer core conjugated to paramagnetic contrast agents and fluorescent probes was synthesized. Anesthetized mice were injected with the nanoparticulates in the hind footpads and imaged by MR and fluorescence microscopy. High resolution MR and fluorescence images were obtained and compared to traditional techniques for lymphatic visualization using Evans blue dye. Lymph nodes and lymphatic vessels were clearly observed by both MRI and fluorescence microscopy using the bimodal nanoparticulate contrast agent. Characteristic tail-lymphatics were also visualized by both modalities. Contrast imaging yielded a higher resolution than the traditional method employing Evans blue dye. MR data correlated with fluorescence and Evans blue dye imaging. A bimodal nanoparticulate contrast agent facilitates the visualization of lymphatic vessels and lymph nodes by both fluorescence microscopy and MRI with strong correlation between the two modalities. This agent may translate to applications

  20. Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling.

    PubMed

    Morooka, Nanami; Futaki, Sugiko; Sato-Nishiuchi, Ryoko; Nishino, Masafumi; Totani, Yuta; Shimono, Chisei; Nakano, Itsuko; Nakajima, Hiroyuki; Mochizuki, Naoki; Sekiguchi, Kiyotoshi

    2017-04-14

    Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9β1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. We generated Polydom-deficient mice. Polydom(-/-) mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom(-/-) embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in Polydom(-/-) mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in Polydom(-/-) mice. Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system. © 2017 American Heart Association, Inc.

  1. Predictive factors for lymph node metastasis in early gastric cancer with lymphatic invasion after endoscopic resection.

    PubMed

    Park, Ji Won; Ahn, Sangjeong; Lee, Hyuk; Min, Byung-Hoon; Lee, Jun Haeng; Rhee, Poong-Lyul; Kim, Kyoung-Mee; Kim, Jae J

    2017-04-04

    Lymph node (LN) metastasis is found in only about 5-10% of the patients who undergo additional surgery after non-curative endoscopic resection. Lymphatic invasion after endoscopic submucosal dissection (ESD) is regarded as non-curative resection due to risk of reginal LN metastasis. This study was aimed to identify clinicopathologic predictive factors for LN metastasis in early gastric cancer (EGC) with lymphatic invasion after endoscopic resection. Among a total of 2036 patients who underwent endoscopic resection for EGC at Samsung Medical Center from April 2000 to May 2011, 146 patients were diagnosed with lymphatic invasion. And 123 patients who had gastrectomy with LN dissection due to presence of lymphatic invasion as one of the non-curative factors were included in this study. Demographics, endoscopic tumor findings, histological findings, surgical findings with pathologic reports, and follow-up data were collected from the patient's medical records. Pathological re-evaluation of resected specimens was performed. Among a total of 123 patients, LN metastases were found in seven patients (5.7%). The univariate analysis revealed that the LN metastasis was significantly more frequent in patients with certain morphology of lymphatic invasion that shows adhesion to endothelium of lymphatic tumor emboli (p = 0.016), higher number of lymphatic tumor emboli in whole section (p < 0.001) and papillary adenocarcinoma component (p = 0.024). In multivariate analysis, the number of lymphatic tumor emboli [OR 93.5, 95% CI (2.62-3330.81)] and the presence of papillary adenocarcinoma component [OR 552.5, 95% CI (1.20-254871.81)] were identified as independent predictors of LN metastasis in patients with lymphatic invasion after endoscopic resection. The number of lymphatic tumor emboli and the presence of papillary adenocarcinoma component were significant predictors for LN metastasis in patients with lymphatic invasion after endoscopic resection.

  2. A pilot in vivo model of human microcystic lymphatic malformations.

    PubMed

    Hou, Fang; Dai, Yuemeng; Buckmiller, Lisa M; Shafirstein, Gal; Fan, Chun-Yang; Saad, Ali G; Suen, James Y; Richter, Gresham T

    2011-12-01

    To develop an in vivo mouse model of human microcystic lymphatic malformations (LMs) and provide a tool for investigating the biological mechanisms and treatment of microcystic disease. Animal model and histologic analysis. Tertiary referral center. Fresh microcystic LM from human subjects were harvested and xenografted in the immunologically naïve nude mice (Athymic Nude- Foxn1(nu)). Specimens were divided (5 × 5 × 5 mm) and secured in 4 quadrants subcutaneously along the dorsum of 4 nude mice. Weekly observations for volume, color, and texture of the grafts were performed with sequential harvesting from each quadrant at 30-day intervals. All grafts (n = 16) were sectioned and stained with hematoxylin-eosin. Comparative pathologic evaluation of the grafts and native LM was performed by 2 blinded pathologists. Immunohistochemical analysis for D2-40 (a known lymphatic endothelial cell marker), Ki-67, and human-specific nuclear antigen was performed. Near complete microcystic LM xenograft survival (n = 13 [81%]) was achieved in the mouse irrespective of the period of implantation. Xenografts underwent a brief growth phase to day 20 to 30 and were quiescent until approximately day 65 but ultimately had a gradual loss of volume following transplant. Histologic analysis revealed structural characteristics matching the native LM tissue. Immunohistochemical analysis found that 10 (77%) of the surviving xenografts (77%) were positive for D2-40, 9 (69%) were positive for human-specific nuclear antigen, and 8 (62%) were positive for Ki-67. This preliminary in vivo model suggests that microcystic LM can survive in the athymic nude mouse. The presence of markers for human antibodies, lymphatic endothelium, and cellular proliferation demonstrates the stability of native tissue qualities within the xenografts.

  3. Isolation, Characterization, and Functional Analysis of Ferret Lymphatic Endothelial Cells

    PubMed Central

    Berendam, Stella J.; Fallert-Junecko, Beth A.; Murphy-Corb, Michael A.; Fuller, Deborah H.; Reinhart, Todd A.

    2014-01-01

    The lymphatic endothelium (LE) serves as a conduit for transport of immune cells and soluble antigens from peripheral tissues to draining lymph nodes (LNs), contributing to development of host immune responses and possibly dissemination of microbes. Lymphatic endothelial cells (LECs) are major constituents of the lymphatic endothelium. These specialized cells could play important roles in initiation of host innate immune responses through sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including toll-like receptors (TLRs). LECs secrete pro-inflammatory cytokines and chemokines to create local inflammatory conditions for recruitment of naïve antigen presenting cells (APCs) such as dendritic cells (DCs) to sites of infection and/or vaccine administration. In this study, we examined the innate immune potential of primary LEC populations derived from multiple tissues of an animal model for human infectious diseases -- the ferret. We generated a total of six primary LEC populations from lung, tracheal, and mesenteric LN tissues from three different ferrets. Standard RT-PCR characterization of these primary LECs showed that they varied in their expression of LEC markers. The ferret LECs were examined for their ability to respond to poly I:C (TLR3 and RIG-1 ligand) and other known TLR ligands as measured by production of proinflammatory cytokine (IFNα, IL6, IL10, Mx1, and TNFα) and chemokine (CCL5, CCL20, and CXCL10) mRNAs using real time RT-PCR. Poly I:C exposure induced robust proinflammatory responses by all of the primary ferret LECs. Chemotaxis was performed to determine the functional activity of CCL20 produced by the primary lung LECs and showed that the LEC-derived CCL20 was abundant and functional. Taken together, our results continue to reveal the innate immune potential of primary LECs during pathogen-host interactions and expand our understanding of the roles of LECs might play in health and disease in

  4. Lymphatic filariasis in Brazil: epidemiological situation and outlook for elimination

    PubMed Central

    2012-01-01

    Since the World Health Assembly’s (Resolution WHA 50.29, 1997) call for the elimination of lymphatic filariasis by the year 2020, most of the endemic countries identified have established programmes to meet this objective. In 1997, a National Lymphatic Filariasis Elimination Plan was drawn up by the Ministry of Health of Brazil, creating local programs for the elimination of Bancroftian filariasis in areas with active transmission. Based on a comprehensive bibliographic search for available studies and reports of filariasis epidemiology in Brazil, current status of this parasitic infection and the outlook for its elimination in the country were analysed. From 1951 to 1958 a nationwide epidemiological study conducted in Brazil confirmed autochthonous transmission of Bancroftian filariasis in 11 cities of the country. Control measures led to a decline in parasite rates, and in the 1980s only the cities of Belém in the Amazonian region (Northern region) and Recife (Northeastern region) were considered to be endemic. In the 1990s, foci of active transmission of LF were also described in the cities of Maceió, Olinda, Jaboatão dos Guararapes, and Paulista, all in the Northeastern coast of Brazil. Data provide evidence for the absence of microfilaremic subjects and infected mosquitoes in Belém, Salvador and Maceió in the past few years, attesting to the effectiveness of the measures adopted in these cities. Currently, lymphatic filariasis is a public health problem in Brazil only in four cities of the metropolitan Recife region (Northeastern coast). Efforts are being concentrated in these areas, with a view to eliminating the disease in the country. PMID:23181663

  5. Mathematical models and lymphatic filariasis control: monitoring and evaluating interventions.

    PubMed

    Michael, Edwin; Malecela-Lazaro, Mwele N; Maegga, Bertha T A; Fischer, Peter; Kazura, James W

    2006-11-01

    Monitoring and evaluation are crucially important to the scientific management of any mass parasite control programme. Monitoring enables the effectiveness of implemented actions to be assessed and necessary adaptations to be identified; it also determines when management objectives are achieved. Parasite transmission models can provide a scientific template for informing the optimal design of such monitoring programmes. Here, we illustrate the usefulness of using a model-based approach for monitoring and evaluating anti-parasite interventions and discuss issues that need addressing. We focus on the use of such an approach for the control and/or elimination of the vector-borne parasitic disease, lymphatic filariasis.

  6. [Retroperitoneal "lymphatic cysts" after radical operations in uterine cancer].

    PubMed

    Dekster, L I; Vasil'ev, B V

    1979-01-01

    The authors report the results of studying the complications of iliac lymphadenectomy--lymphocysts developed after radical operations in 16 of 415 operated patients with cancer of the uterus. The method of indirect radioisotope lymphography may be considered to be the most simple method of detecting lymphatic cysts. Small size lymphocysts require no special surgical intervention. Extensive incapsulated lymph accumulation renders mandatory the incision and drainage of the lymphocyst in the iliac region at the site of the involvement. The most rational prophylactic measures against lymphocysts seem to be the provision for active lymph outflow by vacuum drainage.

  7. The resurgence of lymphatic filariasis in the Nile delta.

    PubMed Central

    Harb, M.; Faris, R.; Gad, A. M.; Hafez, O. N.; Ramzy, R.; Buck, A. A.

    1993-01-01

    A study of 325,000 residents of 314 villages in six governorates of the Nile delta area of Egypt revealed that the prevalence of lymphatic filariasis increased from < 1% in 1965 to > 20% in 1991, especially in the governorates of Qalyubiya, Monufiya, Dakhaliya, and Giza. The distribution of the communites with endemic filariasis is focal. Clusters of villages with high prevalences are surrounded by others in which the disease is absent, although their environmental, social, and agricultural features appear similar. The article analyses why the significant decline in filariasis between 1945 and 1965 in Egypt has been followed by a resurgence of the disease. PMID:8440037

  8. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  9. Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps

    PubMed Central

    Dongaonkar, R. M.; Nguyen, T. L.; Heaps, C. L.; Hardy, J.; Laine, G. A.; Wilson, E.; Stewart, R. H.

    2014-01-01

    Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca2+ in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca2+ concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca2+ concentration. PMID:25519727

  10. Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature

    PubMed Central

    2013-01-01

    Background Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. Methods We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature. Results and conclusions Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation. PMID:24124909

  11. Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature.

    PubMed

    Chaitanya, Ganta Vijay; Omura, Seiichi; Sato, Fumitaka; Martinez, Nicholas E; Minagar, Alireza; Ramanathan, Murali; Guttman, Bianca Weinstock; Zivadinov, Robert; Tsunoda, Ikuo; Alexander, Jonathan S

    2013-10-14

    Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature. Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.

  12. An Apparent Deficiency of Lymphatic Capillaries in the Islets of Langerhans in the Human Pancreas.

    PubMed

    Korsgren, Erik; Korsgren, Olle

    2016-04-01

    The lymphatic system is crucial for efficient immune surveillance and for the maintenance of a physiological pressure in the interstitial space. Even so, almost no information is available concerning the lymph drainage of the islets of Langerhans in the human pancreas. Immunohistochemical staining allowed us to distinguish lymphatic capillaries from blood capillaries. Almost no lymphatic capillaries were found within the islets in pancreatic biopsy specimens from subjects without diabetes or from subjects with type 1 or type 2 diabetes. Lymphatic capillaries were, however, found at the islet-exocrine interface, frequently located along blood capillaries and other fibrotic structures within or close to the islet capsule. Lymphatic capillaries were regularly found in the exocrine pancreas, with small lymphatic vessels located close to and around acini. Larger collecting lymphatic vessels were located in fibrotic septa between the exocrine lobules and adjacent to the ductal system of the pancreas. In summary, we report a pronounced deficiency of lymphatic capillaries in human islets, a finding with implications for immune surveillance and the regulation of interstitial fluid transport in the endocrine pancreas as well as for the pathophysiology of both type 1 and type 2 diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  13. Adipose veno-lymphatic transfer for management of post-radiation lymphedema

    SciTech Connect

    Pho, R.W.; Bayon, P.; Tan, L.

    1989-01-01

    In a patient who had post-radiation lymphedema after excision of liposarcoma, a method is described that is called adipose veno-lymphatic transfer. The technique involves transferring adipose tissue containing lymphatic vessels that surround the long saphenous vein, from the normal, healthy leg to the irradiated leg, with the creation of an arteriovenous fistula.

  14. Technique of right lymphatic duct cannulation for pulmonary lymph collection in an acute porcine model.

    PubMed

    Chuang, G J; Gao, C X; Mulder, D S; Chiu, R C

    1986-12-01

    The pig is an increasingly preferred model for biomedical research, including studies for pulmonary pathophysiology. However, in piglets, the technique for cannulating the right lymphatic duct, which is subject to more anatomical variations and technically more demanding than that in dogs, has not been described. Our technique evolved to enable this collection of porcine lung lymph in acute experiments. The lymphatic ampulla is cannulated via one of the cervical lymphatics. The right lymphatic duct is invariably dorsal to the cranial vena cava and classically leads to the lymphatic ampulla. Yet in 18% of our pigs, cannulation was difficult or not feasible because the lymphatic duct either drained directly into the cranial vena cava at a distance from the lymphatic ampulla, or into the axillary lymph node of the first rib or the caudal deep cervical lymph nodes. Gently squeezing back regurgitated blood in the lymphatic ampulla before tying the suture and frequently withdrawing lymph with a syringe when the flow is small enabled us to collect clear lymph, usually immediately after completing the cannulation. The rate of lymph flow varied widely (1.7 +/- 0.6 ml/hr) and increased when the left atrial pressure was raised. The lymph protein was 2.8 +/- 0.2 g% with lymph/plasma protein ratio at 0.55 +/- 0.04. The anatomical variations encountered in our 34 dissections, as well as the technical maneuvers found to be useful in the successful cannulation and collection of the porcine lung lymph, are described in detail.

  15. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity.

    PubMed

    Wang, Yixin; Jin, Yi; Mäe, Maarja Andaloussi; Zhang, Yang; Ortsäter, Henrik; Betsholtz, Christer; Mäkinen, Taija; Jakobsson, Lars

    2017-08-29

    Tissue-fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and their role in vessel maturation are unknown. Here we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, PDGFB overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate a requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels and suggest an ECM-controlled checkpoint preventing SMC investment of capillaries, which is a common feature in lymphedematous skin. © 2017. Published by The Company of Biologists Ltd.

  16. Enhanced transdermal lymphatic drug delivery of hyaluronic acid modified transfersomes for tumor metastasis therapy.

    PubMed

    Kong, Ming; Hou, Lin; Wang, Juan; Feng, Chao; Liu, Ya; Cheng, Xiaojie; Chen, Xiguang

    2015-01-28

    A novel hyaluronic acid modified transfersome was prepared to deliver drugs to lymphatics through the transdermal route. Doxorubicin loaded HA-GMS-T was able to efficiently penetrate into the deep skin tissue, leading to enhanced absorption by lymphatics. Most importantly, hyaluronic acid effectively improved the uptake of drug loaded nanocarriers by tumor cells.

  17. Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis.

    PubMed

    Carramolino, Laura; Fuentes, Joana; García-Andrés, Clara; Azcoitia, Valeria; Riethmacher, Dieter; Torres, Miguel

    2010-04-16

    Several mutations that impair the development of blood lineages in the mouse also impair the formation of the lymphatic vasculature and its separation from the blood vasculature. However, the basis for these defects has remained unknown because the mutations characterized affect more than one blood lineage. We tested the hypothesis that megakaryocytes/platelets are required for the formation of the lymphatic vasculature and its separation from the blood vascular system. We characterized the vascular patterning defects of mice deficient for the homeodomain transcription factor Meis1 (myeloid ecotropic viral integration site 1), which completely lack megakaryocyte/platelets. Meis1 null embryos fail to separate the blood and lymphatic vasculature, showing blood-filled primary lymphatic sacs and superficial lymphatic vessels. To test the involvement of megakaryocytes/platelets in this phenotype, we generated megakaryocyte/platelet-specific deficient mice by targeted lineage ablation, without affecting other blood lineages. This model reproduces the lymphatic/blood vasculature separation defects observed in Meis1 mutants. A similar phenotype was induced by antibody-mediated ablation of circulating platelets in wild type mice. Strong association of platelets with vascular endothelium at regions of contact between lymphatic sacs and veins confirmed a direct role of platelets in the separation of the 2 vasculatures. In addition to their known protective function in the response accidental vascular injury, platelets are also required during embryonic lymphangiogenesis for the separation of the nascent lymphatic vasculature from blood vessels.

  18. Flow cytometry-based isolation of dermal lymphatic endothelial cells from newborn rats.

    PubMed

    Thiele, W; Rothley, M; Schmaus, A; Plaumann, D; Sleeman, J

    2014-12-01

    The lymphatic system plays a key role in tissue homeostasis, fatty acid transport, and immune surveillance. Pathologically, dysfunction of the lymphatic system results in edema, and increased lymphangiogenesis can contribute to tumor metastasis. Lymphatic vessels are composed of lymphatic endothelial cells (LECs) that can be identified by distinct marker molecules such as Prox-1, podoplanin, VEGFR-3 and LYVE-1. Primary LECs represent a valuable tool for the study of basic functions of the lymphatic system. However, their isolation remains a challenge, particularly if rodent tissues are used as a source. We developed a method for the isolation of rat dermal LECs from the skin of newborn rats based on sequential enzymatic digestion with trypsin and Liberase followed by flow cytometric sorting using LYVE-1 specific antibodies. Cells isolated according to this protocol expressed the lymphatic markers Prox-1, podoplanin, LYVE-1 and VEGFR-3, and displayed an endothelial-like morphology when taken into culture. These primary cells can be used for studying lymphatic biology in rat models, and the protocol we describe here therefore represents an important extension of the experimental repertoire available for rats and for modeling the human lymphatic system.

  19. Development and validation of a custom made indocyanine green fluorescence lymphatic vessel imager

    NASA Astrophysics Data System (ADS)

    Pallotta, Olivia J.; van Zanten, Malou; McEwen, Mark; Burrow, Lynne; Beesley, Jack; Piller, Neil

    2015-06-01

    Lymphoedema is a chronic progressive condition often producing significant morbidity. An in-depth understanding of an individual's lymphatic architecture is valuable both in the understanding of underlying pathology and for targeting and tailoring treatment. Severe lower limb injuries resulting in extensive loss of soft tissue require transposition of a flap consisting of muscle and/or soft tissue to close the defect. These patients are at risk of lymphoedema and little is known about lymphatic regeneration within the flap. Indocyanine green (ICG), a water-soluble dye, has proven useful for the imaging of lymphatic vessels. When injected into superficial tissues it binds to plasma proteins in lymph. By exposing the dye to specific wavelengths of light, ICG fluoresces with near-infrared light. Skin is relatively transparent to ICG fluorescence, enabling the visualization and characterization of superficial lymphatic vessels. An ICG fluorescence lymphatic vessel imager was manufactured to excite ICG and visualize real-time fluorescence as it travels through the lymphatic vessels. Animal studies showed successful ICG excitation and detection using this imager. Clinically, the imager has assisted researchers to visualize otherwise hidden superficial lymphatic pathways in patients postflap surgery. Preliminary results suggest superficial lymphatic vessels do not redevelop in muscle flaps.

  20. Development and validation of a custom made indocyanine green fluorescence lymphatic vessel imager.

    PubMed

    Pallotta, Olivia J; van Zanten, Malou; McEwen, Mark; Burrow, Lynne; Beesley, Jack; Piller, Neil

    2015-06-01

    Lymphoedema is a chronic progressive condition often producing significant morbidity. An in-depth understanding of an individual's lymphatic architecture is valuable both in the understanding of underlying pathology and for targeting and tailoring treatment. Severe lower limb injuries resulting in extensive loss of soft tissue require transposition of a flap consisting of muscle and/or soft tissue to close the defect. These patients are at risk of lymphoedema and little is known about lymphatic regeneration within the flap. Indocyanine green (ICG), a water-soluble dye, has proven useful for the imaging of lymphatic vessels. When injected into superficial tissues it binds to plasma proteins in lymph. By exposing the dye to specific wavelengths of light, ICG fluoresces with near-infrared light. Skin is relatively transparent to ICG fluorescence, enabling the visualization and characterization of superficial lymphatic vessels. An ICG fluorescence lymphatic vessel imager was manufactured to excite ICG and visualize real-time fluorescence as it travels through the lymphatic vessels. Animal studies showed successful ICG excitation and detection using this imager. Clinically, the imager has assisted researchers to visualize otherwise hidden superficial lymphatic pathways in patients postflap surgery. Preliminary results suggest superficial lymphatic vessels do not redevelop in muscle flaps.

  1. Immunohistochemical identification of lymphatic vessels in the periodontium of equine cheek teeth.

    PubMed

    Staszyk, Carsten; Duesterdieck, Katja F; Gasse, Hagen; Bienert, Astrid

    2005-12-01

    Immunohistochemical detection of lymphatic capillaries was performed in the periodontium of maxillary and mandibular cheek teeth from 6 horses (aged 3-23 years). Tissue sections of the periodontium were taken at 4 different horizontal levels along the long axis of the tooth. The specimens were processed for immunoreaction with anti-Prox1, in order to distinguish lymphatic endothelium from blood vascular endothelium. Lymphatic vessels were detected in all periodontal tissues except for the dental cementum. Lymphatic capillaries were most densely distributed in the gingiva compared to other tissues of the periodontium. Lymphatic capillaries were found most consistently in samples taken from the gingival and subgingival regions in all horses examined. Within these levels, the gingiva as well as the spongiosa of the maxillary and mandibular bone had the greatest incidence of lymphatic vessels. Considering the distinct distribution of the lymphatic capillaries in the periodontium of the maxillary and mandibular cheek teeth, two complementary lymphatic drainage pathways are proposed: (1) superficial lymph drainage via the gingiva, emptying into the mandibular lymph nodes; (2) deep lymph drainage via the mandibular and maxillary spongiosa, emptying into the mandibular and retropharyngeal lymph nodes, respectively.

  2. Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps.

    PubMed

    Dongaonkar, R M; Nguyen, T L; Quick, C M; Heaps, C L; Hardy, J; Laine, G A; Wilson, E; Stewart, R H

    2015-03-01

    Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca(2+) in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca(2+) concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca(2+) concentration. Copyright © 2015 the American Physiological Society.

  3. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  4. Abnormal rubbing and keratectasia.

    PubMed

    McMonnies, Charles W

    2007-11-01

    Hypotheses for the varied pathogenesis of the different forms of keratoconus have been outlined. Against this background, the possibility that abnormal rubbing causes or contributes to the development or progression of some forms of keratoconus has been examined. Circumstantial evidence that shows an association between abnormal rubbing and keratoconus is reviewed, and a wide range of different forms of abnormal rubbing is described. Also examined is evidence of several processes whereby the cornea appears to be, or could be, adversely affected by mechanical trauma caused by rubbing. Conditions that may increase susceptibility to mechanical rubbing trauma have been discussed. Evidence of a role for inflammatory mediators in the pathogenesis of keratoconus appears to void the description of keratoconus as a noninflammatory condition. When vigorous knuckle-rubbing forces are located on the normal peripheral cornea, the thinner or weakened cone apex may be exposed to high intraocular pressure distending forces that may tend to promote ectasia. It appears reasonable to conclude that abnormal rubbing is a cause of some types of keratoconus, not because all abnormal rubbing, or only abnormal rubbing, leads to the development of some types of keratoconus, but because abnormal rubbing may increase the likelihood of the development of some forms of keratoconus. Abnormal rubbing habits may commence or continue after routine contact lens wear is established. Any associated rubbing or contact lens trauma may contribute to the progression of keratoconus. The abnormal rubbing-ectasia association in keratoconus may extend to other forms of keratectasia, including that seen after laser in situ keratomileusis, for which a contributory abnormal rubbing hypothesis may be appropriate.

  5. Dextran sulfate sodium-induced acute colitis impairs dermal lymphatic function in mice.

    PubMed

    Agollah, Germaine D; Wu, Grace; Peng, Ho-Lan; Kwon, Sunkuk

    2015-12-07

    To investigate whether dermal lymphatic function and architecture are systemically altered in dextran sulfate sodium (DSS)-induced acute colitis. Balb/c mice were administered 4% DSS in lieu of drinking water ad libitum for 7 d and monitored to assess disease activity including body weight, diarrhea severity, and fecal bleeding. Control mice received standard drinking water with no DSS. Changes in mesenteric lymphatics were assessed following oral administration of a fluorescently-labelled fatty acid analogue, while dermal lymphatic function and architecture was longitudinally characterized using dynamic near-infrared fluorescence (NIRF) imaging following intradermal injection of indocyanine green (ICG) at the base of the tail or to the dorsal aspect of the left paw prior to, 4, and 7 d after DSS administration. We also measured dye clearance rate after injection of Alexa680-bovine serum albumin (BSA). NIRF imaging data was analyzed to reveal lymphatic contractile activity after selecting fixed regions of interest (ROIs) of the same size in fluorescent lymphatic vessels on fluorescence images. The averaged fluorescence intensity within the ROI of each fluorescence image was plotted as a function of imaging time and the lymphatic contraction frequency was computed by assessing the number of fluorescent pulses arriving at a ROI. Mice treated with DSS developed acute inflammation with clinical symptoms of loss of body weight, loose feces/watery diarrhea, and fecal blood, all of which were aggravated as disease progressed to 7 d. Histological examination of colons of DSS-treated mice confirmed acute inflammation, characterized by segmental to complete loss of colonic mucosa with an associated chronic inflammatory cell infiltrate that extended into the deeper layers of the wall of the colon, compared to control mice. In situ intravital imaging revealed that mice with acute colitis showed significantly fewer fluorescent mesenteric lymphatic vessels, indicating impaired

  6. microRNAs in the Lymphatic Endothelium: Master Regulators of Lineage Plasticity and Inflammation

    PubMed Central

    Yee, Daniel; Coles, Mark C.; Lagos, Dimitris

    2017-01-01

    microRNAs (miRNAs) are highly conserved, small non-coding RNAs that regulate gene expression at the posttranscriptional level. They have crucial roles in organismal development, homeostasis, and cellular responses to pathological stress. The lymphatic system is a large vascular network that actively regulates the immune response through antigen trafficking, cytokine secretion, and inducing peripheral tolerance. Here, we review the role of miRNAs in the lymphatic endothelium with a particular focus on their role in lymphatic endothelial cell (LEC) plasticity, inflammation, and regulatory function. We highlight the lineage plasticity of LECs during inflammation and the importance of understanding the regulatory role of miRNAs in these processes. We propose that targeting miRNA expression in lymphatic endothelium can be a novel strategy in treating human pathologies associated with lymphatic dysfunction. PMID:28232833

  7. The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

    PubMed Central

    Choi, Inho; Lee, Sunju; Hong, Young-Kwon

    2012-01-01

    The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being. PMID:22474611

  8. Role of lymphatic vessels in tumor immunity: passive conduits or active participants?

    PubMed

    Lund, Amanda W; Swartz, Melody A

    2010-09-01

    Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis.

  9. Indocyanine Green Lymphographic Signs of Lymphatic Collateral Formation in Lower Extremity Lymphedema After Cancer Resection.

    PubMed

    Tashiro, Kensuke; Shibata, Takashi; Mito, Daisuke; Ishiura, Ryohei; Kato, Motoi; Yamashita, Shuji; Narushima, Mitsunaga; Iida, Takuya; Koshima, Isao

    2016-08-01

    Indocyanine green lymphography has recently been used to assess lymphatic vessel function in lymphedema patients. Postoperative collateral lymphatic vessels toward ipsilateral axillary lymph nodes are rarely seen above the umbilical level in lower lymphedema patients. Between January 2012 and December 2014, we performed indocyanine green lymphography of 192 limbs in 96 lower extremity lymphedema cases. As a result, dermal back flow appeared in 95 cases, with 38 in the lower abdominal area and 31 in the genital area. We confirmed 3 cases of superficial lymphatic collateral ways extending above the umbilical level to the axillary lymph nodes. All 3 cases had similarity in lower abdominal edema, so excessive lymphatic fluid in the lower abdomen was assumed to be the cause. Lymphatic collateral ways from abdomen to axillary lymph nodes in this study was likely to be designed to prevent the progress of lymphedema.

  10. Hydraulic control of tuna fins: A role for the lymphatic system in vertebrate locomotion.

    PubMed

    Pavlov, Vadim; Rosental, Benyamin; Hansen, Nathaniel F; Beers, Jody M; Parish, George; Rowbotham, Ian; Block, Barbara A

    2017-07-21

    The lymphatic system in teleost fish has genetic and developmental origins similar to those of the mammalian lymphatic system, which is involved in immune response and fluid homeostasis. Here, we show that the lymphatic system of tunas functions in swimming hydrodynamics. Specifically, a musculo-vascular complex, consisting of fin muscles, bones, and lymphatic vessels, is involved in the hydraulic control of median fins. This specialization of the lymphatic system is associated with fish in the family Scombridae and may have evolved in response to the demand for swimming and maneuvering control in these high-performance species. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  11. Regulation of lymphatic-blood vessel separation by endothelial Rac1

    PubMed Central

    D'Amico, Gabriela; Jones, Dylan T.; Nye, Emma; Sapienza, Karen; Ramjuan, Antoine R.; Reynolds, Louise E.; Robinson, Stephen D.; Kostourou, Vassiliki; Martinez, Dolores; Aubyn, Deborah; Grose, Richard; Thomas, Gareth J.; Spencer-Dene, Bradley; Zicha, Daniel; Davies, Derek; Tybulewicz, Victor; Hodivala-Dilke, Kairbaan M.

    2009-01-01

    Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown. Here, we deleted endothelial Rac1 in mice (Tie1-Cre+;Rac1fl/fl) and revealed, unexpectedly, that whereas blood vessel morphology appeared normal, lymphatic-blood vessel separation was impaired, with corresponding edema, haemorrhage and embryonic lethality. Importantly, normal levels of Rac1 were essential for directed endothelial cell migratory responses to lymphatic-inductive signals. Our studies identify Rac1 as a crucial part of the migratory machinery required for endothelial cells to separate and form lymphatic vasculature. PMID:19906871

  12. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature.

    PubMed

    Srinivasan, R Sathish; Dillard, Miriam E; Lagutin, Oleg V; Lin, Fu-Jung; Tsai, Sophia; Tsai, Ming-Jer; Samokhvalov, Igor M; Oliver, Guillermo

    2007-10-01

    The origin of the mammalian lymphatic vasculature has been debated for more than 100 years. Whether lymphatic endothelial cells have a single or dual, venous or mesenchymal origin remains controversial. To resolve this debate, we performed Cre/loxP-based lineage-tracing studies using mouse strains expressing Cre recombinase under the control of the Tie2, Runx1, or Prox1 promoter elements. These studies, together with the analysis of Runx1-mutant embryos lacking definitive hematopoiesis, conclusively determined that from venous-derived lymph sacs, lymphatic endothelial cells sprouted, proliferated, and migrated to give rise to the entire lymphatic vasculature, and that hematopoietic cells did not contribute to the developing lymph sacs. We conclude that the mammalian lymphatic system has a solely venous origin.

  13. Laparoscopy as a Diagnostic and Definitive Therapeutic Tool in Cases of Inflamed Simple Lymphatic Cysts of the Mesentery

    PubMed Central

    Abdelaal, Abdelrahman; Sulieman, Ibnouf; Aftab, Zia; Ahmed, Ayman; Al-Mudares, Saif; Al Tarakji, Mohannad; Almuzrakchi, Ahmad; Di Carlo, Isidoro

    2015-01-01

    Mesenteric cysts are rare benign abdominal tumors. These cysts, especially those of lymphatic origin, very rarely become inflamed. The diagnosis of inflamed lymphatic cysts of the mesentery may be difficult. We herein report two cases of inflamed simple lymphatic cysts of the mesentery definitively diagnosed and excised by laparoscopy. PMID:26064760

  14. Laparoscopy as a Diagnostic and Definitive Therapeutic Tool in Cases of Inflamed Simple Lymphatic Cysts of the Mesentery.

    PubMed

    Abdelaal, Abdelrahman; Sulieman, Ibnouf; Aftab, Zia; Ahmed, Ayman; Al-Mudares, Saif; Al Tarakji, Mohannad; Almuzrakchi, Ahmad; Toro, Adriana; Di Carlo, Isidoro

    2015-01-01

    Mesenteric cysts are rare benign abdominal tumors. These cysts, especially those of lymphatic origin, very rarely become inflamed. The diagnosis of inflamed lymphatic cysts of the mesentery may be difficult. We herein report two cases of inflamed simple lymphatic cysts of the mesentery definitively diagnosed and excised by laparoscopy.

  15. Angiopoietin–Tie signalling in the cardiovascular and lymphatic systems

    PubMed Central

    Eklund, Lauri; Kangas, Jaakko; Saharinen, Pipsa

    2016-01-01

    Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)–Tie system is a second endothelial cell specific ligand–receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang–Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang–Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang–Tie system in vascular development and pathogenesis of vascular diseases. PMID:27941161

  16. The embryonic development of the main lymphatics in man.

    PubMed

    van der Putte, S C; van Limborgh, J

    1980-12-01

    A study of microscopical serial sections of 40 well-preserved human embryos, ranging in age from about 40 to 65 days (8-33 mm C.-R. length), revealed that the prevertebral main lymphatics develop from a number of separate primordia, all derived from venous walls. These primordia are: paired jugular and axillary lymph sacs and paratracheal, internal throacic, lumbar and iliac lymph plexuses, and single subtracheal and mesenteric lymph plexuses. Probably, the thoracic ducts develop from a series of small additional primordia. All these primordia, except the jugulo-axillary lymph sacs, lose their connections with the veins. They rapidly enlarge, fuse with one another and send out sprouts into peripheral regions, so that soon the definitive pattern of the major lymphatics can be recognized. During development some variations may occur, in particular in the area where the lower extensions of the two throacic ducts meet the lumbar lymph plexuses. Usually, the right thoracic duct primarily comes into contact with the jugulo-axillary lymph sac. The conclusion is drawn that on an embryological basis in the prevertebral region additional lymphatico-venous communications might be expected, but that possible lymphatico-venous communications elsewhere in the body always point to developmental aberrations or to pathology.

  17. The geographical distribution of lymphatic filariasis infection in Malawi

    PubMed Central

    Ngwira, Bagrey MM; Tambala, Phillimon; Perez, A Maria; Bowie, Cameron; Molyneux, David H

    2007-01-01

    Mapping distribution of lymphatic filariasis (LF) is a prerequisite for planning national elimination programmes. Results from a nation wide mapping survey for lymphatic filariasis (LF) in Malawi are presented. Thirty-five villages were sampled from 23 districts excluding three districts (Karonga, Chikwawa and Nsanje) that had already been mapped and Likoma, an Island, where access was not possible in the time frame of the survey. Antigenaemia prevalence [based on immunochromatographic card tests (ICT)] ranged from 0% to 35.9%. Villages from the western side of the country and distant from the lake tended to be of lower prevalence. The exception was a village in Mchinji district on the Malawi-Zambia border where a prevalence of 18.2% was found. In contrast villages from lake shore districts [Salima, Mangochi, Balaka and Ntcheu (Bwanje valley)] and Phalombe had prevalences of over 20%. A national map is developed which incorporates data from surveys in Karonga, Chikwawa and Nsanje districts, carried out in 2000. There is a marked decline in prevalence with increasing altitude. Further analysis revealed a strong negative correlation (R2 = 0.7 p < 0.001) between altitude and prevalence. These results suggest that the lake shore, Phalombe plain and the lower Shire valley will be priority areas for the Malawi LF elimination programme. Implications of these findings as regards implementing a national LF elimination programme in Malawi are discussed. PMID:18047646

  18. Primary mucinous carcinoma with direct histopathologic evidence of lymphatic invasion.

    PubMed

    Warycha, Melanie; Kamino, Hideko; Mobini, Narciss; Hale, Elizabeth K

    2006-01-01

    Primary mucinous carcinoma of the skin is a rare sweat gland neoplasm which occurs most commonly in the periorbital region. Although the tumor has a propensity for local recurrence and regional spread, distant metastases are rare. The standard treatment of primary mucinous carcinoma is wide local excision. Mohs micrographic surgery may also be utilized in cases where tissue conservation is of utmost concern. We present a case of primary mucinous carcinoma arising in the scalp, which was treated with wide local excision. A case report and literature review are presented. Histopathologic evaluation revealed a well-circumscribed neoplasm characterized by lobules and aggregates of epithelial cells embedded in abundant pools of mucin. In addition, small aggregates of neoplastic cells were found at a distance from the primary nodule, indicative of lymphatic invasion. Primary mucinous carcinoma has a high propensity for locoregional metastases and recurrence. To our knowledge, this is the first report demonstrating direct histopathologic evidence of lymphatic invasion which correlates with this tumor's biologic behavior.

  19. Lymphatic endothelial cells support tumor growth in breast cancer

    PubMed Central

    Lee, Esak; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Tumor lymphatic vessels (LV) serve as a conduit of tumor cell dissemination, due to their leaky nature and secretion of tumor-recruiting factors. Though lymphatic endothelial cells (LEC) lining the LV express distinct factors (also called lymphangiocrine factors), these factors and their roles in the tumor microenvironment are not well understood. Here we employ LEC, microvascular endothelial cells (MEC), and human umbilical vein endothelial cells (HUVEC) cultured in triple-negative MDA-MB-231 tumor-conditioned media (TCM) to determine the factors that may be secreted by various EC in the MDA-MB-231 breast tumor. These factors will serve as endothelium derived signaling molecules in the tumor microenvironment. We co-injected these EC with MDA-MB-231 breast cancer cells into animals and showed that LEC support tumor growth, HUVEC have no significant effect on tumor growth, whereas MEC suppress it. Focusing on LEC-mediated tumor growth, we discovered that TCM-treated LEC (‘tumor-educated LEC') secrete high amounts of EGF and PDGF-BB, compared to normal LEC. LEC-secreted EGF promotes tumor cell proliferation. LEC-secreted PDGF-BB induces pericyte infiltration and angiogenesis. These lymphangiocrine factors may support tumor growth in the tumor microenvironment. This study shows that LV serve a novel role in the tumor microenvironment apart from their classical role as conduits of metastasis. PMID:25068296

  20. Aberrant pulmonary lymphatic development in the nitrofen mouse model of congenital diaphragmatic hernia

    PubMed Central

    Shue, Eveline; Wu, Jianfeng; Schecter, Samuel; Miniati, Doug

    2013-01-01

    Purpose Many infants develop a postsurgical chylothorax after diaphragmatic hernia repair. The pathogenesis remains elusive but may be due to dysfunctional lymphatic development. This study characterizes pulmonary lymphatic development in the nitrofen mouse model of CDH. Methods CD1 pregnant mice were fed nitrofen/bisdiamine (N/B) or olive oil at E8.5. At E14.5 and E15.5, lung buds were categorized by phenotype: normal, N/B without CDH (N/B−CDH), or N/B with CDH (N/B+CDH). Anti-CD31 was used to localize all endothelial cells, while anti-LYVE-1 was used to identify lymphatic endothelial cells in lung buds using immunofluorescence. Differential protein expression of lymphatic-specific markers was analyzed. Results Lymphatic endothelial cells localized to the mesenchyme surrounding the airway epithelium at E15.5. CD31 and LYVE-1 colocalization identified lymphatic endothelial cells. LYVE-1 expression was upregulated in N/B+CDH lung buds in comparison to N/B−CDH and normal lung buds by immunofluorescence. Western blotting shows that VEGF-D, LYVE-1, Prox-1, and VEGFR-3 expression was upregulated in N/B+CDH lung buds in comparison to N/B−CDH or control lung buds at E14.5. Conclusions Lung lymphatics are hyperplastic in N/B+CDH. Upregulation of lymphatic-specific genes suggest that lymphatic hyperplasia plays an important role in dysfunctional lung lymphatic development in the nitrofen mouse model of CDH. PMID:23845607

  1. Electrophysiological Properties of Rat Mesenteric Lymphatic Vessels and their Regulation by Stretch

    PubMed Central

    Lee, Stewart; Imtiaz, Mohammad S.; Zawieja, David C.; Davis, Michael J.

    2014-01-01

    Abstract Background: In mammals, lymph is propelled centrally primarily via the phasic contractions of collecting lymphatic vessels, known as lymphatic pumping. Electrophysiological studies conducted in guinea pig and sheep mesenteric lymphatic vessels indicate that contractions are initiated in the lymphatic muscle by nifedipine-sensitive action potentials (APs). Lymphatic pumping is highly sensitive to luminal fluid loading and the mechanical properties of this stretch-induced pumping have been consistently studied, in particular in rat mesenteric lymphatic vessels. However, membrane potential (Vm) and the electrophysiological events underlying stretch-induced lymphatic pumping have not been investigated in the rat. The aim of this study was thus to examine the properties of rat mesenteric lymphatic muscle Vm under resting conditions and to assess changes in Vm caused by distension. Methods and Results: Lymphatic muscle Vm was measured with sharp intracellular microelectrodes either in unstretched conditions or under isometric tension provided by a wire-myograph. In unstretched vessels, Vm was −48±2 mV (n=30). APs (amplitude ∼25 mV) were observed at a frequency of ∼8/min and were abolished by nifedipine. Under isometric tension, Vm was less polarized (-36±1 mV, n=23), even at minimum tension. Increase in tension led to increase in contraction strength and contraction/AP frequency, while Vm was slightly hyperpolarized and AP amplitude not markedly altered. Conclusions: In our experimental conditions, rat lymphatic muscle has electrophysiological characteristics similar to that in other species. It responds to an increase in isometric tension with an increase in AP frequency, but resting Vm is not significantly affected. PMID:24865781

  2. Downregulation of FoxC2 Increased Susceptibility to Experimental Colitis: Influence of Lymphatic Drainage Function?

    PubMed Central

    Becker, Felix; Potepalov, Sergey; Shehzahdi, Romana; Bernas, Michael; Witte, Marlys; Abreo, Fleurette; Traylor, James; Orr, Wayne A.; Tsunoda, Ikuo

    2015-01-01

    Background: Although inflammation-induced expansion of the intestinal lymphatic vasculature (lymphangiogenesis) is known to be a crucial event in limiting inflammatory processes, through clearance of interstitial fluid and immune cells, considerably less is known about the impact of an impaired lymphatic clearance function (as seen in inflammatory bowel diseases) on this cascade. We aimed to investigate whether the impaired intestinal lymphatic drainage function observed in FoxC2(+/−) mice would influence the course of disease in a model of experimental colitis. Methods: Acute dextran sodium sulfate colitis was induced in wild-type and haploinsufficient FoxC2(+/−) mice, and survival, disease activity, colonic histopathological injury, neutrophil, T-cell, and macrophage infiltration were evaluated. Functional and structural changes in the intestinal lymphatic vessel network were analyzed, including submucosal edema, vessel morphology, and lymphatic vessel density. Results: We found that FoxC2 downregulation in FoxC2(+/−) mice significantly increased the severity and susceptibility to experimental colitis, as displayed by lower survival rates, increased disease activity, greater histopathological injury, and elevated colonic neutrophil, T-cell, and macrophage infiltration. These findings were accompanied by structural (dilated torturous lymphatic vessels) and functional (greater submucosal edema, higher immune cell burden) changes in the intestinal lymphatic vasculature. Conclusions: These results indicate that sufficient lymphatic clearance plays a crucial role in limiting the initiation and perpetuation of experimental colitis and those disturbances in the integrity of the intestinal lymphatic vessel network could intensify intestinal inflammation. Future therapies might be able to exploit these processes to restore and maintain adequate lymphatic clearance function in inflammatory bowel disease. PMID:25822012

  3. The maintenance of lymphatic vessels in the cornea is dependent on the presence of macrophages.

    PubMed

    Maruyama, Kazuichi; Nakazawa, Toru; Cursiefen, Claus; Maruyama, Yuko; Van Rooijen, Nico; D'Amore, Patricia A; Kinoshita, Shigeru

    2012-05-31

    It has been shown previously that the presence in the cornea of antigen-presenting cells (APC), such as macrophages (MPS) and lymphangiogenesis, is a risk for corneal transplantation. We sought to determine whether the existence of lymphatic vessels in the non-inflamed cornea is associated with the presence of MPS. Flat mounts were prepared from corneas of untreated C57BL/6, CD11b(-/-), F4/80(-/-), and BALB/c mice, and after suture placement or corneal transplantation, observed by immunofluorescence for the presence of lymphatic vessels using LYVE-1 as a marker of lymphatic endothelium. Innate immune cells were detected in normal mouse corneas using CD11b, F4/80, CD40, as well as MHC-class II. Digital images of the flat mounts were taken using a spot image analysis system, and the area covered by lymphatic vessels was measured using NIH Image software. The number of spontaneous lymphatic vessels in C57BL/6 corneas was significantly greater than in BALB/c corneas (P = 0.03). There were more CD11b(+) (P < 0.01) and CD40(+), MHC-class II (+) cells in the C57BL/6 corneas than in BALB/c mouse corneas. MPS depletion via clodronate liposome in C57BL/6 mice led to fewer spontaneous lymphatic vessels and reduced inflammation-induced lymphangiogenesis relative to control mice. Mice deficient in CD11b or F4/80 had fewer spontaneous lymphatic vessels and less lymphangiogenesis than control C57BL/6 mice. C57BL/6 mouse corneas have more endogenous CD11b(+) cells and lymphatic vessels. The endogenous lymphatic vessels, along with pro-inflammatory MPS, account for the high risk of corneal graft rejection in C57BL/6 mice. CD11b(+) and F4/80(+) MPS appear to have an important role in of the formation of new lymphatic vessels.

  4. Direct lymphangiography as treatment option of lymphatic leakage: indications, outcomes and role in patient's management.

    PubMed

    Gruber-Rouh, Tatjana; Naguib, Nagy N N; Lehnert, Thomas; Harth, Marc; Thalhammer, Axel; Beeres, Martin; Tsaur, Igor; Hammersting, Renate; Wichmann, Julian L; Vogl, Thomas J; Jacobi, Volkmar

    2014-12-01

    To evaluate the effectiveness of lymphography as a minimally invasive treatment option of lymphatic leakage in terms of local control and to investigate which parameters influence the success rate. This retrospective study protocol was approved by the ethic committee. Patient history, imaging data, therapeutic options and follow-up were recorded and retrospectively analyzed. Between June 1998 and February 2013, 71 patients (m:w = 42:29, mean age, 52.4; range 42–75 years) with lymphatic leakage in form of lymphatic fistulas (n = 37), lymphocele (n = 11), chylothorax (n = 13) and chylous ascites (n = 10)underwent lymphography. Sixty-four patients (90.1%) underwent successful lymphography while lymphography failed in 7 cases. Therapeutic success was evaluated and correlated to the volume of lymphatic leakage and to the volume of the applied iodized oil. Signs of leakage or contrast extravasation were directly detected in 64 patients. Of 64 patients, 45 patients (70.3%) were treated and cured after lymphography. Based on the lymphography findings, 19 patients (29.7%) underwent surgical intervention with a completely occlusion of lymphatic leakage. The lymphatic leak could be completely occluded in 96.8% of patients when the lymphatic drainage volume was less than 200 mL/day (n = 33). Even when lymphatic drainage was higher than 200 mL/day (n = 31),therapeutic lymphography was still successful in 58.1% of the patients. Lymphography is an effective, minimally invasive method in the detection and treatment of lymphatic leakage. The volume of lymphatic drainage per day is a significant predictor of the therapeutic success rate. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases.

    PubMed

    Sun, Bao-Liang; Wang, Li-Hua; Yang, Tuo; Sun, Jing-Yi; Mao, Lei-Lei; Yang, Ming-Feng; Yuan, Hui; Colvin, Robert A; Yang, Xiao-Yi

    2017-09-10

    The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange. Copyright © 2017. Published by Elsevier Ltd.

  6. Identification of lymphatics in the ciliary body of the human eye: a novel "uveolymphatic" outflow pathway.

    PubMed

    Yücel, Yeni H; Johnston, Miles G; Ly, Tina; Patel, Manoj; Drake, Brian; Gümüş, Ersin; Fraenkl, Stephan A; Moore, Sara; Tobbia, Dalia; Armstrong, Dianna; Horvath, Eva; Gupta, Neeru

    2009-11-01

    Impaired aqueous humor flow from the eye may lead to elevated intraocular pressure and glaucoma. Drainage of aqueous fluid from the eye occurs through established routes that include conventional outflow via the trabecular meshwork, and an unconventional or uveoscleral outflow pathway involving the ciliary body. Based on the assumption that the eye lacks a lymphatic circulation, the possible role of lymphatics in the less well defined uveoscleral pathway has been largely ignored. Advances in lymphatic research have identified specific lymphatic markers such as podoplanin, a transmembrane mucin-type glycoprotein, and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). Lymphatic channels were identified in the human ciliary body using immunofluorescence with D2-40 antibody for podoplanin, and LYVE-1 antibody. In keeping with the criteria for lymphatic vessels in conjunctiva used as positive control, D2-40 and LYVE-1-positive lymphatic channels in the ciliary body had a distinct lumen, were negative for blood vessel endothelial cell marker CD34, and were surrounded by either discontinuous or no collagen IV-positive basement membrane. Cryo-immunogold electron microscopy confirmed the presence D2-40-immunoreactivity in lymphatic endothelium in the human ciliary body. Fluorescent nanospheres injected into the anterior chamber of the sheep eye were detected in LYVE-1-positive channels of the ciliary body 15, 30, and 45 min following injection. Four hours following intracameral injection, Iodine-125 radio-labeled human serum albumin injected into the sheep eye (n = 5) was drained preferentially into cervical, retropharyngeal, submandibular and preauricular lymph nodes in the head and neck region compared to reference popliteal lymph nodes (P < 0.05). These findings collectively indicate the presence of distinct lymphatic channels in the human ciliary body, and that fluid and solutes flow at least partially through this system. The discovery of a uveolymphatic

  7. Prognostic significance of lymphatic, vascular and perineural invasion for bladder cancer patients treated by radical cystectomy.

    PubMed

    Muppa, Prasuna; Gupta, Sounak; Frank, Igor; Boorjian, Stephen A; Karnes, R Jeffrey; Thompson, R Houston; Thapa, Prabin; Tarrell, Robert F; Herrera Hernandez, Loren P; Jimenez, Rafael E; Cheville, John C

    2017-04-01

    In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often reported as 'angiolymphatic' or 'lymphovascular' invasion, terms that combine the findings of tumour within simple endothelial-lined lymphatic spaces and tumour within muscle-lined blood vessels. It is unclear if these patterns of invasion have different prognostic significance. In addition, there are conflicting data regarding the significance of lymphatic, vascular and perineural invasion in patients with bladder cancer. Herein, we studied 1504 patients treated by radical cystectomy for bladder cancer at our institution and followed for a mean of 10.6 years. Cases were re-reviewed by a urological pathologist for lymphatic invasion defined as tumour within a non-muscle-lined endothelial-lined lymphatic space, vascular invasion defined as tumour in a muscle-lined blood vessel, and perineural invasion defined as tumour within the perineural sheath. Associations of clinical and pathological features with bladder cancer death were evaluated using Cox proportional hazards regression models and summarised with hazard ratios and 95% confidence intervals. Survival was estimated by the Kaplan-Meier method. Multivariate analysis showed that lymphatic and vascular invasion but not perineural invasion were significantly associated with cancer specific survival (p<0.0001 and p=0.02, respectively). There was a significant association of lymphatic and vascular invasion but not perineural invasion with involved regional lymph nodes (p<0.0001 and p=0.004, respectively). In patients with metastasis to regional lymph nodes, lymphatic invasion remained significantly associated with outcome (p=0.02). The frequency of lymphatic and vascular invasion varied amongst histological subtypes of bladder cancer. Vascular and lymphatic invasion should be clearly defined and reported for radical cystectomy specimens containing bladder cancer. Copyright © 2017 Royal College of Pathologists of

  8. Electrophysiological properties of rat mesenteric lymphatic vessels and their regulation by stretch.

    PubMed

    von der Weid, Pierre-Yves; Lee, Stewart; Imtiaz, Mohammad S; Zawieja, David C; Davis, Michael J

    2014-06-01

    In mammals, lymph is propelled centrally primarily via the phasic contractions of collecting lymphatic vessels, known as lymphatic pumping. Electrophysiological studies conducted in guinea pig and sheep mesenteric lymphatic vessels indicate that contractions are initiated in the lymphatic muscle by nifedipine-sensitive action potentials (APs). Lymphatic pumping is highly sensitive to luminal fluid loading and the mechanical properties of this stretch-induced pumping have been consistently studied, in particular in rat mesenteric lymphatic vessels. However, membrane potential (Vm) and the electrophysiological events underlying stretch-induced lymphatic pumping have not been investigated in the rat. The aim of this study was thus to examine the properties of rat mesenteric lymphatic muscle Vm under resting conditions and to assess changes in Vm caused by distension. Lymphatic muscle Vm was measured with sharp intracellular microelectrodes either in unstretched conditions or under isometric tension provided by a wire-myograph. In unstretched vessels, Vm was -48 ± 2 mV (n=30). APs (amplitude ∼25 mV) were observed at a frequency of ∼8/min and were abolished by nifedipine. Under isometric tension, Vm was less polarized (-36 ± 1 mV, n=23), even at minimum tension. Increase in tension led to increase in contraction strength and contraction/AP frequency, while Vm was slightly hyperpolarized and AP amplitude not markedly altered. In our experimental conditions, rat lymphatic muscle has electrophysiological characteristics similar to that in other species. It responds to an increase in isometric tension with an increase in AP frequency, but resting Vm is not significantly affected.

  9. Abnormal menstrual periods (image)

    MedlinePlus

    ... have a variety of causes, such as endometrial hyperplasia, endometrial polyps, uterine fibroids, and abnormal thyroid or ... endometrium becomes unusually thick it is called endometrial hyperplasia. Hyperplasia may cause profuse or extended menstrual bleeding.

  10. Abnormal haemoglobins: detection & characterization

    PubMed Central

    Wajcman, Henri; Moradkhani, Kamran

    2011-01-01

    Haemoglobin (Hb) abnormalities though quite frequent, are generally detected in populations during surveys and programmes run for prevention of Hb disorders. Several methods are now available for detection of Hb abnormalities. In this review, the following are discussed: (i) the methods used for characterization of haemoglobin disorders; (ii) the problems linked to diagnosis of thalassaemic trait; (iii) the strategy for detection of common Hb variants; and (iv) the difficulties in identification of rare variants. The differences between developing and industrialized countries for the strategies employed in the diagnosis of abnormal haemoglobins are considered. We mention the limits and pitfalls for each approach and the necessity to characterize the abnormalities using at least two different methods. The recommended strategy is to use a combination of cation-exchange high performance chromatography (CE-HPLC), capillary electrophoresis (CE) and when possible isoelectric focusing (IEF). Difficult cases may demand further investigations requiring specialized protein and/or molecular biology techniques. PMID:22089618

  11. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  12. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  13. Muscle tone abnormalities.

    PubMed

    Habel, M

    1997-01-01

    Rehabilitation nurses frequently encounter clients with neurological disorders that adversely affect muscle tone. By understanding the physiological etiology of abnormal muscle tone, individual practitioners can design nursing interventions for various care settings that appropriately protect clients from injury and that can help clients and caregivers learn effective techniques for managing muscle tone problems. This article explains muscle tone abnormalities in detail and offers insight into how rehabilitation nurses can play a key role in managing clients' alterations in muscle tone.

  14. Isolation, characterization, and functional analysis of ferret lymphatic endothelial cells.

    PubMed

    Berendam, Stella J; Fallert Junecko, Beth A; Murphey-Corb, Michael A; Fuller, Deborah H; Reinhart, Todd A

    2015-02-15

    The lymphatic endothelium (LE) serves as a conduit for transport of immune cells and soluble antigens from peripheral tissues to draining lymph nodes (LNs), contributing to development of host immune responses and possibly dissemination of microbes. Lymphatic endothelial cells (LECs) are major constituents of the lymphatic endothelium. These specialized cells could play important roles in initiation of host innate immune responses through sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including toll-like receptors (TLRs). LECs secrete pro-inflammatory cytokines and chemokines to create local inflammatory conditions for recruitment of naïve antigen presenting cells (APCs) such as dendritic cells (DCs) to sites of infection and/or vaccine administration. In this study, we examined the innate immune potential of primary LEC populations derived from multiple tissues of an animal model for human infectious diseases - the ferret. We generated a total of six primary LEC populations from lung, tracheal, and mesenteric LN tissues from three different ferrets. Standard RT-PCR characterization of these primary LECs showed that they varied in their expression of LEC markers. The ferret LECs were examined for their ability to respond to poly I:C (TLR3 and RIG-I ligand) and other known TLR ligands as measured by production of proinflammatory cytokine (IFNα, IL6, IL10, Mx1, and TNFα) and chemokine (CCL5, CCL20, and CXCL10) mRNAs using real time RT-PCR. Poly I:C exposure induced robust proinflammatory responses by all of the primary ferret LECs. Chemotaxis was performed to determine the functional activity of CCL20 produced by the primary lung LECs and showed that the LEC-derived CCL20 was abundant and functional. Taken together, our results continue to reveal the innate immune potential of primary LECs during pathogen-host interactions and expand our understanding of the roles LECs might play in health and disease in animal

  15. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1

    PubMed Central

    Norrmén, Camilla; Ivanov, Konstantin I.; Cheng, Jianpin; Zangger, Nadine; Delorenzi, Mauro; Jaquet, Muriel; Miura, Naoyuki; Puolakkainen, Pauli; Horsley, Valerie; Hu, Junhao; Augustin, Hellmut G.; Ylä-Herttuala, Seppo; Alitalo, Kari

    2009-01-01

    The mechanisms of blood vessel maturation into distinct parts of the blood vasculature such as arteries, veins, and capillaries have been the subject of intense investigation over recent years. In contrast, our knowledge of lymphatic vessel maturation is still fragmentary. In this study, we provide a molecular and morphological characterization of the major steps in the maturation of the primary lymphatic capillary plexus into collecting lymphatic vessels during development and show that forkhead transcription factor Foxc2 controls this process. We further identify transcription factor NFATc1 as a novel regulator of lymphatic development and describe a previously unsuspected link between NFATc1 and Foxc2 in the regulation of lymphatic maturation. We also provide a genome-wide map of FOXC2-binding sites in lymphatic endothelial cells, identify a novel consensus FOXC2 sequence, and show that NFATc1 physically interacts with FOXC2-binding enhancers. As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention. PMID:19398761

  16. Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations.

    PubMed

    Nitschké, Maximilian; Bell, Alexander; Karaman, Sinem; Amouzgar, Meelad; Rutkowski, Joseph M; Scherer, Philipp E; Alitalo, Kari; McDonald, Donald M

    2017-09-01

    Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Herein, we use a novel transgenic mouse model, where doxycycline-induced overexpression of vascular endothelial growth factor (VEGF)-C was driven by the adipocyte-specific promoter adiponectin (ADN), to determine how chylothorax forms. Surprisingly, 100% of adult ADN-VEGF-C mice developed chylothorax within 7 days. Rapid, consistent appearance of chylothorax enabled us to examine the step-by-step development in otherwise normal adult mice. Dynamic imaging with a fluorescent tracer revealed that lymph in the thoracic duct of these mice could enter the thoracic cavity by retrograde flow into enlarged paravertebral lymphatics and subpleural lymphatic plexuses that had incompetent lymphatic valves. Pleural mesothelium overlying the lymphatic plexuses underwent exfoliation that increased during doxycycline exposure. Together, the findings indicate that chylothorax in ADN-VEGF-C mice results from retrograde flow of chyle from the thoracic duct into lymphatic tributaries with defective valves. Chyle extravasates from these plexuses and enters the thoracic cavity through exfoliated regions of the pleural mesothelium. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Intestinal Lymphatic Transport: an Overlooked Pathway for Understanding Absorption of Plant Secondary Compounds in Vertebrate Herbivores.

    PubMed

    Kohl, Kevin D; Dearing, M Denise

    2017-03-01

    Herbivores employ numerous strategies to reduce their exposure to toxic plant secondary chemicals (PSCs). However, the physiological mechanisms of PSC absorption have not been extensively explored. In particular, the absorption of PSCs via intestinal lymphatic absorption has been largely overlooked in herbivores, even though this pathway is well recognized for pharmaceutical uptake. Here, we investigated for the first time whether PSCs might be absorbed by lymphatic transport. We fed woodrats (Neotoma albigula) diets with increasing concentrations of terpene-rich juniper (Juniperus monosperma) either with or without a compound that blocks intestinal lymphatic absorption (Pluronic L-81). Woodrats consuming diets that contained the intestinal lymphatic absorption blocker exhibited increased food intakes and maintained higher body masses on juniper diets. Our study represents the first demonstration that PSCs may be absorbed by intestinal lymphatic absorption. This absorption pathway has numerous implications for the metabolism and distribution of PSCs in the systemic circulation, given that compounds absorbed via lymphatic transport bypass first-pass hepatic metabolism. The area of lymphatic transport of PSCs represents an understudied physiological pathway in plant-herbivore interactions.

  18. Pathological Steps of Cancer-Related Lymphedema: Histological Changes in the Collecting Lymphatic Vessels after Lymphadenectomy

    PubMed Central

    Hayashi, Yohei; Narushima, Mitsunaga; Yamamoto, Takumi; Todokoro, Takeshi; Iida, Takuya; Sawamoto, Naoya; Araki, Jun; Kikuchi, Kazuki; Murai, Noriyuki; Okitsu, Taro; Kisu, Iori; Koshima, Isao

    2012-01-01

    Introduction To date, an electron microscopy study of the collecting lymphatic vessels has not been conducted to examine the early stages of lymphedema. However, such histological studies could be useful for elucidating the mechanism of lymphedema onset. The aim of this study was to clarify the changes occurring in collecting lymphatic vessels after lymphadenectomy. Methods The study was conducted on 114 specimens from 37 patients who developed lymphedema of the lower limbs after receiving surgical treatment for gynecologic cancers and who consulted the University of Tokyo Hospital and affiliated hospitals from April 2009 to March 2011. Lymphatic vessels that were not needed for lymphatico venous anastomosis surgery were trimmed and subsequently examined using electron microscopy and light microscopy. Results Based on macroscopic findings, the histochemical changes in the collecting lymphatic vessels were defined as follows: normal, ectasis, contraction, and sclerosis type (NECST). In the ectasis type, an increase in endolymphatic pressure was accompanied by a flattening of the lymphatic vessel endothelial cells. In the contraction type, smooth muscle cells were transformed into synthetic cells and promoted the growth of collagen fibers. In the sclerosis type, fibrous elements accounted for the majority of the components, the lymphatic vessels lost their transport and concentrating abilities, and the lumen was either narrowed or completely obstructed. Conclusions The increase in pressure inside the collecting lymphatic vessels after lymphadenectomy was accompanied by histological changes that began before the onset of lymphedema. PMID:22911751

  19. Microneedles for the Noninvasive Structural and Functional Assessment of Dermal Lymphatic Vessels.

    PubMed

    Brambilla, Davide; Proulx, Steven T; Marschalkova, Patrizia; Detmar, Michael; Leroux, Jean-Christophe

    2016-02-24

    The medical and scientific communities' interest in the lymphatic system has been growing rapidly in recent years. It has become evident that the lymphatic system is much more than simply a homeostasis controller and that it plays key roles in several pathological conditions. This work describes the identification of the optimal combination of poly(N-vinylpyrrolidone) and a near-infrared dye (indocyanine green) for the manufacturing of soluble microneedles and their application to the imaging of the lymphatic system. Upon application to the skin, the microneedle-bearing indocyanine green is delivered in the dermal layer, where the lymphatic vessels are abundant. The draining lymphatics can then be visualized and the clearance kinetics from the administration site simply determined using a near-infrared camera. This painless functional "tattooing" procedure can be used for quantitative assessment of the dermal lymphatic function in several dermal conditions and treatment-response evaluations. The two components of these microneedles are extensively used in routine medical care, potentially leading to rapid clinical translation. Moreover, this procedure may have a significant impact on preclinical lymphatic studies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

    PubMed Central

    Aspelund, Aleksanteri; Antila, Salli; Proulx, Steven T.; Karlsen, Tine Veronica; Karaman, Sinem; Detmar, Michael; Wiig, Helge

    2015-01-01

    The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease. PMID:26077718

  1. The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density

    PubMed Central

    Lee, Kit M; Danuser, Renzo; Stein, Jens V; Graham, Delyth; Nibbs, Robert JB; Graham, Gerard J

    2014-01-01

    Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro-lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels. PMID:25271254

  2. Current concepts and future directions in the diagnosis and management of lymphatic vascular disease.

    PubMed

    Rockson, Stanley G

    2010-06-01

    Despite the central, complex role for the lymphatic system in the maintenance of human health, the biology of this important and complex vasculature has been relatively under-investigated. However, the last decade has witnessed a substantial growth in the elucidation of lymphatic structural biology and the function of this system in health and in disease. These newly gained insights can be used to formulate our evolving concepts about the diagnostic and therapeutic approaches to patients with lymphatic vascular disorders. In lymphedema, there is a spectrum of disease that extends from primary (heritable) to secondary (acquired) causes. Once detected, the presence of lymphatic edema mandates very specific modalities of intervention, predominated by physiotherapeutic techniques. In addition, a physiological basis for adjunctive, intermittent pneumatic compression has been established, and these modalities may be indicated in selected patient populations. The acknowledgement of a unique biology in lymphatic edemas is, increasingly, guiding research efforts within this field. Increasing investigative attention is being directed toward animal models of lymphatic vascular disease. As insight into the complex biology of the lymphatic vasculature continues to expand through focused biomedical investigation, the translation of these mechanistic insights into targeted, rationally conceived therapeutics will become increasingly feasible.

  3. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation.

    PubMed

    Uhrin, Pavel; Zaujec, Jan; Breuss, Johannes M; Olcaydu, Damla; Chrenek, Peter; Stockinger, Hannes; Fuertbauer, Elke; Moser, Markus; Haiko, Paula; Fässler, Reinhard; Alitalo, Kari; Binder, Bernd R; Kerjaschki, Dontscho

    2010-05-13

    During embryonic development, lymph sacs form from the cardinal vein, and sprout centrifugally to form mature lymphatic networks. Separation of the lymphatic from the blood circulation by a hitherto unknown mechanism is essential for the homeostatic function of the lymphatic system. O-glycans on the lymphatic endothelium have recently been suggested to be required for establishment and maintenance of distinct blood and lymphatic systems, primarily by mediating proper function of podoplanin. Here, we show that this separation process critically involves platelet activation by podoplanin. We found that platelet aggregates build up in wild-type embryos at the separation zone of podoplanin(+) lymph sacs and cardinal veins, but not in podoplanin(-/-) embryos. Thus, podoplanin(-/-) mice develop a "nonseparation" phenotype, characterized by a blood-filled lymphatic network after approximately embryonic day 13.5, which, however, partially resolves in postnatal mice. The same embryonic phenotype is also induced by treatment of pregnant mice with acetyl salicylic acid, podoplanin-blocking antibodies, or by inactivation of the kindlin-3 gene required for platelet aggregation. Therefore, interaction of endothelial podoplanin of the developing lymph sac with circulating platelets from the cardinal vein is critical for separating the lymphatic from the blood vascular system.

  4. Mechanics of interstitial-lymphatic fluid transport: theoretical foundation and experimental validation.

    PubMed

    Swartz, M A; Kaipainen, A; Netti, P A; Brekken, C; Boucher, Y; Grodzinsky, A J; Jain, R K

    1999-12-01

    Interstitial fluid movement is intrinsically linked to lymphatic drainage. However, their relationship is poorly understood, and associated pathologies are mostly untreatable. In this work we test the hypothesis that bulk tissue fluid movement can be evaluated in situ and described by a linear biphasic theory which integrates the regulatory function of the lymphatics with the mechanical stresses of the tissue. To accomplish this, we develop a novel experimental and theoretical model using the skin of the mouse tail. We then use the model to demonstrate how interstitial-lymphatic fluid movement depends on a balance between the elasticity, hydraulic conductivity, and lymphatic conductance as well as to demonstrate how chronic swelling (edema) alters the equipoise between tissue fluid balance parameters. Specifically, tissue fluid equilibrium is perturbed with a continuous interstitial infusion of saline into the tip of the tail. The resulting gradients in tissue stress are measured in terms of interstitial fluid pressure using a servo-null system. These measurements are then fit to the theory to provide in vivo estimates of the tissue hydraulic conductivity, elastic modulus, and overall resistance to lymphatic drainage. Additional experiments are performed on edematous tails to show that although chronic swelling causes an increase in the hydraulic conductivity, its greatly increased distensibility (due to matrix remodeling) dampens the driving forces for fluid movement and leads to fluid stagnation. This model is useful for examining potential treatments for edema and lymphatic disorders as well as substances which may alter tissue fluid balance and/or lymphatic drainage.

  5. Effect of lidocaine with and without epinephrine on lymphatic contractile activity in mice in vivo.

    PubMed

    Kwon, Sunkuk; Sevick-Muraca, Eva M

    2016-12-01

    A local anesthetic, lidocaine, is known to affect cutaneous blood flow when injected into the skin. However, it is unknown if dermal lymphatic function can also be affected. Therefore, we characterized lymphatic function in response to administration of lidocaine with and without epinephrine. Non-invasive near-infrared fluorescence imaging (NIRFI) with intradermal injection of indocyanine green (ICG) was used to characterize the lymphatic "pumping" function in mice after subcutaneous injection of 2 % lidocaine with and without 1:100,000 epinephrine or saline. NIRFI was performed for 10-20 min immediately after and 1, 3, and 5 h after these interventions. Lymphatic contraction frequencies significantly decreased 10 min after subcutaneous injection of lidocaine and remained plateaued for another 5 min, before returning to baseline. However, addition of 1:100,000 epinephrine to 2 % lidocaine rapidly increased lymphatic contraction frequencies at 5 min post-injection, which returned to baseline levels 15 min later. Injection of saline also increased lymphatic contraction frequency 5 min after injection, which returned to baseline 10 min post-injection. Although lidocaine administration showed a decrease in lymphatic function, the combination of epinephrine with lidocaine resulted in a predominant net effect of increased contractile activity.

  6. Efficacy of AdipoDren® in Reducing Interleukin-1-Induced Lymphatic Endothelial Hyperpermeability.

    PubMed

    Ciccone, Valerio; Monti, Martina; Antonini, Giulia; Mattoli, Luisa; Burico, Michela; Marini, Francesca; Maidecchi, Anna; Morbidelli, Lucia

    2016-01-01

    Lymphatic leakage can be seen as a detrimental phenomenon associated with fluid retention and deposition as well as gain of weight. Moreover, lymphatic dysfunction is associated with an inflammatory environment and can be a substrate for other health conditions. A number of treatments can ameliorate lymphatic vasculature: natural substances have been used as treatment options particularly suitable for their consolidated effectiveness and safety profile. Here we report the protective effect of AdipoDren®, an association of a series of plant-derived natural complexes, on lymphatic endothelium permeability promoted by interleukin-1 beta (IL-1β) and the associated molecular mechanisms. AdipoDren® demonstrated a protective effect on dermal lymphatic endothelial cell permeability increased by IL-1β. Reduced permeability was due to the maintenance of tight junctions and cell-cell localisation of occludin and zonula occludens-1 (ZO-1). Moreover, AdipoDren® reduced the expression of the inflammatory key element cyclooxygenase-2 (COX-2), while not altering the levels of endothelial and inducible nitric oxide synthases (eNOS and iNOS). The upregulation of antioxidant enzymatic systems (catalase and superoxide dismutase-1, SOD-1) and the downregulation of pro-oxidant markers (p22 phox subunit of NADPH oxidase) were also evident. In conclusion, AdipoDren® would be useful to ameliorate conditions of altered lymphatic vasculature and to support the physiological functionality of the lymphatic endothelium.

  7. Obliteration of the lymphatic trunks draining diaphragmatic lymph causes peritoneal fluid to enter the pleural cavity.

    PubMed

    Ohtani, Y; Ohtani, O

    1997-12-01

    Pathways of peritoneal fluids to the pleural cavity in the rat were investigated by light microscopy and transmission electron microscopy (TEM). Intraperitoneally injected India ink was demonstrated to enter the subperitoneal lymphatics through lymphatic stomata, and to drain through the subpleural collecting lymphatics, into the parasternal, paravertebral and mediastinal lymphatic trunks as well as the thoracic duct. Five to 10 min after the intraperitoneal injection of India ink, the parasternal lymphatic trunk was ligated at the third intercostal space. Thirty minutes, 1 h, or 2 h after the ligation of either the right or the left trunk, India ink was macroscopically recognized only around the ligated trunk. When the right and left trunks were simultaneously ligated, India ink leaked around both trunks. Five hours after the ligation of both trunks, a massive amount of ink was located in the interstitium of the anterior thoracic wall. TEM revealed carbon particles passing through gaps of the lymphatic endothelial cells into the interstitial space, and partly reaching the mesothelial surface lining the anterior thoracic wall. Results show that obstruction or narrowing of the lymphatic trunks draining the diaphragmatic lymph causes a hydrothorax, indicating that this is at least one mechanism causing this during continuous ambulatory peritoneal dialysis and diseases with ascites.

  8. Lymphatic trafficking kinetics and near-infrared imaging using star polymer architectures with controlled anionic character

    PubMed Central

    Bagby, Taryn R.; Cai, Shuang; Duan, Shaofeng; Yang, Qiuhong; Thati, Sharadvi; Berkland, Cory; Aires, Daniel J.; Forrest, M. Laird

    2015-01-01

    Targeted lymphatic delivery of nanoparticles for drug delivery and imaging is primarily dependent on size and charge. Prior studies have observed increased lymphatic uptake and retentions of over 48 hrs for negatively charged particles compared to neutral and positively charged particles. We have developed new polymeric materials that extend retention over a more pharmaceutically relevant 7-day period. We used whole body fluorescence imaging to observe in mice the lymphatic trafficking of a series of anionic star poly-(6-O-methacryloyl-D-galactose) polymer-NIR dye (IR820) conjugates. The anionic charge of polymers was increased by modifying galactose moieties in the star polymers with succinic anhydride. Increasing anionic nature was associated with enhanced lymphatic uptake up to a zeta potential of ca. -40 mV; further negative charge did not affect lymphatic uptake. Compared to the 20% acid-conjugate, the 40 to 90% acid-star-polymer conjugates exhibited a 2.5- to 3.5-fold increase in lymphatic uptake in both the popliteal and iliac nodes. The polymer conjugates exhibited node half-lives of 2 to 20 hrs in the popliteal nodes and 19 to 114 hrs in the deeper iliac nodes. These polymer conjugates can deliver drugs or imaging agents with rapid lymphatic uptake and prolonged deep-nodal retention; thus they may provide a useful vehicle for sustained intralymphatic drug delivery with low toxicity. PMID:22546180

  9. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.

    PubMed

    Aspelund, Aleksanteri; Antila, Salli; Proulx, Steven T; Karlsen, Tine Veronica; Karaman, Sinem; Detmar, Michael; Wiig, Helge; Alitalo, Kari

    2015-06-29

    The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease. © 2015 Aspelund et al.

  10. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy.

    PubMed

    Mihara, Makoto; Hara, Hisako; Hayashi, Yohei; Narushima, Mitsunaga; Yamamoto, Takumi; Todokoro, Takeshi; Iida, Takuya; Sawamoto, Naoya; Araki, Jun; Kikuchi, Kazuki; Murai, Noriyuki; Okitsu, Taro; Kisu, Iori; Koshima, Isao

    2012-01-01

    To date, an electron microscopy study of the collecting lymphatic vessels has not been conducted to examine the early stages of lymphedema. However, such histological studies could be useful for elucidating the mechanism of lymphedema onset. The aim of this study was to clarify the changes occurring in collecting lymphatic vessels after lymphadenectomy. The study was conducted on 114 specimens from 37 patients who developed lymphedema of the lower limbs after receiving surgical treatment for gynecologic cancers and who consulted the University of Tokyo Hospital and affiliated hospitals from April 2009 to March 2011. Lymphatic vessels that were not needed for lymphatico venous anastomosis surgery were trimmed and subsequently examined using electron microscopy and light microscopy. Based on macroscopic findings, the histochemical changes in the collecting lymphatic vessels were defined as follows: normal, ectasis, contraction, and sclerosis type (NECST). In the ectasis type, an increase in endolymphatic pressure was accompanied by a flattening of the lymphatic vessel endothelial cells. In the contraction type, smooth muscle cells were transformed into synthetic cells and promoted the growth of collagen fibers. In the sclerosis type, fibrous elements accounted for the majority of the components, the lymphatic vessels lost their transport and concentrating abilities, and the lumen was either narrowed or completely obstructed. The increase in pressure inside the collecting lymphatic vessels after lymphadenectomy was accompanied by histological changes that began before the onset of lymphedema.

  11. Invasion of lymphatic vessels into the eye after open globe injuries.

    PubMed

    Wessel, Julia M; Hofmann-Rummelt, Carmen; Kruse, Friedrich E; Cursiefen, Claus; Heindl, Ludwig M

    2012-06-20

    We analyzed whether lymphatic vessels can be detected in eyes enucleated after an open globe injury. The presence of lymphatic vessels was analyzed immunohistochemically using podoplanin as a specific lymphatic endothelial marker in 21 globes that had been enucleated after open globe injury. The localization of pathologic lymphatic vessels (within the eye wall or inside the eye) was correlated with the mechanism of trauma, anatomic site of perforation or rupture, and time interval between trauma and enucleation. Pathologic lymphatic vessels were detected in 15 of 21 eyes (71%) enucleated after an open globe injury. In 5 globes (24%) they were found within the eye, located in retrocorneal membranes, underneath the sclera, and adjacent to uveal tissue (ciliary body, iris). No significant association was observed between the presence of pathologic lymphatic vessels and the mechanism of trauma (P = 0.598), anatomic site of perforation or rupture (P = 0.303), and time interval between trauma and enucleation (P = 0.145). The human eye can be invaded secondarily by lymphatic vessels if the eye wall is opened by trauma. This mechanism could be important for wound healing, immunologic defense against intruding microorganisms, and autoimmune reactions against intraocular antigens.

  12. Regression of mature lymphatic vessels in the cornea by photodynamic therapy.

    PubMed

    Bucher, F; Bi, Y; Gehlsen, U; Hos, D; Cursiefen, C; Bock, F

    2014-03-01

    Corneal (lymph) angiogenesis is a predominant risk-factor for immune rejection after transplantation. Techniques to regress pre-existing pathological corneal lymphatic vessels prior to transplantation are missing so far. Therefore we analysed the possibility to regress corneal lymphatic vessels by photodynamic therapy (PDT), after intrastromal verteporfin injection. Combined hemangiogenesis and lymphangiogenesis was induced in female BALB/c mice using the murine model of suture-induced inflammatory neovascularisation. Thereafter, the treatment group received an intrastromal injection of verteporfin (controls: phosphate buffered saline (PBS)) followed by PDT. Corneas were excised at different time points (1 day, 5 days and 10 days) after PDT and corneal whole mounts were stained with CD31 and LYVE-1 to quantify hemangiogenesis and lymphangiogenesis. Whereas blood vessels showed no significant reduction after PDT, lymphatic vessels could significantly be reduced with PDT after intrastromal verteporfin injection: 1 day after PDT, lymphatic vessels were reduced by 62% (p=0.20). After 5 days and 10 days, lymphatic vessels were reduced by 51% and 48% (p<0.001), respectively. This study for the first time shows that PDT after corneal intrastromal verteporfin injection can selectively regress lymphatic vessels. This may become a new 'preconditioning strategy' to reduce pre-existing corneal lymphatic vessels prior to transplantation and thereby reduce allograft rejection in high-risk patients.

  13. Expansion of the lymphatic vasculature in cancer and inflammation: new opportunities for in vivo imaging and drug delivery.

    PubMed

    Proulx, Steven T; Luciani, Paola; Dieterich, Lothar C; Karaman, Sinem; Leroux, Jean-Christophe; Detmar, Michael

    2013-12-10

    Over the last 15 years, discovery of key growth factors and specific molecular markers for lymphatic vessels has enabled a new era of molecular research on the lymphatic vascular system. As a result, it has been found that lymphangiogenesis, the expansion of existing lymphatic vessels, plays an important role in tumor progression and in the control of chronic inflammation. At the same time, technical advancements have been made to improve the visualization of the lymphatic system. We have recently developed liposomal and polymer-based formulations of near-infrared lymphatic-specific imaging tracers for the non-invasive quantitative in vivo imaging of lymphatic vessel function. Using these tracers, a near-infrared stereomicroscope system allows imaging of initial and collecting lymphatic vessels with high spatial and temporal resolution in mice. In addition, we have developed a new method, using antibodies to a lymphatic specific marker and positron emission tomography, to sensitively detect lymphatic expansion in lymph nodes as the earliest sign of cancer metastasis. These imaging methods have great potential to provide non-invasive measures to assess the functionality of the lymphatic system and to assess the efficiency of lymphatic drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Quantitative measurement of lymphatic function in mice by noninvasive near-infrared imaging of a peripheral vein

    PubMed Central

    Ma, Qiaoli; Andina, Diana; Leroux, Jean-Christophe; Detmar, Michael

    2017-01-01

    Optical imaging methods have been developed to measure lymphatic function in skin; however, the lymphatic system of many organs is not accessible to this technology. Since lymphatic transport of macromolecules from any organ proceeds to the blood circulation, we aimed to develop a method that can measure lymphatic function by monitoring the fluorescence in a superficial vein of an interstitially injected tracer. We selected a 40-kDa PEGylated near-infrared dye conjugate, as it showed lymphatic system–specific uptake and extended circulation in blood. Lymphatic transport to blood from subcutaneous tissue required a transit time before signal enhancement was seen in blood followed by a steady rise in signal over time. Increased lymphatic transport was apparent in awake mice compared with those under continuous anesthesia. The methods were validated in K14-VEGFR-3-Fc and K14-VEGF-C transgenic mice with loss and gain of lymphatic function, respectively. Reduced lymphatic transport to blood was also found in aged mice. The technique was also able to measure lymphatic transport from the peritoneal cavity, a location not suitable for optical imaging. The method is a promising, simple approach for assessment of lymphatic function and for monitoring of therapeutic regimens in mouse models of disease and may have potential for clinical translation. PMID:28097238

  15. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL.

    PubMed

    Lim, Hwee Ying; Thiam, Chung Hwee; Yeo, Kim Pin; Bisoendial, Radjesh; Hii, Chung Shii; McGrath, Kristine C Y; Tan, Kar Wai; Heather, Alison; Alexander, J Steven Jonathan; Angeli, Veronique

    2013-05-07

    Removal of cholesterol from peripheral tissues to the bloodstream via reverse cholesterol transport (RCT) is a process of major biological importance. Here we demonstrate that lymphatic drainage is required for RCT. We have previously shown that hypercholesterolemia in mice is associated with impaired lymphatic drainage and increased lipid accumulation in peripheral tissues. We now show that restoration of lymphatic drainage in these mice significantly improves cholesterol clearance. Conversely, obstruction of lymphatic vessels in wild-type mice significantly impairs RCT. Finally, we demonstrate using silencing RNA interference, neutralizing antibody, and transgenic mice that removal of cholesterol by lymphatic vessels is dependent on the uptake and transcytosis of HDL by scavenger receptor class B type I expressed on lymphatic endothelium. Collectively, this study challenges the current view that lymphatic endothelium is a passive exchange barrier for cholesterol transport and provides further evidence for its interplay with lipid biology in health and disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Nitric Oxide Regulates The Lymphatic Reactivity Following Hemorrhagic Shock Through Atp-Sensitive Potassium Channel.