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Sample records for lymphatic collecting vessels

  1. 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

  2. In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging.

    PubMed

    Chong, Chloé; Scholkmann, Felix; Bachmann, Samia B; Luciani, Paola; Leroux, Jean-Christophe; Detmar, Michael; Proulx, Steven T

    2016-01-01

    Techniques to image lymphatic vessel function in either animal models or in the clinic are limited. In particular, imaging methods that can provide robust outcome measures for collecting lymphatic vessel function are sorely needed. In this study, we aimed to develop a method to visualize and quantify collecting lymphatic vessel function in mice, and to establish an in vivo system for evaluation of contractile agonists and antagonists using near-infrared fluorescence imaging. The flank collecting lymphatic vessel in mice was exposed using a surgical technique and a near-infrared tracer was infused into the inguinal lymph node. Collecting lymphatic vessel contractility and valve function could be easily visualized after the infusion. A diameter tracking method was established and the diameter of the vessel was found to closely correlate to near-infrared fluorescence signal. Phasic contractility measures of frequency and amplitude were established using an automated algorithm. The methods were validated by tracking the vessel response to topical application of a contractile agonist, prostaglandin F2α, and by demonstrating the potential of the technique for non-invasive evaluation of modifiers of lymphatic function. These new methods will enable high-resolution imaging and quantification of collecting lymphatic vessel function in animal models and may have future clinical applications. PMID:26960708

  3. In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging

    PubMed Central

    Chong, Chloé; Scholkmann, Felix; Bachmann, Samia B.; Luciani, Paola; Leroux, Jean-Christophe; Detmar, Michael; Proulx, Steven T.

    2016-01-01

    Techniques to image lymphatic vessel function in either animal models or in the clinic are limited. In particular, imaging methods that can provide robust outcome measures for collecting lymphatic vessel function are sorely needed. In this study, we aimed to develop a method to visualize and quantify collecting lymphatic vessel function in mice, and to establish an in vivo system for evaluation of contractile agonists and antagonists using near-infrared fluorescence imaging. The flank collecting lymphatic vessel in mice was exposed using a surgical technique and a near-infrared tracer was infused into the inguinal lymph node. Collecting lymphatic vessel contractility and valve function could be easily visualized after the infusion. A diameter tracking method was established and the diameter of the vessel was found to closely correlate to near-infrared fluorescence signal. Phasic contractility measures of frequency and amplitude were established using an automated algorithm. The methods were validated by tracking the vessel response to topical application of a contractile agonist, prostaglandin F2α, and by demonstrating the potential of the technique for non-invasive evaluation of modifiers of lymphatic function. These new methods will enable high-resolution imaging and quantification of collecting lymphatic vessel function in animal models and may have future clinical applications. PMID:26960708

  4. CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability

    PubMed Central

    Ivanov, Stoyan; Scallan, Joshua P.; Kim, Ki-Wook; Werth, Kathrin; Johnson, Michael W.; Saunders, Brian T.; Wang, Peter L.; Kuan, Emma L.; Straub, Adam C.; Ouhachi, Melissa; Weinstein, Erica G.; Williams, Jesse W.; Briseño, Carlos; Colonna, Marco; Isakson, Brant E.; Gautier, Emmanuel L.; Förster, Reinhold; Davis, Michael J.; Zinselmeyer, Bernd H.

    2016-01-01

    Lymphatic collecting vessels direct lymph into and from lymph nodes (LNs) and can become hyperpermeable as the result of a previous infection. Enhanced permeability has been implicated in compromised immunity due to reduced flow of lymph and immune cells to LNs, which are the primary site of antigen presentation to T cells. Presently, very little is known about the molecular signals that affect lymphatic collecting vessel permeability. Here, we have shown that lymphatic collecting vessel permeability is controlled by CCR7 and that the chronic hyperpermeability of collecting vessels observed in Ccr7–/– mice is followed by vessel fibrosis. Reexpression of CCR7 in DCs, however, was sufficient to reverse the development of such fibrosis. IFN regulatory factor 4–positive (IRF4+) DCs constitutively interacted with collecting lymphatics, and selective ablation of this DC subset in Cd11c-Cre Irf4fl/fl mice also rendered lymphatic collecting vessels hyperpermeable and fibrotic. Together, our data reveal that CCR7 plays multifaceted roles in regulating collecting vessel permeability and fibrosis, with one of the key players being IRF4-dependent DCs. PMID:26999610

  5. Effects of dynamic shear and transmural pressure on wall shear stress sensitivity in collecting lymphatic vessels.

    PubMed

    Kornuta, Jeffrey A; Nepiyushchikh, Zhanna; Gasheva, Olga Y; Mukherjee, Anish; Zawieja, David C; Dixon, J Brandon

    2015-11-01

    Given the known mechanosensitivity of the lymphatic vasculature, we sought to investigate the effects of dynamic wall shear stress (WSS) on collecting lymphatic vessels while controlling for transmural pressure. Using a previously developed ex vivo lymphatic perfusion system (ELPS) capable of independently controlling both transaxial pressure gradient and average transmural pressure on an isolated lymphatic vessel, we imposed a multitude of flow conditions on rat thoracic ducts, while controlling for transmural pressure and measuring diameter changes. By gradually increasing the imposed flow through a vessel, we determined the WSS at which the vessel first shows sign of contraction inhibition, defining this point as the shear stress sensitivity of the vessel. The shear stress threshold that triggered a contractile response was significantly greater at a transmural pressure of 5 cmH2O (0.97 dyne/cm(2)) than at 3 cmH2O (0.64 dyne/cm(2)). While contraction frequency was reduced when a steady WSS was applied, this inhibition was reversed when the applied WSS oscillated, even though the mean wall shear stresses between the conditions were not significantly different. When the applied oscillatory WSS was large enough, flow itself synchronized the lymphatic contractions to the exact frequency of the applied waveform. Both transmural pressure and the rate of change of WSS have significant impacts on the contractile response of lymphatic vessels to flow. Specifically, time-varying shear stress can alter the inhibition of phasic contraction frequency and even coordinate contractions, providing evidence that dynamic shear could play an important role in the contractile function of collecting lymphatic vessels. PMID:26333787

  6. Permeability and contractile responses of collecting lymphatic vessels elicited by atrial and brain natriuretic peptides.

    PubMed

    Scallan, Joshua P; Davis, Michael J; Huxley, Virginia H

    2013-10-15

    Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones released into the bloodstream in response to hypervolaemia or fluid shifts to the central circulation. The actions of both peptides include natriuresis and diuresis, a decrease in systemic blood pressure, and inhibition of the renin-angiotensin-aldosterone system. Further, ANP and BNP elicit increases in blood microvessel permeability sufficient to cause protein and fluid extravasation into the interstitium to reduce the vascular volume. Given the importance of the lymphatic vasculature in maintaining fluid balance, we tested the hypothesis that ANP or BNP (100 nM) would likewise elevate lymphatic permeability (Ps) to serum albumin. Using a microfluorometric technique adapted to in vivo lymphatic vessels, we determined that rat mesenteric collecting lymphatic Ps to rat serum albumin increased by 2.0 ± 0.4-fold (P = 0.01, n = 7) and 2.7 ± 0.8-fold (P = 0.07, n = 7) with ANP and BNP, respectively. In addition to measuring Ps responses, we observed changes in spontaneous contraction amplitude and frequency from the albumin flux tracings in vivo. Notably, ANP abolished spontaneous contraction amplitude (P = 0.005) and frequency (P = 0.006), while BNP augmented both parameters by ∼2-fold (P < 0.01 each). These effects of ANP and BNP on contractile function were examined further by using an in vitro assay. In aggregate, these data support the theory that an increase in collecting lymphatic permeability opposes the absorptive function of the lymphatic capillaries, and aids in the retention of protein and fluid in the interstitial space to counteract volume expansion. PMID:23897233

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

    PubMed

    Kwon, Sunkuk; Price, Roger E

    2016-04-01

    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

  8. 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.

  9. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue DCs

    PubMed Central

    Kuan, Emma L.; Ivanov, Stoyan; Bridenbaugh, Eric A.; Victora, Gabriel; Wang, Wei; Childs, Ed W.; Platt, Andrew M.; Jakubzick, Claudia V.; Mason, Robert J.; Gashev, Anatoliy A.; Nussenzweig, Michel; Swartz, Melody A.; Dustin, Michael L.; Zawieja, David C.; Randolph, Gwendalyn J.

    2015-01-01

    Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. Here, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived antigens by these cells supported recall T cell responses in the fat and also generated antigen-bearing DCs for emigration into adjacent lymph nodes. Enhanced recruitment of DCs to inflammation-reactive lymph nodes significantly relied on adipose tissue DCs to maintain sufficient numbers of antigen-bearing DCs as the lymph node expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for antigen transport into the adjacent lymph node. PMID:25917096

  10. Hypercholesterolemic Mice Exhibit Lymphatic Vessel Dysfunction and Degeneration

    PubMed Central

    Lim, Hwee Ying; Rutkowski, Joseph M.; Helft, Julie; Reddy, Sai T.; Swartz, Melody A.; Randolph, Gwendalyn J.; Angeli, Véronique

    2009-01-01

    Lymphatic vessels are essential for lipid absorption and transport. Despite increasing numbers of observations linking lymphatic vessels and lipids, little research has been devoted to address how dysregulation of lipid balance in the blood, ie, dyslipidemia, may affect the functional biology of lymphatic vessels. Here, we show that hypercholesterolemia occurring in apolipoprotein E-deficient (apoE−/−) mice is associated with tissue swelling, lymphatic leakiness, and decreased lymphatic transport of fluid and dendritic cells from tissue. Lymphatic dysfunction results in part from profound structural abnormalities in the lymphatic vasculature: namely, initial lymphatic vessels were greatly enlarged, and collecting vessels developed notably decreased smooth muscle cell coverage and changes in the distribution of lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1). Our results provide evidence that hypercholesterolemia in adult apoE−/− mice is associated with a degeneration of lymphatic vessels that leads to decreased lymphatic drainage and provides an explanation for why dendritic cell migration and, thus, immune priming, are compromised in hypercholesterolemic mice. PMID:19679879

  11. Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation.

    PubMed

    Welsh, John D; Kahn, Mark L; Sweet, Daniel T

    2016-09-01

    Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation. This process, known as "lymphovenous hemostasis," is mediated by activation of platelet CLEC-2 receptors by the transmembrane ligand podoplanin expressed by lymphatic endothelial cells. Lymphovenous hemostasis is required for normal lymph flow, and mice deficient in lymphovenous hemostasis exhibit lymphedema and sometimes chylothorax phenotypes indicative of lymphatic insufficiency. Unexpectedly, the loss of lymph flow in these mice causes defects in maturation of collecting lymphatic vessels and lymphatic valve formation, uncovering an important role for fluid flow in driving endothelial cell signaling during development of collecting lymphatics. This article summarizes the current understanding of lymphovenous hemostasis and its effect on lymphatic vessel maturation and synthesizes the outstanding questions in the field, with relationship to human disease. PMID:27385789

  12. Mechanisms of VIP-induced inhibition of the lymphatic vessel pump.

    PubMed

    von der Weid, Pierre-Yves; Rehal, Sonia; Dyrda, Peter; Lee, Stewart; Mathias, Ryan; Rahman, Mozibur; Roizes, Simon; Imtiaz, Mohammad S

    2012-06-01

    Lymphatic vessels serve as a route by which interstitial fluid, protein and other macromolecules are returned to the blood circulation and immune cells and antigens gain access to lymph nodes. Lymph flow is an active process promoted by rhythmical contraction-relaxation events occurring in the collecting lymphatic vessels. This lymphatic pumping is an intrinsic property of the lymphatic muscles in the vessel wall and consequent to action potentials. Compromised lymphatic pumping may affect lymph and immune cell transport, an action which could be particularly detrimental during inflammation. Importantly, many inflammatory mediators alter lymphatic pumping. Vasoactive intestinal peptide (VIP) is a neuro- and immuno-modulator thought to be released by nerve terminals and immune cells in close proximity to lymphatic vessels. We demonstrated the presence of the peptide in lymphatic vessels and in the lymph and examined the effects of VIP on mesenteric collecting lymphatic vessels of the guinea pig using pharmacological bioassays, intracellular microelectrode electrophysiology, immunofluorescence and quantitative real-time PCR. We showed that VIP alters lymphatic pumping by decreasing the frequency of lymphatic contractions and hyperpolarizing the lymphatic muscle membrane potential in a concentration-dependent manner. Our data further suggest that these effects are mainly mediated by stimulation of the VIP receptor VPAC2 located on the lymphatic muscle and the downstream involvement of protein kinase A (PKA) and ATP-sensitive K⁺ (KATP) channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes. PMID:22451438

  13. 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. PMID:27263409

  14. Embryonic development and malformation of lymphatic vessels.

    PubMed

    Wilting, Jörg; Buttler, Kerstin; Rössler, Jochen; Norgall, Susanne; Schweigerer, Lothar; Weich, Herbert A; Papoutsi, Maria

    2007-01-01

    In the human, malformations of lymphatic vessels can be observed as lymphangiectasia, lymphangioma and lymphangiomatosis, with a prevalence of 1.2-2.8 per thousand. Their aetiology is unknown and a causal therapy does not exist. We investigated the origin of lymphatic endothelial cells (LECs) in avian and murine embryos, and compared the molecular profile of LECs from normal and malformed lymphatics of children. In avian embryos, Prox1+ lymphangioblasts are located in the confluence of the cranial and caudal cardinal veins, where the jugular lymph sac (JLS) forms. Cell lineage studies show that the JLS is of venous origin. In contrast, the lymphatics of the dermis are derived from mesenchymal lymphangioblasts located in the dermatomes, suggesting a dual origin of LECs in avian embryos. The same may hold true for murine embryos, where Lyve1+ LEC precursors are found in the cardinal veins, and in the mesenchyme. The mesenchymal cells express the pan-leukocyte marker CD45, indicating a cell type with lymphendothelial and leukocyte characteristics. In the human, such cells might give rise to Kaposi's sarcoma. Microarray analyses of LECs from lymphangiomas of children show a large number of regulated genes, such as VEGFR3. Our studies show that lymphvasculogenesis and lymphangiogenesis occur simultaneously in the embryo, and suggest a function for VEGFR3 in lymphangiomas. PMID:18300425

  15. 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

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

    PubMed

    Kume, Tsutomu

    2015-08-01

    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. PMID:26214518

  17. Lymphatic Vessel Function in Head and Neck Inflammation

    PubMed Central

    Truman, Lucy A.; A-Gonzalez, Noelia; Bentley, Kevin L.

    2013-01-01

    Abstract Background Serious infections of the head and neck cause lymphedema that can lead to airway compromise and oropharyngeal obstruction. Lymphangiogenesis occurs in the head and neck during infection and after immunization. The goal of this project was to develop tools to image lymphatic vessels in living animals and to be able to isolate individual lymphatic endothelial cells in order to quantify changes in single cells caused by inflammation. Methods The ProxTom transgenic red-fluorescent reporter mouse was developed specifically for the purpose of imaging lymphatic vessels in vivo. Prox1 is a transcription factor that is necessary for lymphangiogenesis in development and for the maintenance of lymphatics in adulthood. Mice were immunized and their lymphatic vessels in lymph nodes were imaged in vivo. Individual lymphatic endothelial cells were isolated by means of their fluorescence. Results The ProxTom transgene has the red-fluorescent reporter td-Tomato under the control of Prox1 regulatory elements. tdTomato was faithfully expressed in lymphatic vessels coincident with endogenous Prox1 expression. We show lymphangiogenesis in vivo after immunization and demonstrate a method for the isolation of lymphatic endothelial cells by their tdTomato red-fluorescence. Conclusions The faithful expression of the red-fluorescent reporter in the lymphatic vessels of ProxTom means that these mice have proven utility for in vivo study of lymphatic vessels in the immune response. ProxTom has been made available for distribution from the Jackson Laboratory: http://jaxmice.jax.org/strain/018128.html. PMID:24044758

  18. 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

  19. Prominent Lymphatic Vessel Hyperplasia with Progressive Dysfunction and Distinct Immune Cell Infiltration in Lymphedema.

    PubMed

    Gousopoulos, Epameinondas; Proulx, Steven T; Scholl, Jeannette; Uecker, Maja; Detmar, Michael

    2016-08-01

    Lymphedema is a common complication that occurs after breast cancer treatment in up to 30% of the patients undergoing surgical lymph node excision. It is associated with tissue swelling, fibrosis, increased risk of infection, and impaired wound healing. Despite the pronounced clinical manifestations of the disease, little is known about the morphological and functional characteristics of the lymphatic vasculature during the course of lymphedema progression. We used an experimental murine tail lymphedema model where sustained fluid stasis was generated on disruption of lymphatic flow, resulting in chronic edema formation with fibrosis and adipose tissue deposition. Morphological analysis of the lymphatic vessels revealed a dramatic expansion during the course of the disease, with active proliferation of lymphatic endothelial cells at the early stages of lymphedema. The lymphatic capillaries exhibited progressively impaired tracer filling and retrograde flow near the surgery site, whereas the collecting lymphatic vessels showed a gradually decreasing contraction amplitude with unchanged contraction frequency, leading to lymphatic contraction arrest at the later stages of the disease. Lymphedema onset was associated with pronounced infiltration by immune cells, predominantly Ly6G(+) and CD4(+) cells, which have been linked to impaired lymphatic vessel function. PMID:27315777

  20. 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. PMID:27525437

  1. Diaphragmatic lymphatic vessel behavior during local skeletal muscle contraction.

    PubMed

    Moriondo, Andrea; Solari, Eleonora; Marcozzi, Cristiana; Negrini, Daniela

    2015-02-01

    The mechanism through which the stresses developed in the diaphragmatic tissue during skeletal muscle contraction sustain local lymphatic function was studied in 10 deeply anesthetized, tracheotomized adult Wistar rats whose diaphragm was exposed after thoracotomy. To evaluate the direct effect of skeletal muscle contraction on the hydraulic intraluminal lymphatic pressures (Plymph) and lymphatic vessel geometry, the maximal contraction of diaphragmatic fibers adjacent to a lymphatic vessel was elicited by injection of 9.2 nl of 1 M KCl solution among diaphragmatic fibers while Plymph was recorded through micropuncture and vessel geometry via stereomicroscopy video recording. In lymphatics oriented perpendicularly to the longitudinal axis of muscle fibers and located at <300 μm from KCl injection, vessel diameter at maximal skeletal muscle contraction (Dmc) decreased to 61.3 ± 1.4% of the precontraction value [resting diameter (Drest)]; however, if injection was at >900 μm from the vessel, Dmc enlarged to 131.1 ± 2.3% of Drest. In vessels parallel to muscle fibers, Dmc increased to 122.8 ± 2.9% of Drest. During contraction, Plymph decreased as much as 22.5 ± 2.6 cmH2O in all submesothelial superficial vessels, whereas it increased by 10.7 ± 5.1 cmH2O in deeper vessels running perpendicular to contracting muscle fibers. Hence, the three-dimensional arrangement of the diaphragmatic lymphatic network seems to be finalized to efficiently exploit the stresses exerted by muscle fibers during the contracting inspiratory phase to promote lymph formation in superficial submesothelial lymphatics and its further propulsion in deeper intramuscular vessels. PMID:25485903

  2. 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. PMID:26228815

  3. 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. PMID:27460561

  4. 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

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

    SciTech Connect

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

    2013-10-25

    Highlights: •We newly developed the whole-mount imaging method of the tympanic membrane. •Lymphatic vessel loops were localized around the malleus handle and annulus tympanicus. •In regeneration, abundant lymphatic vessels were observed in the pars tensa. •Site-specific lymphatic vessels may play an important role in the tympanic membrane. -- Abstract: 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.

  6. 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

  7. 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. PMID:26030524

  8. 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. PMID:21472692

  9. Distinct roles of L- and T-type voltage-dependent Ca2+ channels in regulation of lymphatic vessel contractile activity

    PubMed Central

    Lee, Stewart; Roizes, Simon; von der Weid, Pierre-Yves

    2014-01-01

    Lymph drainage maintains tissue fluid homeostasis and facilitates immune response. It is promoted by phasic contractions of collecting lymphatic vessels through which lymph is propelled back into the blood circulation. This rhythmic contractile activity (i.e. lymphatic pumping) increases in rate with increase in luminal pressure and relies on activation of nifedipine-sensitive voltage-dependent Ca2+ channels (VDCCs). Despite their importance, these channels have not been characterized in lymphatic vessels. We used pressure- and wire-myography as well as intracellular microelectrode electrophysiology to characterize the pharmacological and electrophysiological properties of L-type and T-type VDCCs in rat mesenteric lymphatic vessels and evaluated their particular role in the regulation of lymphatic pumping by stretch. We complemented our study with PCR and confocal immunofluorescence imaging to investigate the expression and localization of these channels in lymphatic vessels. Our data suggest a delineating role of VDCCs in stretch-induced lymphatic vessel contractions, as the stretch-induced increase in force of lymphatic vessel contractions was significantly attenuated in the presence of L-type VDCC blockers nifedipine and diltiazem, while the stretch-induced increase in contraction frequency was significantly decreased by the T-type VDCC blockers mibefradil and nickel. The latter effect was correlated with a hyperpolarization. We propose that activation of T-type VDCCs depolarizes membrane potential, regulating the frequency of lymphatic contractions via opening of L-type VDCCs, which drive the strength of contractions. PMID:25326448

  10. 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

  11. Higher blood vessel density in comparison to the lymphatic vessels in oral squamous cell carcinoma

    PubMed Central

    Maturana-Ramírez, Andrea; Espinoza, Iris; Reyes, Montserrat; Aitken, Juan Pablo; Aguayo, Francisco; Hartel, Steffen; Rojas-Alcayaga, Gonzalo

    2015-01-01

    Introduction: Oral squamous cell carcinoma (OSCC) is characterized by local invasion and the development of cervical metastasis. In the tongue, an association between the invasion of the lymphatic vessels and the development of metastasis in the regional lymph nodes has been demonstrated. Moreover, invasion of the blood vessels is associated with greater recurrence and poorer prognoses. Therefore, the presence and density of lymphatic and blood vessels in intra- and peritumoral tissues should play an important role in the progression, dissemination and metastasis of carcinomas. However, the evidence regarding OSCC is inconclusive. The aim of this study was to determine the comparison and association between the lymphatic (D2-40) and blood vessel (CD34) densities in intratumoral OSCC tissue. Materials and Methods: Thirty-seven cases diagnosed as OSCC between the years 2000 and 2008 were obtained from the Anatomic Pathology Service of the School of Dentistry, University of Chile. The immunohistochemical markers D2-40 and CD34 were used, and the densities (mm2) of lymphatic vessels (LVD) and blood vessels (BVD) in the intratumoral region were determined. The relationship between LVD and BVD values was evaluated. Results: There were significant association between the CD34 and D2-40 expression (rho=0.4, P<0.05) and between the LVD and the location in the tongue (P=0.019). The BVD was greater (128.0 vessels/mm2) than the LVD (42.9 vessels/mm2), and there was a positive correlation between the LVD and BVD. Conclusions: In OSCC, the BVD is greater than the LVD, and there is a moderate correlation between the two quantities. PMID:26722595

  12. Intralymphatic CCL21 Promotes Tissue Egress of Dendritic Cells through Afferent Lymphatic Vessels.

    PubMed

    Russo, Erica; Teijeira, Alvaro; Vaahtomeri, Kari; Willrodt, Ann-Helen; Bloch, Joël S; Nitschké, Maximilian; Santambrogio, Laura; Kerjaschki, Dontscho; Sixt, Michael; Halin, Cornelia

    2016-02-23

    To induce adaptive immunity, dendritic cells (DCs) migrate through afferent lymphatic vessels (LVs) to draining lymph nodes (dLNs). This process occurs in several consecutive steps. Upon entry into lymphatic capillaries, DCs first actively crawl into downstream collecting vessels. From there, they are next passively and rapidly transported to the dLN by lymph flow. Here, we describe a role for the chemokine CCL21 in intralymphatic DC crawling. Performing time-lapse imaging in murine skin, we found that blockade of CCL21-but not the absence of lymph flow-completely abolished DC migration from capillaries toward collecting vessels and reduced the ability of intralymphatic DCs to emigrate from skin. Moreover, we found that in vitro low laminar flow established a CCL21 gradient along lymphatic endothelial monolayers, thereby inducing downstream-directed DC migration. These findings reveal a role for intralymphatic CCL21 in promoting DC trafficking to dLNs, through the formation of a flow-induced gradient. PMID:26876174

  13. 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

  14. Rho kinase enhances contractions of rat mesenteric collecting lymphatics.

    PubMed

    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 that

  15. Lysophosphatidic acid does not cause blood/lymphatic vessel plasticity in the rat mesentery culture model.

    PubMed

    Sweat, Richard S; Azimi, Mohammad S; Suarez-Martinez, Ariana D; Katakam, Prasad; Murfee, Walter L

    2016-07-01

    Understanding the mechanisms behind endothelial cell identity is crucial for the goal of manipulating microvascular networks. Lysophosphatidic acid (LPA) and serum stimulation have been suggested to induce a lymphatic identity in blood endothelial cells in vitro. The objective of this study was to determine if LPA or serum induces blood-to-lymphatic vessel phenotypic transition in microvascular networks. The rat mesentery culture model was used to observe the effect of stimulation on blood and lymphatic microvascular networks ex vivo. Vascularized mesenteric tissues were harvested from adult Wistar rats and cultured with LPA or 10% serum for up to 5 days. Tissues were then immunolabeled with PECAM to identify blood vessels and LYVE-1 or Prox1 to identify lymphatic vessels. We show that while LPA caused capillary sprouting and increased vascular length density in adult microvascular networks, LPA did not cause a blood-to-lymphatic phenotypic transition. The results suggest that LPA is not sufficient to cause blood endothelial cells to adopt a lymphatic identity in adult microvascular networks. Similarly, serum stimulation caused robust angiogenesis and increased lymphatic/blood vessel connections, yet did not induce a blood-to-lymphatic phenotypic transition. Our study highlights an understudied area of lymphatic research and warrants future investigation into the mechanisms responsible for the maintenance of blood and lymphatic vessel identity. PMID:27401461

  16. 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. PMID:26453331

  17. 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. PMID:25519727

  18. 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

  19. By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

    NASA Technical Reports Server (NTRS)

    Parsons-Wingerter, Patricia; McKay, Terri L.; Leontiev, Dmitry; Condrich, Terence K.; DiCorleto, Paul E.

    2005-01-01

    The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

  20. 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. PMID:27507214

  1. Lymphatic vessels transition to state of summation above a critical contraction frequency.

    PubMed

    Meisner, Joshua K; Stewart, Randolph H; Laine, Glen A; Quick, Christopher M

    2007-07-01

    Although behavior of lymphatic vessels is analogous to that of ventricles, which completely relax between contractions, and blood vessels, which maintain a tonic constriction, the mixture of contractile properties can yield behavior unique to lymphatic vessels. In particular, because of their limited refractory period and slow rate of relaxation, lymphatic vessels lack the contractile properties that minimize summation in ventricles. We, therefore, hypothesized that lymphatic vessels transition to a state of summation when lymphatic vessel contraction frequency exceeds a critical value. We used an isovolumic, controlled-flow preparation to compare the time required for full relaxation with the time available to relax during diastole. We measured transmural pressure and diameter on segments of spontaneously contracting bovine mesenteric lymphatic vessels during 10 isovolumic volume steps. We found that beat-to-beat period (frequency(-1)) decreased with increases in diameter and that total contraction time was constant or slightly increased with diameter. We further found that the convergence of beat-to-beat period and contraction cycle duration predicted a critical transition value, beyond which the vessel does not have time to fully relax. This incomplete relaxation and resulting mechanical summation significantly increase active tension in diastole. Because this transition occurs within a physiological range, contraction summation may represent a fundamental feature of lymphatic vessel function. PMID:17363681

  2. Effects of Bothrops asper Snake Venom on Lymphatic Vessels: Insights into a Hidden Aspect of Envenomation

    PubMed Central

    Mora, Javier; Mora, Rodrigo; Lomonte, Bruno; Gutiérrez, José María

    2008-01-01

    Background Envenomations by the snake Bothrops asper represent a serious medical problem in Central America and parts of South America. These envenomations concur with drastic local tissue pathology, including a prominent edema. Since lymph flow plays a role in the maintenance of tissue fluid balance, the effect of B. asper venom on collecting lymphatic vessels was studied. Methodology/Principal Findings B. asper venom was applied to mouse mesentery, and the effects were studied using an intravital microscopy methodology coupled with an image analysis program. B. asper venom induced a dose-dependent contraction of collecting lymphatic vessels, resulting in a reduction of their lumen and in a halting of lymph flow. The effect was reproduced by a myotoxic phospholipase A2 (PLA2) homologue isolated from this venom, but not by a hemorrhagic metalloproteinase or a coagulant thrombin-like serine proteinase. In agreement with this, treatment of the venom with fucoidan, a myotoxin inhibitor, abrogated the effect, whereas no inhibition was observed after incubation with the peptidomimetic metalloproteinase inhibitor Batimastat. Moreover, fucoidan significantly reduced venom-induced footpad edema. The myotoxic PLA2 homologue, known to induce skeletal muscle necrosis, was able to induce cytotoxicity in smooth muscle cells in culture and to promote an increment in the permeability to propidium iodide in these cells. Conclusions/Significance Our observations indicate that B. asper venom affects collecting lymphatic vessels through the action of myotoxic PLA2s on the smooth muscle of these vessels, inducing cell contraction and irreversible cell damage. This activity may play an important role in the pathogenesis of the pronounced local edema characteristic of viperid snakebite envenomation, as well as in the systemic biodistribution of the venom, thus representing a potential therapeutical target in these envenomations. PMID:18923712

  3. Ex-Vivo Lymphatic Perfusion System for Independently Controlling Pressure Gradient and Transmural Pressure in Isolated Vessels

    PubMed Central

    Kornuta, Jeffrey A.; Dixon, J. Brandon

    2015-01-01

    In addition to external forces, collecting lymphatic vessels intrinsically contract to transport lymph from the extremities to the venous circulation. As a result, the lymphatic endothelium is routinely exposed to a wide range of dynamic mechanical forces, primarily fluid shear stress and circumferential stress, which have both been shown to affect lymphatic pumping activity. Although various ex-vivo perfusion systems exist to study this innate pumping activity in response to mechanical stimuli, none are capable of independently controlling the two primary mechanical forces affecting lymphatic contractility: transaxial pressure gradient, ΔP, which governs fluid shear stress; and average transmural pressure, Pavg, which governs circumferential stress. Hence, the authors describe a novel ex-vivo lymphatic perfusion system (ELPS) capable of independently controlling these two outputs using a linear, explicit model predictive control (MPC) algorithm. The ELPS is capable of reproducing arbitrary waveforms within the frequency range observed in the lymphatics in vivo, including a time-varying ΔP with a constant Pavg, time-varying ΔP and Pavg, and a constant ΔP with a time-varying Pavg. In addition, due to its implementation of syringes to actuate the working fluid, a post-hoc method of estimating both the flow rate through the vessel and fluid wall shear stress over multiple, long (5 sec) time windows is also described. PMID:24809724

  4. 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.

  5. 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. PMID:26057032

  6. Label-free optical lymphangiography: development of an automatic segmentation method applied to optical coherence tomography to visualize lymphatic vessels using Hessian filters

    NASA Astrophysics Data System (ADS)

    Yousefi, Siavash; Qin, Jia; Zhi, Zhongwei; Wang, Ruikang K.

    2013-08-01

    Lymphatic vessels are a part of the circulatory system that collect plasma and other substances that have leaked from the capillaries into interstitial fluid (lymph) and transport lymph back to the circulatory system. Since lymph is transparent, lymphatic vessels appear as dark hallow vessel-like regions in optical coherence tomography (OCT) cross sectional images. We propose an automatic method to segment lymphatic vessel lumen from OCT structural cross sections using eigenvalues of Hessian filters. Compared to the existing method based on intensity threshold, Hessian filters are more selective on vessel shape and less sensitive to intensity variations and noise. Using this segmentation technique along with optical micro-angiography allows label-free noninvasive simultaneous visualization of blood and lymphatic vessels in vivo. Lymphatic vessels play an important role in cancer, immune system response, inflammatory disease, wound healing and tissue regeneration. Development of imaging techniques and visualization tools for lymphatic vessels is valuable in understanding the mechanisms and studying therapeutic methods in related disease and tissue response.

  7. 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

  8. Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels.

    PubMed

    Telinius, Niklas; Majgaard, Jens; Kim, Sukhan; Katballe, Niels; Pahle, Einar; Nielsen, Jørn; Hjortdal, Vibeke; Aalkjaer, Christian; Boedtkjer, Donna Briggs

    2015-07-15

    Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In the present study, we report the electrical activity and APs of small human lymphatic collecting vessels, as well as mRNA expression and function of VGSC in small and large human lymphatic vessels. The VGSC blocker TTX inhibited spontaneous contractions in six of 10 spontaneously active vessels, whereas ranolazine, which has a narrower VGSC blocking profile, had no influence on spontaneous activity. TTX did not affect noradrenaline-induced contractions. The VGSC opener veratridine induced contractions in a concentration-dependent manner (0.1-30 μm) eliciting a stable tonic contraction and membrane depolarization to -18 ± 0.6 mV. Veratridine-induced depolarizations and contractions were reversed ∼80% by TTX, and were dependent on Ca(2+) influx via L-type calcium channels and the sodium-calcium exchanger in reverse mode. Molecular analysis determined NaV 1.3 to be the predominantly expressed VGSC isoform. Electrophysiology of mesenteric lymphatics determined the resting membrane potential to be -45 ± 1.7 mV. Spontaneous APs were preceded by a slow depolarization of 5.3 ± 0.6 mV after which a spike was elicited that almost completely repolarized before immediately depolarizing again to plateau. Vessels transiently hyperpolarized prior to returning to the resting membrane potential. TTX application blocked APs. We have shown that VGSC are necessary for initiating and maintaining APs and spontaneous contractions in human lymphatic vessels and our data suggest the main contribution from comes NaV 1.3. We have also shown that activation of these channels augments the contractile activity of the vessels. PMID:25969124

  9. Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma.

    PubMed

    Storr, Sarah J; Safuan, Sabreena; Mitra, Angana; Elliott, Faye; Walker, Christopher; Vasko, Mark J; Ho, Bernard; Cook, Martin; Mohammed, Rabab A A; Patel, Poulam M; Ellis, Ian O; Newton-Bishop, Julia A; Martin, Stewart G

    2012-04-01

    The aims of this study were to investigate the role of vascular invasion (blood and lymphatic), vessel density and the presence of tumour-associated macrophages as prognostic markers in 202 cutaneous melanoma patients. Sections of primary melanoma were stained with lymphatic-specific antibody D2-40 to assess lymphatic vessel invasion and density in intratumoural and peritumoural areas; an antibody against endothelial marker CD34 was used to determine blood vessel invasion and density, and an antibody against CD68 was used to determine macrophage counts. Immunohistochemically determined vascular invasion (combined blood and lymphatic) was compared with that determined using haematoxylin and eosin (H&E) staining. The use of immunohistochemistry increased detection of vascular invasion from 8-30% of patients, and histological exam of H&E-stained tissue was associated with a false positive rate of 64%. Lymphatic vessel invasion occurred at a much higher frequency than blood vessel invasion (27 and 4% of patients, respectively). Although immunohistochemically detected vessel invasion was significantly associated with histological markers of adverse prognosis, such as increased Breslow thickness, ulceration and mitotic rate (all P<0.001), no associations with relapse-free or overall survival were observed. High macrophage counts were significantly associated with markers of aggressive disease, such as Breslow thickness, ulceration and mitotic rate (P<0.001, P<0.001, P=0.005, respectively), and lymphatic vessel invasion and high microvessel density (P=0.002 and P=0.003, respectively). These results suggest that vascular invasion is more accurately detected using immunohistochemistry and occurs predominantly via lymphatic vessels. The association of vessel characteristics with histological characteristics of the primary melanoma provides evidence for their biological importance in melanoma, but that they were not associated with clinical outcome attests to the value of

  10. An in situ optical imaging system for measuring lipid uptake, vessel contraction, and lymph flow in small animal lymphatic vessels

    NASA Astrophysics Data System (ADS)

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

    2012-03-01

    All dietary lipids are transported to venous circulation through the lymphatic system, yet the underlying mechanisms that regulate this process remain unclear. Understanding how the lymphatics functionally respond to changes in lipid load is important in the diagnosis and treatment of lipid and lymphatic related diseases such as obesity, hypercholesterolemia, and lymphedema. Therefore, we sought to develop an in situ imaging system to quantify and correlate lymphatic function as it relates to lipid transport. A custom-built optical set-up provides us with the capability of dual-channel imaging of both high-speed bright-field video and fluorescence simultaneously. This is achieved by dividing the light path into two optical bands. Utilizing high-speed and back-illuminated CCD cameras and post-acquisition image processing algorithms, we have the potential quantify correlations between vessel contraction, lymph flow and lipid concentration of mesenteric lymphatic vessels in situ. Local flow velocity is measured through lymphocyte tracking, vessel contraction through measurements of the vessel walls and lipid uptake through fluorescence intensity tracking of a fluorescent long chain fatty acid analogue, Bodipy FL C16. This system will prove to be an invaluable tool for both scientists studying lymphatic function in health and disease, and those investigating strategies for targeting the lymphatic system with orally delivered drugs.

  11. Podoplanin Immunopositive Lymphatic Vessels at the Implant Interface in a Rat Model of Osteoporotic Fractures

    PubMed Central

    Lips, Katrin Susanne; Kauschke, Vivien; Hartmann, Sonja; Thormann, Ulrich; Ray, Seemun; Kampschulte, Marian; Langheinrich, Alexander; Schumacher, Matthias; Gelinsky, Michael; Heinemann, Sascha; Hanke, Thomas; Kautz, Armin R.; Schnabelrauch, Matthias; Schnettler, Reinhard; Heiss, Christian; Alt, Volker; Kilian, Olaf

    2013-01-01

    Insertion of bone substitution materials accelerates healing of osteoporotic fractures. Biodegradable materials are preferred for application in osteoporotic patients to avoid a second surgery for implant replacement. Degraded implant fragments are often absorbed by macrophages that are removed from the fracture side via passage through veins or lymphatic vessels. We investigated if lymphatic vessels occur in osteoporotic bone defects and whether they are regulated by the use of different materials. To address this issue osteoporosis was induced in rats using the classical method of bilateral ovariectomy and additional calcium and vitamin deficient diet. In addition, wedge-shaped defects of 3, 4, or 5 mm were generated in the distal metaphyseal area of femur via osteotomy. The 4 mm defects were subsequently used for implantation studies where bone substitution materials of calcium phosphate cement, composites of collagen and silica, and iron foams with interconnecting pores were inserted. Different materials were partly additionally functionalized by strontium or bisphosphonate whose positive effects in osteoporosis treatment are well known. The lymphatic vessels were identified by immunohistochemistry using an antibody against podoplanin. Podoplanin immunopositive lymphatic vessels were detected in the granulation tissue filling the fracture gap, surrounding the implant and growing into the iron foam through its interconnected pores. Significant more lymphatic capillaries were counted at the implant interface of composite, strontium and bisphosphonate functionalized iron foam. A significant increase was also observed in the number of lymphatics situated in the pores of strontium coated iron foam. In conclusion, our results indicate the occurrence of lymphatic vessels in osteoporotic bone. Our results show that lymphatic vessels are localized at the implant interface and in the fracture gap where they might be involved in the removal of lymphocytes, macrophages

  12. Podoplanin immunopositive lymphatic vessels at the implant interface in a rat model of osteoporotic fractures.

    PubMed

    Lips, Katrin Susanne; Kauschke, Vivien; Hartmann, Sonja; Thormann, Ulrich; Ray, Seemun; Kampschulte, Marian; Langheinrich, Alexander; Schumacher, Matthias; Gelinsky, Michael; Heinemann, Sascha; Hanke, Thomas; Kautz, Armin R; Schnabelrauch, Matthias; Schnettler, Reinhard; Heiss, Christian; Alt, Volker; Kilian, Olaf

    2013-01-01

    Insertion of bone substitution materials accelerates healing of osteoporotic fractures. Biodegradable materials are preferred for application in osteoporotic patients to avoid a second surgery for implant replacement. Degraded implant fragments are often absorbed by macrophages that are removed from the fracture side via passage through veins or lymphatic vessels. We investigated if lymphatic vessels occur in osteoporotic bone defects and whether they are regulated by the use of different materials. To address this issue osteoporosis was induced in rats using the classical method of bilateral ovariectomy and additional calcium and vitamin deficient diet. In addition, wedge-shaped defects of 3, 4, or 5 mm were generated in the distal metaphyseal area of femur via osteotomy. The 4 mm defects were subsequently used for implantation studies where bone substitution materials of calcium phosphate cement, composites of collagen and silica, and iron foams with interconnecting pores were inserted. Different materials were partly additionally functionalized by strontium or bisphosphonate whose positive effects in osteoporosis treatment are well known. The lymphatic vessels were identified by immunohistochemistry using an antibody against podoplanin. Podoplanin immunopositive lymphatic vessels were detected in the granulation tissue filling the fracture gap, surrounding the implant and growing into the iron foam through its interconnected pores. Significant more lymphatic capillaries were counted at the implant interface of composite, strontium and bisphosphonate functionalized iron foam. A significant increase was also observed in the number of lymphatics situated in the pores of strontium coated iron foam. In conclusion, our results indicate the occurrence of lymphatic vessels in osteoporotic bone. Our results show that lymphatic vessels are localized at the implant interface and in the fracture gap where they might be involved in the removal of lymphocytes, macrophages

  13. Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure.

    PubMed

    Dongaonkar, R M; Nguyen, T L; Quick, C M; Hardy, J; Laine, G A; Wilson, E; Stewart, R H

    2013-07-15

    In vitro studies have revealed that acute increases in transmural pressure increase lymphatic vessel contractile function. However, adaptive responses to prolonged changes in transmural pressure in vivo have not been reported. Therefore, we developed a novel bovine mesenteric lymphatic partial constriction model to test the hypothesis that lymphatic vessels exposed to higher transmural pressures adapt functionally to become stronger pumps than vessels exposed to lower transmural pressures. Postnodal mesenteric lymphatic vessels were partially constricted for 3 days. On postoperative day 3, constricted vessels were isolated, and divided into upstream (UP) and downstream (DN) segment groups, and instrumented in an isolated bath. Although there were no differences between the passive diameters of the two groups, both diastolic diameter and systolic diameter were significantly larger in the UP group than in the DN group. The pump index of the UP group was also higher than that in the DN group. In conclusion, this is the first work to report how lymphatic vessels adapt to prolonged changes in transmural pressure in vivo. Our results suggest that vessel segments upstream of the constriction adapt to become both better fluid conduits and lymphatic pumps than downstream segments. PMID:23666672

  14. Functional adaptation of bovine mesenteric lymphatic vessels to mesenteric venous hypertension

    PubMed Central

    Criscione, John C.; Kotiya, Akhilesh; Dongaonkar, Ranjeet M.; Hardy, Joanne; Wilson, Emily; Gashev, Anatoliy A.; Laine, Glen A.; Stewart, Randolph H.

    2014-01-01

    Lymph flow is the primary mechanism for returning interstitial fluid to the blood circulation. Currently, the adaptive response of lymphatic vessels to mesenteric venous hypertension is not known. This study sought to determine the functional responses of postnodal mesenteric lymphatic vessels. We surgically occluded bovine mesenteric veins to create mesenteric venous hypertension to elevate mesenteric lymph flow. Three days after surgery, postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 7) and sham surgery (Sham; n = 6) group animals were evaluated and compared. Contraction frequency (MVH: 2.98 ± 0.75 min−1; Sham: 5.42 ± 0.81 min−1) and fractional pump flow (MVH: 1.14 ± 0.30 min−1; Sham: 2.39 ± 0.32 min−1) were significantly lower in the venous occlusion group. These results indicate that postnodal mesenteric lymphatic vessels adapt to mesenteric venous hypertension by reducing intrinsic contractile activity. PMID:24671245

  15. Functional adaptation of bovine mesenteric lymphatic vessels to mesenteric venous hypertension.

    PubMed

    Quick, Christopher M; Criscione, John C; Kotiya, Akhilesh; Dongaonkar, Ranjeet M; Hardy, Joanne; Wilson, Emily; Gashev, Anatoliy A; Laine, Glen A; Stewart, Randolph H

    2014-06-15

    Lymph flow is the primary mechanism for returning interstitial fluid to the blood circulation. Currently, the adaptive response of lymphatic vessels to mesenteric venous hypertension is not known. This study sought to determine the functional responses of postnodal mesenteric lymphatic vessels. We surgically occluded bovine mesenteric veins to create mesenteric venous hypertension to elevate mesenteric lymph flow. Three days after surgery, postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 7) and sham surgery (Sham; n = 6) group animals were evaluated and compared. Contraction frequency (MVH: 2.98 ± 0.75 min(-1); Sham: 5.42 ± 0.81 min(-1)) and fractional pump flow (MVH: 1.14 ± 0.30 min(-1); Sham: 2.39 ± 0.32 min(-1)) were significantly lower in the venous occlusion group. These results indicate that postnodal mesenteric lymphatic vessels adapt to mesenteric venous hypertension by reducing intrinsic contractile activity. PMID:24671245

  16. Visualisation of blood and lymphatic vessels with increasing exposure time of the detector

    NASA Astrophysics Data System (ADS)

    Kalchenko, V. V.; Kuznetsov, Yu L.; Meglinski, I. V.

    2013-07-01

    We describe the laser speckle contrast method for simultaneous noninvasive imaging of blood and lymphatic vessels of living organisms, based on increasing detector exposure time. In contrast to standard methods of fluorescent angiography, this technique of vascular bed imaging and lymphatic and blood vessel demarcation does not employ toxic fluorescent markers. The method is particularly promising with respect to the physiology of the cardiovascular system under in vivo conditions.

  17. Visualisation of blood and lymphatic vessels with increasing exposure time of the detector

    SciTech Connect

    Kalchenko, V V; Kuznetsov, Yu L; Meglinski, I V

    2013-07-31

    We describe the laser speckle contrast method for simultaneous noninvasive imaging of blood and lymphatic vessels of living organisms, based on increasing detector exposure time. In contrast to standard methods of fluorescent angiography, this technique of vascular bed imaging and lymphatic and blood vessel demarcation does not employ toxic fluorescent markers. The method is particularly promising with respect to the physiology of the cardiovascular system under in vivo conditions. (laser applications in biology and medicine)

  18. Pump function curve shape for a model lymphatic vessel.

    PubMed

    Bertram, C D; Macaskill, C; Moore, J E

    2016-07-01

    The transport capacity of a contractile segment of lymphatic vessel is defined by its pump function curve relating mean flow-rate and adverse pressure difference. Numerous system characteristics affect curve shape and the magnitude of the generated flow-rates and pressures. Some cannot be varied experimentally, but their separate and interacting effects can be systematically revealed numerically. This paper explores variations in the rate of change of active tension and the form of the relation between active tension and muscle length, factors not known from experiment to functional precision. Whether the pump function curve bends toward or away from the origin depends partly on the curvature of the passive pressure-diameter relation near zero transmural pressure, but rather more on the form of the relation between active tension and muscle length. A pump function curve bending away from the origin defines a well-performing pump by maximum steady output power. This behaviour is favoured by a length/active-tension relationship which sustains tension at smaller lengths. Such a relationship also favours high peak mechanical efficiency, defined as output power divided by the input power obtained from the lymphangion diameter changes and active-tension time-course. The results highlight the need to pin down experimentally the form of the length/active-tension relationship. PMID:27185045

  19. Involvement of histamine in endothelium-dependent relaxation of mesenteric lymphatic vessels

    PubMed Central

    Nizamutdinova, Irina Tsoy; Maejima, Daisuke; Nagai, Takashi; Bridenbaugh, Eric; Thangaswamy, Sangeetha; Chatterjee, Victor; Meininger, Cynthia J.; Gashev, Anatoliy A.

    2014-01-01

    Objectives The knowledge of the basic principles of lymphatic function, still remains, to a large degree, rudimentary and will require significant research efforts. Recent studies of the physiology of the mesenteric lymphatic vessels (MLVs) suggested the presence of an endothelium-derived relaxing factor (EDRF) other than nitric oxide. In this study we tested the hypothesis that lymphatic endothelium-derived histamine relaxes MLVs. Methods We measured and analyzed parameters of lymphatic contractility in isolated and pressurized rat mesenteric lymphatic vessels under control conditions and after pharmacological blockade of nitric oxide by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 100 μM) or/and histamine production by α-methyl-DL-histidine dihydrochloride (α-MHD, 10 μM). Effectiveness of α-MHD was confirmed immunohistochemically. We also used immunohistochemical labeling and western blot analysis of the histamine-producing enzyme, histidine decarboxylase (HDC). Additionally we blocked HDC protein expression in MLVs by transient transfection with vivo-morpholino oligos. Results We found that only combined pharmacological blockade of nitric oxide and histamine production completely eliminates flow-dependent relaxation of lymphatic vessels, thus confirming a role for histamine as an EDRF in MLVs. We also confirmed the presence of histidine decarboxylase and histamine inside lymphatic endothelial cells. Conclusions Our study supports a role for histamine as an EDRF in MLVs. PMID:24750494

  20. Evaluation of immunohistochemical markers of lymphatic and blood vessels in canine mammary tumours.

    PubMed

    Sleeckx, N; Van Brantegem, L; Fransen, E; Van den Eynden, G; Casteleyn, C; Veldhuis Kroeze, E; Van Ginneken, C

    2013-05-01

    Canine mammary tumours (CMTs) are the most common neoplasms in intact female dogs. Bitches with spontaneously arising CMTs represent a promising animal model for human breast cancer research. The aim of the present study was to develop an immunohistochemical protocol for the identification of blood and lymphatic vessels in CMTs. Antibodies specific for human lymphatic vessels (prox-1, lyve-1, podoplanin and D2-40) and blood vessels (von Willebrand factor [vWf], CD31 and CD34) were utilized. Serial sections of 18 samples (eight samples of normal canine mammary tissue, five benign and five malignant CMTs) were examined. Antibodies specific for podoplanin, D2-40 and CD34 showed no immunoreactivity with canine tissue. Prox-1 and CD31 were determined to be the most suitable markers for lymphatic and blood vessels, respectively. PMID:23123127

  1. Mechanical forces and lymphatic transport.

    PubMed

    Breslin, Jerome W

    2014-11-01

    This review examines the 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 the 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. An improved understanding of the physiological mechanisms by which 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

  2. 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

  3. Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation.

    PubMed

    Kesler, Cristina T; Pereira, Ethel R; Cui, Cheryl H; Nelson, Gregory M; Masuck, David J; Baish, James W; Padera, Timothy P

    2015-09-01

    The angiopoietin (Ang) ligands are potential therapeutic targets for lymphatic related diseases, which include lymphedema and cancer. Ang-1 and Ang-2 functions are established, but those of Ang-4 are poorly understood. We used intravital fluorescence microscopy to characterize Ang-4 actions on T241 murine fibrosarcoma-associated vessels in mice. The diameters of lymphatic vessels draining Ang-4- or VEGF-C (positive control)-expressing tumors increased to 123 and 135 μm, respectively, and parental, mock-transduced (negative controls) and tumors expressing Ang-1 or Ang-2 remained at baseline (∼60 μm). Ang-4 decreased human dermal lymphatic endothelial cell (LEC) monolayer permeability by 27% while increasing human dermal blood endothelial cell (BEC) monolayer permeability by 200%. In vivo, Ang-4 stimulated a 4.5-fold increase in tumor-associated blood vessel permeability compared with control when measured using intravital quantitative multiphoton microscopy. Ang-4 activated receptor signaling in both LECs and BECs, evidenced by tyrosine kinase with Ig and endothelial growth factor homology domains-2 (TIE2) receptor, protein kinase B, and Erk1,2 phosphorylation detectable by immunoblotting. These data suggest that Ang-4 actions are mediated through cell-type-specific networks and that lymphatic vessel dilation occurs secondarily to increased vascular leakage. Ang-4 also promoted survival of LECs. Thus, blocking Ang-4 may prune the draining lymphatic vasculature and decrease interstitial fluid pressure (IFP) by reducing vascular permeability. PMID:25977256

  4. Absence of lymphatic vessels in the dog dental pulp: an immunohistochemical study

    PubMed Central

    Martin, Anna; Gasse, Hagen; Staszyk, Carsten

    2010-01-01

    In spite of numerous investigations it has not been precisely determined whether lymphatic vessels are present in the dental pulp of dogs. Therefore, this study attempted a specific immunohistochemical detection of lymphatic endothelium. The canine teeth of 19 healthy beagle dogs were dissected into three segments (apical, intermediate and occlusal). After decalcification, specimens were embedded in paraffin wax and histologic cross-sections were stained immunohistochemically using a reliable antibody (anti-Prox-1) against the homeobox transcription factor Prox-1, which is located within the nucleus of lymphatic endothelium. Anti-Prox-1 reacted positively with canine control tissues (lymph nodes, gingiva, nasal mucosa), but showed no staining in tissue sections of the dental pulp. The dog dental pulp contained no vascular structures lined with lymphatic endothelium. This suggests that drainage of interstitial fluid makes use of other routes, i.e. extravascular pathways. PMID:20854283

  5. Monitoring the primo vascular system in lymphatic vessels by using window chambers.

    PubMed

    Kim, Jungdae; Kim, Dong-Hyun; Jung, Sharon Jiyoon; Gil, Hyun-Ji; Yoon, Seung Zhoo; Kim, Young-Il; Soh, Kwang-Sup

    2016-04-01

    This study aims to develop a window chamber system in the skin of rats and to monitor the primo vascular system (PVS) inside the lymphatic vessels along the superficial epigastric vessels. The PVS in lymphatic vessels has been observed through many experiments under in vivo conditions, but monitoring the in vivo PVS in situ inside lymphatic vessels for a long time is difficult. To overcome the obstacles, we adapted the window chamber system for monitoring the PVS and Alcian blue (AB) staining dye solution for the contrast agent. The lymphatic vessels in the skin on the lateral side of the body, connecting the inguinal lymph nodes to the axillary lymph nodes, were the targets for setting the window system. After AB had been injected into the inguinal lymph nodes with a glass capillary, the morphological changes of the stained PVS were monitored through the window system for up to twenty hours, and the changes in the AB intensity in the PVS were quantified by using image processing. The results and histological images are presented in this study. PMID:27446651

  6. Differential Distribution of Blood and Lymphatic Vessels in the Murine Cornea

    PubMed Central

    Ecoiffier, Tatiana; Yuen, Don

    2010-01-01

    Purpose. Because of its unique characteristics, the cornea has been widely used for blood and lymphatic vessel research. However, whether limbal or corneal vessels are evenly distributed under normal or inflamed conditions has never been studied. The purpose of this study was to investigate this question and to examine whether and how the distribution patterns change during corneal inflammatory lymphangiogenesis (LG) and hemangiogenesis (HG). Methods. Corneal inflammatory LG and HG were induced in two most commonly used mouse strains, BALB/c and C57BL/6 (6–8 weeks of age), by a standardized two-suture placement model. Oriented flat-mount corneas together with the limbal tissues were used for immunofluorescence microscope studies. Blood and lymphatic vessels under normal and inflamed conditions were analyzed and quantified to compare their distributions. Results. The data demonstrate, for the first time, greater distribution of both blood and lymphatic vessels in the nasal side in normal murine limbal areas. This nasal-dominant pattern was maintained during corneal inflammatory LG, whereas it was lost for HG. Conclusions. Blood and lymphatic vessels are not evenly distributed in normal limbal areas. Furthermore, corneal LG and HG respond differently to inflammatory stimuli. These new findings will shed some light on corneal physiology and pathogenesis and on the development of experimental models and therapeutic strategies for corneal diseases. PMID:20019372

  7. Monitoring the primo vascular system in lymphatic vessels by using window chambers

    PubMed Central

    Kim, Jungdae; Kim, Dong-Hyun; Jung, Sharon Jiyoon; Gil, Hyun-Ji; Yoon, Seung Zhoo; Kim, Young-Il; Soh, Kwang-Sup

    2016-01-01

    This study aims to develop a window chamber system in the skin of rats and to monitor the primo vascular system (PVS) inside the lymphatic vessels along the superficial epigastric vessels. The PVS in lymphatic vessels has been observed through many experiments under in vivo conditions, but monitoring the in vivo PVS in situ inside lymphatic vessels for a long time is difficult. To overcome the obstacles, we adapted the window chamber system for monitoring the PVS and Alcian blue (AB) staining dye solution for the contrast agent. The lymphatic vessels in the skin on the lateral side of the body, connecting the inguinal lymph nodes to the axillary lymph nodes, were the targets for setting the window system. After AB had been injected into the inguinal lymph nodes with a glass capillary, the morphological changes of the stained PVS were monitored through the window system for up to twenty hours, and the changes in the AB intensity in the PVS were quantified by using image processing. The results and histological images are presented in this study. PMID:27446651

  8. The lymphatic vasculature in disease.

    PubMed

    Alitalo, Kari

    2011-01-01

    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. PMID:22064427

  9. VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption

    PubMed Central

    Nurmi, Harri; Saharinen, Pipsa; Zarkada, Georgia; Zheng, Wei; Robciuc, Marius R; Alitalo, Kari

    2015-01-01

    Vascular endothelial growth factor C (VEGF-C) binding to its tyrosine kinase receptor VEGFR-3 drives lymphatic vessel growth during development and in pathological processes. Although the VEGF-C/VEGFR-3 pathway provides a target for treatment of cancer and lymphedema, the physiological functions of VEGF-C in adult vasculature are unknown. We show here that VEGF-C is necessary for perinatal lymphangiogenesis, but required for adult lymphatic vessel maintenance only in the intestine. Following Vegfc gene deletion in adult mice, the intestinal lymphatic vessels, including the lacteal vessels, underwent gradual atrophy, which was aggravated when also Vegfd was deleted. VEGF-C was expressed by a subset of smooth muscle cells adjacent to the lacteals in the villus and in the intestinal wall. The Vegfc-deleted mice showed defective lipid absorption and increased fecal excretion of dietary cholesterol and fatty acids. When fed a high-fat diet, the Vegfc-deficient mice were resistant to obesity and had improved glucose metabolism. Our findings indicate that the lymphangiogenic growth factors provide trophic and dynamic regulation of the intestinal lymphatic vasculature, which could be especially important in the dietary regulation of adiposity and cholesterol metabolism. PMID:26459520

  10. GATA2 is required for lymphatic vessel valve development and maintenance

    PubMed Central

    Kazenwadel, Jan; Betterman, Kelly L.; Chong, Chan-Eng; Stokes, Philippa H.; Lee, Young K.; Secker, Genevieve A.; Agalarov, Yan; Demir, Cansaran Saygili; Lawrence, David M.; Sutton, Drew L.; Tabruyn, Sebastien P.; Miura, Naoyuki; Salminen, Marjo; Petrova, Tatiana V.; Matthews, Jacqueline M.; Hahn, Christopher N.; Scott, Hamish S.; Harvey, Natasha L.

    2015-01-01

    Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema. PMID:26214525

  11. Coxsackie- and adenovirus receptor (CAR) is expressed in lymphatic vessels in human skin and affects lymphatic endothelial cell function in vitro

    SciTech Connect

    Vigl, Benjamin; Zgraggen, Claudia; Rehman, Nadia; Banziger-Tobler, Nadia E.; Detmar, Michael; Halin, Cornelia

    2009-01-15

    Lymphatic vessels play an important role in tissue fluid homeostasis, intestinal fat absorption and immunosurveillance. Furthermore, they are involved in pathologic conditions, such as tumor cell metastasis and chronic inflammation. In comparison to blood vessels, the molecular phenotype of lymphatic vessels is less well characterized. Performing comparative gene expression analysis we have recently found that coxsackie- and adenovirus receptor (CAR) is significantly more highly expressed in cultured human, skin-derived lymphatic endothelial cells (LECs), as compared to blood vascular endothelial cells. Here, we have confirmed these results at the protein level, using Western blot and FACS analysis. Immunofluorescence performed on human skin confirmed that CAR is expressed at detectable levels in lymphatic vessels, but not in blood vessels. To address the functional significance of CAR expression, we modulated CAR expression levels in cultured LECs in vitro by siRNA- and vector-based transfection approaches. Functional assays performed with the transfected cells revealed that CAR is involved in distinct cellular processes in LECs, such as cell adhesion, migration, tube formation and the control of vascular permeability. In contrast, no effect of CAR on LEC proliferation was observed. Overall, our data suggest that CAR stabilizes LEC-LEC interactions in the skin and may contribute to lymphatic vessel integrity.

  12. Downregulation of Lymphatic Vessel Formation Factors in PGF2α-induced Luteolysis in the Cow

    PubMed Central

    NITTA, Akane; SHIRASUNA, Koumei; NIBUNO, Sayo; BOLLWEIN, Heinrich; SHIMIZU, Takashi; MIYAMOTO, Akio

    2013-01-01

    Abstract Prostaglandin F2α (PGF2α) induces luteolysis in cows and causes infiltration of immune cells, which resembles inflammatory immune response. Since the general immune response is mediated by the lymphatic system, we hypothesized that luteolysis is associated with generation of an immune response that involves lymphatic vessels in the bovine corpus luteum (CL). The CL was obtained from Holstein cows at the mid-luteal phase (days 10–12, ovulation = day 0) by ovariectomy at various time points after PGF2α injection. Lymphatic endothelial cell (LyEC) marker, endothelial hyaluronan receptor 1 (LYVE1), levels decreased significantly 12 h after PGF2α injection. Podoplanin, another LyEC marker, decreased from 15 min after PGF2α injection. PGF2α also diminished mRNA expression of lymphangiogenic factors, such as vascular endothelial growth factor (VEGF) C, VEGFD and VEGF receptor 3 (VEGFR3). During PGF2α-induced luteolysis, the levels of mRNA expression of tumor necrosis factor α (TNFα; the major pro-inflammatory cytokine) and chemokine (C-X-C motif) ligand 1 (neutrophil chemokine) were increased. On the other hand, chemokine (C-C motif) ligand 21, which regulates outflow of immune cells from tissues via the lymphatic vessels during an immune response, was decreased. This study demonstrated that the lymphatic network in the CL is disrupted during luteolysis and suggests that during luteolysis, immune cells can induce a local immune response in the CL without using the lymphatic vessels. PMID:23524297

  13. Microcirculation-on-a-Chip: A Microfluidic Platform for Assaying Blood- and Lymphatic-Vessel Permeability

    PubMed Central

    Sato, Miwa; Sasaki, Naoki; Ato, Manabu; Hirakawa, Satoshi; Sato, Kiichi; Sato, Kae

    2015-01-01

    We developed a microfluidic model of microcirculation containing both blood and lymphatic vessels for examining vascular permeability. The designed microfluidic device harbors upper and lower channels that are partly aligned and are separated by a porous membrane, and on this membrane, blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs) were cocultured back-to-back. At cell-cell junctions of both BECs and LECs, claudin-5 and VE-cadherin were detected. The permeability coefficient measured here was lower than the value reported for isolated mammalian venules. Moreover, our results showed that the flow culture established in the device promoted the formation of endothelial cell-cell junctions, and that treatment with histamine, an inflammation-promoting substance, induced changes in the localization of tight and adherens junction-associated proteins and an increase in vascular permeability in the microdevice. These findings indicated that both BECs and LECs appeared to retain their functions in the microfluidic coculture platform. Using this microcirculation device, the vascular damage induced by habu snake venom was successfully assayed, and the assay time was reduced from 24 h to 30 min. This is the first report of a microcirculation model in which BECs and LECs were cocultured. Because the micromodel includes lymphatic vessels in addition to blood vessels, the model can be used to evaluate both vascular permeability and lymphatic return rate. PMID:26332321

  14. Lymphangiography: Forgotten Tool or Rising Star in the Diagnosis and Therapy of Postoperative Lymphatic Vessel Leakage

    SciTech Connect

    Kos, Sebastian Haueisen, Harald; Lachmund, Ulrich; Roeren, Thomas

    2007-09-15

    Since the advent of computed tomography, numbers and expertise in Lymphangiography (LAG) have markedly dropped. The intention of our study was to demonstrate the persisting diagnostic and therapeutic impact of LAG on the postoperative patient with known or suspected lymphatic vessel leakage. Between May 1, 1999, and April 30, 2006, we investigated pedal lipiodol-LAGs (18 monopedal, 2 bipedal) on 22 patients (16 male, 6 female) with known or suspected postoperative chylothorax, chylaskos, lymphocele, or lymphatic fistula. Ages varied from 26 to 81 years. The spectrum of operative procedures was broad: 6 thoracic, 5 abdominal, and 11 peripheral operations were performed. In 20 patients who underwent mono- or bipedal LAG for lymphatic vessel injury, we were able to demonstrate the specific site of leakage in 15 cases (75%) and found signs of extravasation in 5 patients (25%). Furthermore, in 11 patients (55%) we were able to avoid surgery because of closure of the leak after LAG. As the conservative therapeutic approach usually takes 2-3 weeks to reveal its therapeutic effects, 73.3% (11/15) of the patients who were not reoperated before this hallmark was passed did not need any further operation. Our study clearly demonstrates that even in the decades of modern cross-sectional imaging, classic LAG is a powerful and highly reliable tool to visualize and even assist occlusion of the postoperatively damaged lymphatic vessel and may thereby avoid the need for reoperation.

  15. NOVEL CHARACTERIZATION OF bEnd.3 CELLS THAT EXPRESS LYMPHATIC VESSEL ENDOTHELIAL HYALURONAN RECEPTOR-1

    PubMed Central

    Yuen, D.; Leu, R.; Tse, J.; Wang, S.; Chen, L.L.; Chen, L.

    2015-01-01

    Murine bEnd.3 endothelioma cell line has been widely used in vascular research and here we report the novel finding that bEnd.3 cells express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR-3). Moreover, these cells express progenitor cell markers of Sca-1 and CD133. Upon stimulation with tumor necrosis factor-alpha (TNF-α), the bEnd.3 cells demonstrate enhanced formation of capillary-type tubes, which express LYVE-1. As the bEnd.3 cell line is derived from murine endothelioma, we further examined human tissues of endothelioma and identified lymphatic vessels in the tumor samples which express both LYVE-1 and podoplanin. Moreover, a significantly higher number of lymphatic vessels were detected in the endothelioma samples compared with normal control. Taken together, this study not only redefines bEnd.3 cells for vascular research, but also indicates a broader category of human diseases that are associated with lymphatics, such as endothelioma. PMID:25282873

  16. Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine

    PubMed Central

    Telinius, Niklas; Mohanakumar, Sheyanth; Majgaard, Jens; Kim, Sukhan; Pilegaard, Hans; Pahle, Einar; Nielsen, Jørn; de Leval, Marc; Aalkjaer, Christian; Hjortdal, Vibeke; Boedtkjer, Donna Briggs

    2014-01-01

    Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4 ± 4.9% of control in the presence of 20 nmol l−1 nifedipine. Transcripts for the L-type calcium channel gene CACNA1C were consistently detected from human thoracic duct samples examined and the CaV1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics ex vivo were highly sensitive to nifedipine, this was not apparent in vivo when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine in vitro but that care must be taken when extrapolating in vitro observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo. PMID:25172950

  17. Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine.

    PubMed

    Telinius, Niklas; Mohanakumar, Sheyanth; Majgaard, Jens; Kim, Sukhan; Pilegaard, Hans; Pahle, Einar; Nielsen, Jørn; de Leval, Marc; Aalkjaer, Christian; Hjortdal, Vibeke; Boedtkjer, Donna Briggs

    2014-11-01

    Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4 ± 4.9% of control in the presence of 20 nmol l(-1) nifedipine. Transcripts for the L-type calcium channel gene CACNA1C were consistently detected from human thoracic duct samples examined and the CaV1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics ex vivo were highly sensitive to nifedipine, this was not apparent in vivo when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine in vitro but that care must be taken when extrapolating in vitro observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo. PMID:25172950

  18. Blood vessels and lymphatics in calcific aortic stenosis--in support of its inflammatory pathogenesis.

    PubMed

    Steiner, I; Krbal, L; Dominik, J

    2010-04-01

    In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease. It is considered a for of atherosclerosis and, like the latter, of inflammatory origin. Majority of cases of CAS are classified etiologically as either senile ("degenerative")--developing on previously normal aortic valve with three cusps, or based on congenitally malformed--bicuspid aortic valve. Twenty-eight cases of CAS (18 of the senile type, 7 of the bicuspid valve type, and 3 of indeterminable type) were examined by means of histology and immunohistochemistry (CD31 for blood vessels; D2-40 for lymphatics). In the calcified cusps, blood vessels were present in all 28 cases, and lymphatics in 14 of them. Vascularization was associated with lymphocytic infiltrates in 24 cases. There was no difference in the pattern between the two types of CAS. The origin of the cusp vessels is discussed. Our finding in the calcified cusps of both blood and lymphatic vessels together with lymphocytic infiltrates supports the inflammatory theory of the CAS pathogenesis. PMID:21275223

  19. Differential lectin binding on walls of thoraco-cervical blood vessels and lymphatics in rats.

    PubMed

    Kagami, H; Uryu, K; Okamoto, K; Sakai, H; Kaneda, T; Sakanaka, M

    1991-08-01

    Lectin binding in the walls of large to medium-sized blood vessels and lymphatics in the rat thoraco-cervical region was examined histochemically. The tunica intima of the aorta and superficial cervical artery showed positive reactions with wheat germ agglutinin (WGA) and Concanavalin A (ConA) but not with Dolichus biflorus agglutinin (DBA). The tunica media of the aorta exhibited intense WGA binding, especially on the smooth muscle cells, but the tunica media of the superficial cervical artery did not react with the lectin. Neither ConA nor DBA bound to the tunica media of the aorta and superficial cervical artery. The tunica adventitia of both arteries contained sites binding the three lectins, although DBA reactivity declined as the vascular diameter decreased. The tunica intima of the superior vena cava and azygos vein exhibited positive WGA and ConA binding, whereas DBA binding was noted on only part of the tunica intima of the superior vena cava and not on that of the azygos vein. The tunica media and tunica adventitia were reactive for all three lectins. The WGA and ConA binding sites in the tunica adventitia showed loose networks, suggesting lectin binding on connective tissue elements interlacing among smooth muscle bundles. Lectin binding sites in the walls of lymphatics exhibited an arrangement similar to those in the walls of the veins. Moreover valves protruding into the lumen showed intense WGA and ConA binding and scattered DBA binding. Three other lectins (Ulex europaeus agglutinin, peanut agglutinin, Maclura pomifera) were examined, but they showed no reactions with the vessels. Thus, the differential binding of lectins on the walls of blood vessels and lymphatics of various sizes suggests the functional complexity of monosaccharide residues in the vascular walls. PMID:1758681

  20. Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse

    PubMed Central

    Choi, Inho; Chung, Hee Kyoung; Ramu, Swapnika; Lee, Ha Neul; Kim, Kyu Eui; Lee, Sunju; Yoo, Jaehyuk; Choi, Dongwon; Lee, Yong Suk; Aguilar, Berenice

    2011-01-01

    Although the blood vessel-specific fluorescent transgenic mouse has been an excellent tool to study vasculogenesis and angiogenesis, a lymphatic-specific fluorescent mouse model has not been established to date. Here we report a transgenic animal model that expresses the green fluorescent protein under the promoter of Prox1, a master control gene in lymphatic development. Generated using an approximately 200-kb-long bacterial artificial chromosome harboring the entire Prox1 gene, this Prox1-green fluorescent protein mouse was found to faithfully recapitulate the expression pattern of the Prox1 gene in lymphatic endothelial cells and other Prox1-expressing organs, and enabled us to conveniently visualize detailed structure and morphology of lymphatic vessels and networks throughout development. Our data demonstrate that this novel transgenic mouse can be extremely useful for detection, imaging, and isolation of lymphatic vessels and monitoring wound-associated lymphangiogenesis. Together, this Prox1-green fluorescent protein transgenic mouse will be a great tool for the lymphatic research. PMID:20962325

  1. 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

  2. Effects of histamine on the contractile and electrical activity in isolated lymphatic vessels of the guinea-pig mesentery

    PubMed Central

    Fox, James L R; von der Weid, Pierre-Yves

    2002-01-01

    The effect of histamine on the rate of lymphatic vessel constrictions and lymphatic smooth muscle membrane potential was examined in the guinea-pig mesentery. Histamine (0.01–5 μM) increased the frequency and decreased the amplitude of constrictions in lymphatic vessels under intraluminal perfusion. This response was accompanied by a depolarization of the smooth muscle membrane potential, an increase in the activity of spontaneous transient depolarizations (STDs), the proposed pacemaker for constrictions in these vessels, and an increase in the occurrence of action potentials. Responses to histamine were inhibited by the H1 receptor antagonist pyrilamine (0.2 μM), but unaffected by NO synthase inhibition with NG-nitro L-arginine (L-NOARG, 100 μM) and lysis of the endothelium. In about 50% of the vessels, a decrease in constriction frequency, STD activity and a smooth muscle hyperpolarization were observed in response to dimaprit (10 μM), suggesting the presence of H2 receptors. These vessels had also a significantly lower basal contractile rate. Lymphatic vessel pumping was not affected by R-α-methylhistamine (10–50 μM), ruling out a role for H3 receptor stimulation in the histamine response. The present results suggest a direct action of histamine on the lymphatic smooth muscle via stimulation of H1 (and in some vessels H2) receptors. H1 receptors enhance and H2 receptors slow down lymphatic pumping, the dominant effect being an increased contractile activity. Correlation of these effects with histamine-induced changes in membrane potential and STD activity suggests the involvement of these electrical changes in the initiation of the contractile response. PMID:12163355

  3. Mechanisms of Acute Alcohol Intoxication-Induced Modulation of Cyclic Mobilization of [Ca2+] in Rat Mesenteric Lymphatic Vessels

    PubMed Central

    Kerut, Edmund K.; Breslin, Jerome W.; Molina, Patricia E.

    2015-01-01

    Abstract Background: We have demonstrated that acute alcohol intoxication (AAI) increases the magnitude of Ca2+ transients in pumping lymphatic vessels. We tested the contribution of extracellular Ca2+ via L-type Ca2+ channels and intracellular Ca2+ release from the sarcoplasmic reticulum (SR) to the AAI-induced increase in Ca2+ transients. Methods and Results: AAI was produced by intragastric administration of 30% alcohol to conscious, unrestrained rats; isovolumic administration of water served as the control. Mesenteric lymphatic vessels were isolated, cannulated, and loaded with Fura-2 AM to measure changes in intracellular Ca2+. Measurements were made at intraluminal pressures of 2, 6, and 10 cm H2O. L-type Ca2+ channels were blocked with nifedipine; IP-3 receptors were inhibited with xestospongin C; and SR Ca2+ release and Ca2+ pool (Ca2+ free APSS) were achieved using caffeine. Nifedipine reduced lymphatic Ca2+ transient magnitude in both AAI and control groups at all pressures tested, but reduced lymphatic contraction frequency only in the control group. Xestospongin C did not significantly change any of the Ca2+ parameters in either group; however, fractional shortening increased in the controls at low transmural pressure. RyR (ryanodine receptor) activation with caffeine resulted in a single contraction with a greater Ca2+ transient in lymphatics from AAI than those from controls. SR Ca2+ pool was also greater in lymphatics isolated from AAI- than from control animals. Conclusions: These data suggest that 1) L-type Ca2+ channels contribute to the AAI-induced increase in lymphatic Ca2+ transient, 2) blockage of IP-3 receptors could increase calcium sensitivity, and 3) AAI increases Ca2+ storage in the SR in lymphatic vessels. PMID:26056854

  4. Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development

    PubMed Central

    Lin, Fu-Jung; Chen, Xinpu; Qin, Jun; Hong, Young-Kwon; Tsai, Ming-Jer; Tsai, Sophia Y.

    2010-01-01

    The lymphatic system plays a key role in tissue fluid homeostasis. Lymphatic dysfunction contributes to the pathogenesis of many human diseases, including lymphedema and tumor metastasis. However, the mechanisms regulating lymphangiogenesis remain largely unknown. Here, we show that COUP-TFII (also known as Nr2f2), an orphan member of the nuclear receptor superfamily, mediates both developmental and pathological lymphangiogenesis in mice. Conditional ablation of COUP-TFII at an early embryonic stage resulted in failed formation of pre-lymphatic ECs (pre-LECs) and lymphatic vessels. COUP-TFII deficiency at a late developmental stage resulted in loss of LEC identity, gain of blood EC fate, and impaired lymphatic vessel sprouting. siRNA-mediated downregulation of COUP-TFII in cultured primary human LECs demonstrated that the maintenance of lymphatic identity and VEGF-C–induced lymphangiogenic activity, including cell proliferation and migration, are COUP-TFII–dependent and cell-autonomous processes. COUP-TFII enhanced the pro-lymphangiogenic actions of VEGF-C, at least in part by directly stimulating expression of neuropilin-2, a coreceptor for VEGF-C. In addition, COUP-TFII inactivation in a mammary gland mouse tumor model resulted in inhibition of tumor lymphangiogenesis, suggesting that COUP-TFII also regulates neo-lymphangiogenesis in the adult. Thus, COUP-TFII is a critical factor that controls lymphangiogenesis in embryonic development and tumorigenesis in adults. PMID:20364082

  5. Absence of Lymphatic Vessels in PCNSL May Contribute to Confinement of Tumor Cells to the Central Nervous System.

    PubMed

    Deckert, Martina; Brunn, Anna; Montesinos-Rongen, Manuel; Siebert, Reiner

    2016-06-01

    Primary central nervous system (CNS) lymphoma (PCNSL) is a mature lymphoma of the diffuse large B-cell lymphoma (DLBCL) type confined to the CNS. Despite cytomorphological similarities between PCNSL and systemic DLBCL, molecular differences between both entities have been identified. The exclusively topographical restriction of PCNSL to the CNS is an unexplained mystery. To address the question of whether the unique lymphatic drainage system of the CNS, which differs from that of other organs, may play a role for this peculiar behavior, we investigated a series of 20 PCNSLs for the presence of lymphatic vessels by immunohistochemistry for Lyve-1, podoplanin, and Prox-1 expression. All PCNSLs lacked lymphatic vessels and, in this regard, were similar to 20 glioblastoma multiforme samples. In contrast to these tumors, all of which were located in the deep brain parenchyma, dural and meningeal DLBCL harbored lymphatic vessels that expressed Lyve-1 (3/8 tumors), podoplanin (5/8 tumors), and Prox-1 (5/8 tumors) in areas where the tumors had invaded the fibrous tissue of the dura. These data indicate that local topographical characteristics of the specific lymphatic drainage system may contribute to confinement of the tumor cells in PCNSL and malignant gliomas. PMID:27142645

  6. Characterization, Localization and Patterning of Lymphatics and Blood Vessels in Oral Squamous Cell Carcinoma: A Comparative Study Using D2-40 and CD-34 IHC Marker

    PubMed Central

    Agarwal, Deshant; Bajpai, Manas; Gupta, Shailendra; Mathur, Nikunj; Vanaki, S S; Puranik, R S; Mittal, Manoj

    2014-01-01

    Objectives: Lymphatic metastasis has always been regarded as a major prognostic indicator for disease progression and as a guide for therapeutic strategies to oral squamous cell carcinoma (OSCC). Differentiating lymphatic vessels from blood vessels is difficult, partly due to lack of specific method for identifying lymphatics. A new lymphatic vessel reactive antibody D2-40 has been introduced recently. Here we examined immunohistochemical localization of lymphatic vessels and blood vessels using D2-40 and CD-34 respectively in different histological grades of OSCC. Their expression in intra-tumoural and peri-tumoural region was also compared. Materials and Methods: Forty two formalin-fixed paraffin-embedded tissue blocks of excised specimens of OSCC were immunohistochemically evaluated using D2-40 and CD-34 antibodies. Lymphatic vessel density (LVD) (D2-40 positivity) and micro vessel density (MVD) (CD34 positivity) in both intratumoural and peritumoural areas were assessed by hot spot method. Results: Regardless of histopathological differentiation, LVD–– and MVD in peritumoural areas were found greater than intratumoural areas (p>0.05). Interestingly, other than lymphatic vessels, D2-40 positivity was also detected in tumour cells as well as in basal layer of epithelium adjacent to OSCC. Two patterns of distribution of CD34 positive vessel - circumscribing type and penetrating type were also observed in the cancer nest area. Conclusion: D2-40 can be used as a marker to differentiate lymphatic vessels from blood vessels. Lymphatic and blood vessel proliferation might be much more extensive in the peritumoural area. D2-40 expression in epithelium adjacent to tumour indicates its role in the process of differentiation. Further, its expression in potential malignant disorder may provide better insight in predicting prognosis and pathogenesis of these lesions. PMID:25478456

  7. Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model

    PubMed Central

    Pivetta, Eliana; Wassermann, Bruna; Belluz, Lisa Del Bel; Danussi, Carla; Modica, Teresa Maria Elisa; Maiorani, Orlando; Bosisio, Giulia; Boccardo, Francesco; Canzonieri, Vincenzo; Colombatti, Alfonso

    2016-01-01

    Lymphatic vasculature critically depends on the connections of lymphatic endothelial cells with the extracellular matrix (ECM), which are mediated by anchoring filaments (AFs). The ECM protein EMILIN1 is a component of AFs and is involved in the regulation of lymphatic vessel functions: accordingly, Emilin1−/− mice display lymphatic vascular morphological alterations, leading to functional defects such as mild lymphoedema, lymph leakage and compromised lymph drainage. In the present study, using a mouse post-surgical tail lymphoedema model, we show that the acute phase of acquired lymphoedema correlates with EMILIN1 degradation due to neutrophil elastase (NE) released by infiltrating neutrophils. As a consequence, the intercellular junctions of lymphatic endothelial cells are weakened and drainage to regional lymph nodes is severely affected. The local administration of sivelestat, a specific NE inhibitor, prevents EMILIN1 degradation and reduces lymphoedema, restoring a normal lymphatic functionality. The finding that, in human secondary lymphoedema samples, we also detected cleaved EMILIN1 with the typical bands of an NE-dependent pattern of fragmentation establishes a rationale for a powerful strategy that targets NE inhibition. In conclusion, the attempts to block EMILIN1 degradation locally represent the basis for a novel ‘ECM’ pharmacological approach to assessing new lymphoedema treatments. PMID:26920215

  8. Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model.

    PubMed

    Pivetta, Eliana; Wassermann, Bruna; Del Bel Belluz, Lisa; Danussi, Carla; Modica, Teresa Maria Elisa; Maiorani, Orlando; Bosisio, Giulia; Boccardo, Francesco; Canzonieri, Vincenzo; Colombatti, Alfonso; Spessotto, Paola

    2016-07-01

    Lymphatic vasculature critically depends on the connections of lymphatic endothelial cells with the extracellular matrix (ECM), which are mediated by anchoring filaments (AFs). The ECM protein EMILIN1 is a component of AFs and is involved in the regulation of lymphatic vessel functions: accordingly, Emilin1(-/-) mice display lymphatic vascular morphological alterations, leading to functional defects such as mild lymphoedema, lymph leakage and compromised lymph drainage. In the present study, using a mouse post-surgical tail lymphoedema model, we show that the acute phase of acquired lymphoedema correlates with EMILIN1 degradation due to neutrophil elastase (NE) released by infiltrating neutrophils. As a consequence, the intercellular junctions of lymphatic endothelial cells are weakened and drainage to regional lymph nodes is severely affected. The local administration of sivelestat, a specific NE inhibitor, prevents EMILIN1 degradation and reduces lymphoedema, restoring a normal lymphatic functionality. The finding that, in human secondary lymphoedema samples, we also detected cleaved EMILIN1 with the typical bands of an NE-dependent pattern of fragmentation establishes a rationale for a powerful strategy that targets NE inhibition. In conclusion, the attempts to block EMILIN1 degradation locally represent the basis for a novel 'ECM' pharmacological approach to assessing new lymphoedema treatments. PMID:26920215

  9. Microparticle image velocimetry approach to flow measurements in isolated contracting lymphatic vessels

    NASA Astrophysics Data System (ADS)

    Margaris, Konstantinos N.; Nepiyushchikh, Zhanna; Zawieja, David C.; Moore, James; Black, Richard A.

    2016-02-01

    We describe the development of an optical flow visualization method for resolving the flow velocity vector field in lymphatic vessels in vitro. The aim is to develop an experimental protocol for accurately estimating flow parameters, such as flow rate and shear stresses, with high spatial and temporal resolution. Previous studies in situ have relied on lymphocytes as tracers, but their low density resulted in a reduced spatial resolution whereas the assumption that the flow was fully developed in order to determine the flow parameters of interest may not be valid, especially in the vicinity of the valves, where the flow is undoubtedly more complex. To overcome these issues, we have applied the time-resolved microparticle image velocimetry (μ-PIV) technique, a well-established method that can provide increased spatial and temporal resolution that this transient flow demands. To that end, we have developed a custom light source, utilizing high-power light-emitting diodes, and associated control and image processing software. This paper reports the performance of the system and the results of a series of preliminary experiments performed on vessels isolated from rat mesenteries, demonstrating, for the first time, the successful application of the μ-PIV technique in these vessels.

  10. Microparticle image velocimetry approach to flow measurements in isolated contracting lymphatic vessels.

    PubMed

    Margaris, Konstantinos N; Nepiyushchikh, Zhanna; Zawieja, David C; Moore, James; Black, Richard A

    2016-02-01

    We describe the development of an optical flow visualization method for resolving the flow velocity vector field in lymphatic vessels in vitro. The aim is to develop an experimental protocol for accurately estimating flow parameters, such as flow rate and shear stresses, with high spatial and temporal resolution. Previous studies in situ have relied on lymphocytes as tracers, but their low density resulted in a reduced spatial resolution whereas the assumption that the flow was fully developed in order to determine the flow parameters of interest may not be valid, especially in the vicinity of the valves, where the flow is undoubtedly more complex. To overcome these issues, we have applied the time-resolved microparticle image velocimetry (μ -PIV) technique, a well-established method that can provide increased spatial and temporal resolution that this transient flow demands. To that end, we have developed a custom light source, utilizing high-power light-emitting diodes, and associated control and image processing software. This paper reports the performance of the system and the results of a series of preliminary experiments performed on vessels isolated from rat mesenteries, demonstrating, for the first time, the successful application of the μ -PIV technique in these vessels. PMID:26830061

  11. NOK/STYK1 promotes the genesis and remodeling of blood and lymphatic vessels during tumor progression.

    PubMed

    Liu, Yue; Li, Tianqi; Hu, Dan; Zhang, Shuping

    2016-09-01

    Previous studies have indicated that the overexpression of NOK, also named STYK1, led to tumorigenesis and metastasis. Here, we provide evidence that increased expression of NOK/STYK1 caused marked alterations in the overall and inner structures of tumors and substantially facilitates the genesis and remodeling of the blood and lymphatic vessels during tumor progression. In particular, NOK-expressed HeLa stable cells (HeLa-K) significantly enhanced tumor growth and metastasis in xenografted nude mice. Hematoxylin and eosin (HE) staining demonstrated that the tumor tissues generated by HeLa-K cells were much more ichorous and had more interspaces than those generated by control HeLa cells (HeLa-C). The fluorescent areas stained with cluster of differentiation 31 (CD31), a marker protein for blood vessels, appeared to be in different patterns. The total blood vessels, especially the ring patterns, within the tumors of the HeLa-K group were highly enriched compared with those in the HeLa-C group. NOK-HA was demonstrated to be well colocalized with CD31 in the wall of the tubular structures within tumor tissues. Interestingly, antibody staining of the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) further revealed the increase in ring (oratretic strip-like) lymphatic vessels in either the peritumoral or intratumoral areas in the HeLa-K group compared with the HeLa-C group. Consistently, the analysis of human cancerous tissue also showed that NOK was highly expressed in the walls of tubular structures. Thus, our results reveal a novel tumorigenic function of NOK to mediate the genesis and remodeling of blood and lymphatic vessels during tumor progression. PMID:27444381

  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). PMID:27622039

  13. 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

  14. Debulking Surgery for Elephantiasis Nostras With Large Ectatic Podoplanin-Negative Lymphatic Vessels in Patients With Lipo-Lymphedema

    PubMed Central

    Wollina, Uwe; Heinig, Birgit; Schönlebe, Jaqueline; Nowak, Andreas

    2014-01-01

    Objective: Elephantiasis nostras is a rare complication in advanced lipo-lymphedema. While lipedema can be treated by liposuction and lymphedema by decongestive lymphatic therapy, elephantiasis nostras may need debulking surgery. Methods: We present 2 cases of advanced lipo-lymphedema complicated by elephantiasis nostras. After tumescent microcannular laser-assisted liposuction both patients underwent a debulking surgery with a modification of Auchincloss-Kim's technique. Histologic examination of the tissue specimen was performed. Results: The surgical treatment was well tolerated and primary healing was uneventful. After primary wound healing and ambulation of the patients, a delayed ulceration with lymphorrhea developed. It was treated by surgical necrectomy and vacuum-assisted closure leading to complete healing. Mobility of the leg was much improved. Histologic examination revealed massive ectatic lymphatic vessels nonreactive for podoplanin. Conclusions: Debulking surgery can be an adjuvant technique for elephantiasis nostras in advanced lipo-lymphedema. Although delayed postoperative wound healing problems were observed, necrectomy and vacuum-assisted closure achieved a complete healing. Histologic data suggest that the ectatic lymphatic vessels in these patients resemble finding in podoplanin knockout mice. The findings would explain the limitations of decongestive lymphatic therapy and tumescent liposuction in such patients and their predisposition to relapsing erysipelas. PMID:24741382

  15. Lymphatic vessel endothelial hyaluronan receptor-1 is a novel prognostic indicator for human hepatocellular carcinoma.

    PubMed

    Kitagawa, Koichi; Nakajima, Go; Kuramochi, Hidekazu; Ariizumi, Shun-Ichi; Yamamoto, Masakazu

    2013-11-01

    Angiogenesis is an important mechanism of tumor development, growth and metastasis in hepatocellular carcinoma (HCC). The poor prognosis of HCC patients has been associated with a failure to detect recurrences following surgery. In the present study, we investigated the association between the patient characteristics and the expression of angiogenic genes to identify early biomarkers of HCC. A comprehensive angiogenic gene expression profile was obtained by paired TaqMan gene array analysis of primary HCC nodules and adjacent non-HCC liver tissue from 12 patients. A total of 14 genes were found to be differentially expressed in HCC liver nodules (>2-fold change); the genes encoding collagen type XVα1, IVα1 and IVα2 were upregulated and the genes associated with vessel growth, neuropilin 2 (NRP2) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) were downregulated. The histopathological analysis revealed that the evolution of HCC nodules from well to poorly differentiated was associated with a 5-fold decrease in LYVE-1 expression, reaching its lowest level early during the transition. The significance of this gene as a biomarker of postoperative survival was demonstrated by a 2-fold decrease in overall survival (OS) rates in the low expression group compared to the high expression group. The multivariate and univariate Cox regression analyses identified LYVE-1 expression as a significant independent prognostic parameter of OS [hazard ratio (HR)=3.067; 95% confidence interval (CI): 1.507-6.273; P=0.0021]. Thus, the results of this study suggested that LYVE-1 expression may constitute a novel early biomarker of postoperative survival in HCC patients. PMID:24649290

  16. 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 ... extensive network of lymphatic vessels in every woman’s breast tissue, which is important in regulating the local ...

  17. Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system.

    PubMed

    Kodama, Tetsuya; Hatakeyama, Yuriko; Kato, Shigeki; Mori, Shiro

    2015-01-01

    Curing/preventing micrometastasis to lymph nodes (LNs) located outside the surgically resected area is essential for improving the morbidity and mortality associated with breast cancer and head and neck cancer. However, no lymphatic therapy system exists that can deliver drugs to LNs located outside the dissection area. Here, we demonstrate proof of concept for a drug delivery system using MXH10/Mo-lpr/lpr mice that exhibit systemic lymphadenopathy, with some peripheral LNs being as large as 10 mm in diameter. We report that a fluorescent solution injected into the subiliac LN (defined as the upstream LN within the dissection area) was delivered successfully to the proper axillary LN (defined as the downstream LN outside the dissection area) through the lymphatic vessels. Our results suggest that this approach could be used before surgical resection to deliver drugs to downstream LNs outside the dissection area. We anticipate that our methodology could be applied clinically, before surgical resection, to cure/prevent micrometastasis in LNs outside the dissection area, using techniques such as ultrasound-guided internal jugular vein catheterization. PMID:25657881

  18. Neutrophils rapidly transit inflamed lymphatic vessel endothelium via integrin-dependent proteolysis and lipoxin-induced junctional retraction.

    PubMed

    Rigby, David A; Ferguson, David J P; Johnson, Louise A; Jackson, David G

    2015-12-01

    Neutrophils are the first leukocyte population to be recruited from the circulation following tissue injury or infection, where they play key roles in host defense. However, recent evidence indicates recruited neutrophils can also enter lymph and shape adaptive immune responses downstream in draining lymph nodes. At present, the cellular mechanisms regulating neutrophil entry to lymphatic vessels and migration to lymph nodes are largely unknown. Here, we have investigated these events in an in vivo mouse Mycobacterium bovis bacillus Calmette-Guérin vaccination model, ex vivo mouse dermal explants, and in vitro Transwell system comprising monolayers of primary human dermal lymphatic endothelial cells. We demonstrate that neutrophils are reliant on endothelial activation for adhesion, initially via E-selectin and subsequently, by integrin-mediated binding to ICAM-1 and VCAM-1, combined with CXCL8-dependent chemotaxis. Moreover, we reveal that integrin-mediated neutrophil adhesion plays a pivotal role in subsequent transmigration by focusing the action of matrix metalloproteinases and the 15-lipoxygenase-1-derived chemorepellent 12(S)-hydroxyeicosatetraenoic acid at neutrophil:endothelial contact sites to induce transient endothelial junctional retraction and rapid, selective neutrophil trafficking. These findings reveal an unexpectedly intimate collaboration between neutrophils and the lymphatic vessel endothelium, in which these phagocytic leukocytes act as pathfinders for their own transit during inflammation. PMID:26216937

  19. 9-Cis Retinoic Acid Promotes Lymphangiogenesis and Enhances Lymphatic Vessel Regeneration: Therapeutic Implications of 9-Cis Retinoic Acid for Secondary Lymphedema

    PubMed Central

    Choi, Inho; Lee, Sunju; Chung, Hee Kyoung; Lee, Yong Suk; Kim, Kyu Eui; Choi, Dongwon; Park, Eun Kyung; Yang, Dongyun; Ecoiffier, Tatiana; Monahan, John; Chen, Wen; Aguilar, Berenice; Lee, Ha Neul; Yoo, Jaehyuk; Koh, Chester J.; Chen, Lu; Wong, Alex K.; Hong, Young-Kwon

    2012-01-01

    Background The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction due to genetic defects or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swellings often associated with fibrosis and recurrent infections without available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema. Methods and Results We report that RAs promote proliferation, migration and tube formation of cultured lymphatic endothelial cells (LECs) by activating FGF-receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27Kip1, p57Kip2 and the aurora kinases through both an Akt-mediated non-genomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals based on mouse trachea, matrigel plug and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating the experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration. Conclusions These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients. PMID:22275501

  20. 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

  1. Functional Lymphatic Collectors in Breast Cancer-Related Lymphedema Arm

    PubMed Central

    Wang, Bing-shun

    2014-01-01

    Abstract Background: The pathophysiology of breast cancer-related lymphedema (BCRL) is poorly understood. The present study evaluated the lymphatic collectors in the arms of patients with BCRL. Methods and Results: In total, 123 patients with ipsilateral BCRL who had undergone magnetic resonance lymphangiography using gadobenate dimeglumine as a contrast agent were enrolled in this study. Morphological changes and the numbers of collecting lymphatic vessels were recorded. Associations between the number of visualized lymphatic collectors and edema accumulation, subcutis thickness, and the BCRL duration and latency were analyzed. Tortuous and significantly dilated lymphatic collectors were visualized in the lymphedematous arms of 104 patients (85%). The median number of visualized lymphatic collectors was four. The duration of BCRL was weakly but significantly correlated with the number of lymphatic collectors (rs=0.2054, p=0.0226). The differences in the tissue water content and thickness of the subcutis between the bilateral arms demonstrated moderate correlations with the number of collecting lymphatics (rs=0.31 and 0.35, respectively; p<0.01). More lymphatic collectors tended to be seen in more advanced cases. There was no statistical difference in the amount of lymphatic vessels among different breast cancer treatment methods. Conclusions: The number of functional remaining lymphatic collectors increases with the prolongation and severity of BCRL. This may imply persistent reactions of lymphatic collectors in response to lymphostasis. PMID:25495381

  2. In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice

    PubMed Central

    Bouta, Echoe M; Wood, Ronald W; Brown, Edward B; Rahimi, Homaira; Ritchlin, Christopher T; Schwarz, Edward M

    2014-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with episodic flares. In TNF-Tg mice, a model of inflammatory–erosive arthritis, the popliteal lymph node (PLN) enlarges during the pre-arthritic ‘expanding’ phase, and then ‘collapses’ with adjacent knee flare associated with the loss of the intrinsic lymphatic pulse. As the mechanisms responsible are unknown, we developed in vivo methods to quantify lymph viscosity and pressure in mice with wild-type (WT), expanding and collapsed PLN. While no differences in viscosity were detected via multiphoton fluorescence recovery after photobleaching (MP-FRAP) of injected FITC-BSA, a 32.6% decrease in lymph speed was observed in vessels afferent to collapsed PLN (P < 0.05). Direct measurement of intra-lymph node pressure (LNP) demonstrated a decrease in expanding PLN versus WT pressure (3.41 ± 0.43 vs. 6.86 ± 0.56 cmH2O; P < 0.01), which dramatically increased to 9.92 ± 1.79 cmH2O in collapsed PLN. Lymphatic pumping pressure (LPP), measured indirectly by slowly releasing a pressurized cuff occluding indocyanine green (ICG), demonstrated an increase in vessels afferent to expanding PLN versus WT (18.76 ± 2.34 vs. 11.04 ± 1.47 cmH2O; P < 0.01), which dropped to 2.61 ± 0.72 cmH2O (P < 0.001) after PLN collapse. Herein, we document the first in vivo measurements of murine lymph viscosity and lymphatic pressure, and provide evidence to support the hypothesis that lymphangiogenesis and lymphatic transport are compensatory mechanisms to prevent synovitis via increased drainage of inflamed joints. Furthermore, the decrease in lymphatic flow and loss of LPP during PLN collapse are consistent with decreased drainage from the joint during arthritic flare, and validate these biomarkers of RA progression and possibly other chronic inflammatory conditions. PMID:24421350

  3. CD8+ T cells suppress viral replication in the cornea but contribute to VEGF-C-induced lymphatic vessel genesis.

    PubMed

    Conrady, Christopher D; Zheng, Min; Stone, Donald U; Carr, Daniel J J

    2012-07-01

    HSV-1 is the leading cause of infectious corneal blindness in the industrialized world. CD4(+) T cells are thought to be the major leukocyte population mediating immunity to HSV-1 in the cornea as well as the likely source of immunopathology that reduces visual acuity. However, the role of CD8(+) T cells in immune surveillance of the cornea is unclear. Thus, we sought to evaluate the role of CD8(+) T cells in ocular immunity using transgenic mice in which >98% of CD8(+) T cells are specific for the immunodominant HSV-1 epitope (gBT-I.1). We found a significant reduction in virus, elevation in HSV-specific CD8(+) T cell influx, and more CD8(+) T cells expressing CXCR3 in the cornea of transgenic mice compared with those in the cornea of wild-type controls yet similar acute corneal pathology. However, by day 30 postinfection, wild-type mice had drastically more blood and lymphatic vessel projections into the cornea compared with gBT-I.1 mice, in which only lymphatic vessel growth in response to VEGF-C could be appreciated. Taken together, these results show that CD8(+) T cells are required to eliminate virus more efficiently from the cornea but play a minimal role in immunopathology as a source of VEGF-C. PMID:22649204

  4. 21 CFR 868.1575 - Gas collection vessel.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Gas collection vessel. 868.1575 Section 868.1575...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1575 Gas collection vessel. (a) Identification. A gas collection vessel is a container-like device intended to collect a patient's exhaled...

  5. 21 CFR 868.1575 - Gas collection vessel.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Gas collection vessel. 868.1575 Section 868.1575...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1575 Gas collection vessel. (a) Identification. A gas collection vessel is a container-like device intended to collect a patient's exhaled...

  6. Bimodal Expansion of the Lymphatic Vessels Is Regulated by the Sequential Expression of IL-7 and Lymphotoxin α1β2 in Newly Formed Tertiary Lymphoid Structures.

    PubMed

    Nayar, Saba; Campos, Joana; Chung, Ming May; Navarro-Núñez, Leyre; Chachlani, Menka; Steinthal, Nathalie; Gardner, David H; Rankin, Philip; Cloake, Thomas; Caamaño, Jorge H; McGettrick, Helen M; Watson, Steve P; Luther, Sanjiv; Buckley, Christopher D; Barone, Francesca

    2016-09-01

    Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)βR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1β2/LTβR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis. PMID:27474071

  7. Bimodal Expansion of the Lymphatic Vessels Is Regulated by the Sequential Expression of IL-7 and Lymphotoxin α1β2 in Newly Formed Tertiary Lymphoid Structures

    PubMed Central

    Nayar, Saba; Campos, Joana; Chung, Ming May; Navarro-Núñez, Leyre; Chachlani, Menka; Steinthal, Nathalie; Gardner, David H.; Rankin, Philip; Cloake, Thomas; Caamaño, Jorge H.; McGettrick, Helen M.; Watson, Steve P.; Luther, Sanjiv; Buckley, Christopher D.

    2016-01-01

    Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)βR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1β2/LTβR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis. PMID:27474071

  8. Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin

    PubMed Central

    Cueni, Leah N.; Chen, Lu; Zhang, Hui; Marino, Daniela; Huggenberger, Reto; Alitalo, Annamari; Bianchi, Roberta

    2010-01-01

    Podoplanin is a small transmembrane protein required for development and function of the lymphatic vascular system. To investigate the effects of interfering with its function, we produced an Fc fusion protein of its ectodomain. We found that podoplanin-Fc inhibited several functions of cultured lymphatic endothelial cells and also specifically suppressed lymphatic vessel growth, but not blood vessel growth, in mouse embryoid bodies in vitro and in mouse corneas in vivo. Using a keratin 14 expression cassette, we created transgenic mice that overexpressed podoplanin-Fc in the skin. No obvious outward phenotype was identified in these mice, but surprisingly, podoplanin-Fc—although produced specifically in the skin—entered the blood circulation and induced disseminated intravascular coagulation, characterized by microthrombi in most organs and by thrombocytopenia, occasionally leading to fatal hemorrhage. These findings reveal an important role of podoplanin in lymphatic vessel formation and indicate the potential of podoplanin-Fc as an inhibitor of lymphangiogenesis. These results also demonstrate the ability of podoplanin to induce platelet aggregation in vivo, which likely represents a major function of lymphatic endothelium. Finally, keratin 14 podoplanin-Fc mice represent a novel genetic animal model of disseminated intravascular coagulation. PMID:20716773

  9. Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A).

    PubMed

    Nishida-Fukuda, Hisayo; Araki, Ryoichi; Shudou, Masachika; Okazaki, Hidenori; Tomono, Yasuko; Nakayama, Hironao; Fukuda, Shinji; Sakaue, Tomohisa; Shirakata, Yuji; Sayama, Koji; Hashimoto, Koji; Detmar, Michael; Higashiyama, Shigeki; Hirakawa, Satoshi

    2016-05-13

    Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a type I transmembrane glycoprotein, is known as one of the most specific lymphatic vessel markers in the skin. In this study, we found that the ectodomain of LYVE-1 undergoes proteolytic cleavage, and this process produces soluble LYVE-1. We further identified the cleavage site for ectodomain shedding and generated an uncleavable mutant of LYVE-1. In lymphatic endothelial cells, ectodomain shedding of LYVE-1 was induced by vascular endothelial growth factor (VEGF)-A, an important factor for angiogenesis and lymphangiogenesis under pathological conditions. VEGF-A-induced LYVE-1 ectodomain shedding was mediated via the extracellular signal-regulated kinase (ERK) and a disintegrin and metalloproteinase (ADAM) 17. Wild-type LYVE-1, but not uncleavable LYVE-1, promoted migration of lymphatic endothelial cells in response to VEGF-A. Immunostaining analyses in human psoriasis skin lesions and VEGF-A transgenic mouse skin suggested that the ectodomain shedding of LYVE-1 occurred in lymphatic vessels undergoing chronic inflammation. These results indicate that the ectodomain shedding of LYVE-1 might be involved in promoting pathological lymphangiogenesis. PMID:26966180

  10. Development of a model of a multi-lymphangion lymphatic vessel incorporating realistic and measured parameter values.

    PubMed

    Bertram, C D; Macaskill, C; Davis, M J; Moore, J E

    2014-04-01

    Our published model of a lymphatic vessel consisting of multiple actively contracting segments between non-return valves has been further developed by the incorporation of properties derived from observations and measurements of rat mesenteric vessels. These included (1) a refractory period between contractions, (2) a highly nonlinear form for the passive part of the pressure-diameter relationship, (3) hysteretic and transmural-pressure-dependent valve opening and closing pressure thresholds and (4) dependence of active tension on muscle length as reflected in local diameter. Experimentally, lymphatic valves are known to be biased to stay open. In consequence, in the improved model, vessel pumping of fluid suffers losses by regurgitation, and valve closure is dependent on backflow first causing an adverse valve pressure drop sufficient to reach the closure threshold. The assumed resistance of an open valve therefore becomes a critical parameter, and experiments to measure this quantity are reported here. However, incorporating this parameter value, along with other parameter values based on existing measurements, led to ineffective pumping. It is argued that the published measurements of valve-closing pressure threshold overestimate this quantity owing to neglect of micro-pipette resistance. An estimate is made of the extent of the possible resulting error. Correcting by this amount, the pumping performance is improved, but still very inefficient unless the open-valve resistance is also increased beyond the measured level. Arguments are given as to why this is justified, and other areas where experimental data are lacking are identified. The model is capable of future adaptation as new experimental data appear. PMID:23801424

  11. Lymphatic anatomy and biomechanics

    PubMed Central

    Negrini, Daniela; Moriondo, Andrea

    2011-01-01

    Abstract Lymph formation is driven by hydraulic pressure gradients developing between the interstitial tissue and the lumen of initial lymphatics. While in vessels equipped with lymphatic smooth muscle cells these gradients are determined by well-synchronized spontaneous contractions of vessel segments, initial lymphatics devoid of smooth muscles rely on tissue motion to form lymph and propel it along the network. Lymphatics supplying highly moving tissues, such as skeletal muscle, diaphragm or thoracic tissues, undergo cyclic compression and expansion of their lumen imposed by local stresses arising in the tissue as a consequence of cardiac and respiratory activities. Active muscle contraction and not passive tissue displacement is required to support an efficient lymphatic drainage, as suggested by the fact that the respiratory activity promotes lymph formation during spontaneous, but not mechanical ventilation. The mechanical properties of the lymphatic wall and of the surrounding tissue also play an important role in lymphatic function. Modelling of stress distribution in the lymphatic wall suggests that compliant vessels behave as reservoirs accommodating absorbed interstitial fluid, while lymphatics with stiffer walls, taking advantage of a more efficient transmission of tissue stresses to the lymphatic lumen, propel fluid through the lumen of the lymphatic circuit. PMID:21486777

  12. Effects of LDL Receptor Modulation on Lymphatic Function

    PubMed Central

    Milasan, Andreea; Dallaire, François; Mayer, Gaétan; Martel, Catherine

    2016-01-01

    Atherosclerosis is driven by the accumulation of immune cells and cholesterol in the arterial wall. Although recent studies have shown that lymphatic vessels play an important role in macrophage reverse cholesterol transport, the specific underlying mechanisms of this physiological feature remain unknown. In the current report, we sought to better characterize the lymphatic dysfunction that is associated with atherosclerosis by studying the physiological and temporal origins of this impairment. First, we assessed that athero-protected Pcsk9−/− mice exhibited improved collecting lymphatic vessel function throughout age when compared to WT mice for up to six months, while displaying enhanced expression of LDLR on lymphatic endothelial cells. Lymphatic dysfunction was present before the atherosclerotic lesion formation in a mouse model that is predisposed to develop atherosclerosis (Ldlr−/−; hApoB100+/+). This dysfunction was presumably associated with a defect in the collecting lymphatic vessels in a non-specific cholesterol- but LDLR-dependent manner. Treatment with a selective VEGFR-3 agonist rescued this impairment observed early in the onset of this arterial disease. We suggest that LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction, and bring forth a pleiotropic role for PCSK9 in lymphatic function. Our study unveils new potential therapeutic targets for the prevention and treatment of atherosclerosis. PMID:27279328

  13. Magnetic resonance lymphography demonstrates spontaneous lymphatic disruption and regeneration in obstructive lymphedema.

    PubMed

    Liu, N-F; Yan, Z-X; Wu, X-F; Luo, Y

    2013-06-01

    The present study was aimed at observing both the damage and change process undergone in lymphatic collectors in obstructive extremity lymphedema. Forty-five patients with obstructive extremity lymphedema who had been examined with magnetic resonance lymphangiography (MRL) were enrolled in the study. Among this group, 36 were diagnosed with secondary lymphedema of the lower extremity and 9 exhibited upper extremity lymphedema after mastectomy. Morphological damage as a result of obstruction of collecting lymph vessels was recorded and analyzed. Obvious damage to the lymph vessels was found in all of the 36 lower extremity lymphedema cases with different lengths of history, including vessel disruption in 21 and lymphatic regeneration in 15. Lymphatic damage occurred in the anterior tibial area of the lower leg in almost every case. In 9 cases with upper extremity lymphedema, collecting lymphatic disruption and lymph tracer leakage was seen in multiple patterns. Imaging displayed that ruptured lymph collectors healed spontaneously or regenerated into a segment of the lymphatic network. The present study provided real-time images of collecting lymphatic vessels in obstructive lymphedema. These were seen to have undergone disruption, displayed lymphorrhoea, and/or lymphatic regeneration. In addition, the images suggest that the anterior tibial lymphatic is the weak point of the lymphatic pathway in the lower limb. PMID:24354104

  14. The Role of the Mesentery in Crohn's Disease: The Contributions of Nerves, Vessels, Lymphatics, and Fat to the Pathogenesis and Disease Course.

    PubMed

    Li, Yi; Zhu, Weiming; Zuo, Lugen; Shen, Bo

    2016-06-01

    Crohn's disease (CD) is a complex gastrointestinal disorder involving multiple levels of cross talk between the immunological, neural, vascular, and endocrine systems. The current dominant theory in CD is based on the unidirectional axis of dysbiosis-innate immunity-adaptive immunity-mesentery-body system. Emerging clinical evidence strongly suggests that the axis be bidirectional. The morphologic and/or functional abnormalities in the mesenteric structures likely contribute to the disease progression of CD, to a less extent the disease initiation. In addition to adipocytes, mesentery contains nerves, blood vessels, lymphatics, stromal cells, and fibroblasts. By the secretion of adipokines that have endocrine functions, the mesenteric fat tissue exerts its activity in immunomodulation mainly through response to afferent signals, neuropeptides, and functional cytokines. Mesenteric nerves are involved in the pathogenesis and prognosis of CD mainly through neuropeptides. In addition to angiogenesis observed in CD, lymphatic obstruction, remodeling, and impaired contraction maybe a cause and consequence of CD. Lymphangiogenesis and angiogenesis play a concomitant role in the progress of chronic intestinal inflammation. Finally, the interaction between neuropeptides, adipokines, and vascular and lymphatic endothelia leads to adipose tissue remodeling, which makes the mesentery an active participator, not a bystander, in the disease initiation and precipitation CD. The identification of the role of mesentery, including the structure and function of mesenteric nerves, vessels, lymphatics, and fat, in the intestinal inflammation in CD has important implications in understanding its pathogenesis and clinical management. PMID:27167572

  15. 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

  16. Primary and secondary lymphatic valve development: molecular, functional and mechanical insights.

    PubMed

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

    2014-11-01

    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

  17. Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development.

    PubMed

    Zhou, Fei; Chang, Zai; Zhang, Luqing; Hong, Young-Kwon; Shen, Bin; Wang, Bo; Zhang, Fan; Lu, Guangming; Tvorogov, Denis; Alitalo, Kari; Hemmings, Brian A; Yang, Zhongzhou; He, Yulong

    2010-10-01

    Akt-mediated signaling plays an important role in blood vascular development. In this study, we investigated the role of Akt in lymphatic growth using Akt-deficient mice. First, we found that lymphangiogenesis occurred in Akt1(-/-), Akt2(-/-), and Akt3(-/-) mice. However, both the diameter and endothelial cell number of lymphatic capillaries were significantly less in Akt1(-/-) mice than in wild-type control mice, whereas there was only a slight change in Akt2(-/-) and Akt3(-/-) mice. Second, valves present in the small collecting lymphatics in the superficial dermal layer of the ear skin were rarely observed in Akt1(-/-) mice, although these valves could be detected in the large collecting lymphatics in the deep layer of the skin tissues. A fluorescence microlymphangiography assay showed that the skin lymphatic network in Akt1(-/-) mice was functional but abnormal as shown by fluorescein isothiocyanate-dextran draining. There was an uncharacteristic enlargement of collecting lymphatic vessels, and further analysis showed that smooth muscle cell coverage of collecting lymphatic vessels became much more sparse in Akt1-deficient mice than in wild-type control animals. Finally, we showed that lymphatic vessels were detected in compound Akt-null mice and that lymphangiogenesis could be induced by vascular endothelial growth factor-C delivered via adenoviral vectors in adult mice lacking Akt1. These results indicate that despite the compensatory roles of other Akt isoforms, Akt1 is more critically required during lymphatic development. PMID:20724596

  18. Schlemm's Canal Is a Unique Vessel with a Combination of Blood Vascular and Lymphatic Phenotypes that Forms by a Novel Developmental Process

    PubMed Central

    Kizhatil, Krishnakumar; Ryan, Margaret; Marchant, Jeffrey K.; Henrich, Stephen; John, Simon W. M.

    2014-01-01

    Schlemm's canal (SC) plays central roles in ocular physiology. These roles depend on the molecular phenotypes of SC endothelial cells (SECs). Both the specific phenotype of SECs and development of SC remain poorly defined. To allow a modern and extensive analysis of SC and its origins, we developed a new whole-mount procedure to visualize its development in the context of surrounding tissues. We then applied genetic lineage tracing, specific-fluorescent reporter genes, immunofluorescence, high-resolution confocal microscopy, and three-dimensional (3D) rendering to study SC. Using these techniques, we show that SECs have a unique phenotype that is a blend of both blood and lymphatic endothelial cell phenotypes. By analyzing whole mounts of postnatal mouse eyes progressively to adulthood, we show that SC develops from blood vessels through a newly discovered process that we name “canalogenesis.” Functional inhibition of KDR (VEGFR2), a critical receptor in initiating angiogenesis, shows that this receptor is required during canalogenesis. Unlike angiogenesis and similar to stages of vasculogenesis, during canalogenesis tip cells divide and form branched chains prior to vessel formation. Differing from both angiogenesis and vasculogenesis, during canalogenesis SECs express Prox1, a master regulator of lymphangiogenesis and lymphatic phenotypes. Thus, SC development resembles a blend of vascular developmental programs. These advances define SC as a unique vessel with a combination of blood vascular and lymphatic phenotypes. They are important for dissecting its functions that are essential for ocular health and normal vision. PMID:25051267

  19. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: Parallels with lymph node stroma

    PubMed Central

    Stranford, Sharon; Ruddle, Nancy H.

    2012-01-01

    In this communication, the contribution of stromal, or non-hematopoietic, cells to the structure and function of lymph nodes (LNs), as canonical secondary lymphoid organs (SLOs), is compared to that of tertiary lymphoid tissue or organs (TLOs), also known as ectopic lymphoid tissues. TLOs can arise in non-lymphoid organs during chronic inflammation, as a result of autoimmune responses, graft rejection, atherosclerosis, microbial infection, and cancer. The stromal components found in SLOs including follicular dendritic cells, fibroblast reticular cells, lymphatic vessels, and high endothelial venules and possibly conduits are present in TLOs; their molecular regulation mimics that of LNs. Advances in visualization techniques and the development of transgenic mice that permit in vivo real time imaging of these structures will facilitate elucidation of their precise functions in the context of chronic inflammation. A clearer understanding of the inflammatory signals that drive non-lymphoid stromal cells to reorganize into TLO should allow the design of therapeutic interventions to impede the progression of autoimmune activity, or alternatively, to enhance anti-tumor responses. PMID:23230435

  20. Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan Organization*

    PubMed Central

    Lawrance, William; Banerji, Suneale; Day, Anthony J.; Bhattacharjee, Shaumick; Jackson, David G.

    2016-01-01

    The lymphatic endothelial receptor LYVE-1 has been implicated in both uptake of hyaluronan (HA) from tissue matrix and in facilitating transit of leukocytes and tumor cells through lymphatic vessels based largely on in vitro studies with recombinant receptor in transfected fibroblasts. Curiously, however, LYVE-1 in lymphatic endothelium displays little if any binding to HA in vitro, and this has led to the conclusion that the native receptor is functionally silenced, a feature that is difficult to reconcile with its proposed in vivo functions. Nonetheless, as we reported recently, LYVE-1 can function as a receptor for HA-encapsulated Group A streptococci and mediate lymphatic dissemination in mice. Here we resolve these paradoxical findings and show that the capacity of LYVE-1 to bind HA is strictly dependent on avidity, demanding appropriate receptor self-association and/or HA multimerization. In particular, we demonstrate the prerequisite of a critical LYVE-1 threshold density and show that HA binding may be elicited in lymphatic endothelium by surface clustering with divalent LYVE-1 mAbs. In addition, we show that cross-linking of biotinylated HA in streptavidin multimers or supramolecular complexes with the inflammation-induced protein TSG-6 enables binding even in the absence of LYVE-1 cross-linking. Finally, we show that endogenous HA on the surface of macrophages can engage LYVE-1, facilitating their adhesion and transit across lymphatic endothelium. These results reveal LYVE-1 as a low affinity receptor tuned to discriminate between different HA configurations through avidity and establish a new mechanistic basis for the functions ascribed to LYVE-1 in matrix HA binding and leukocyte trafficking in vivo. PMID:26823460

  1. Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan Organization.

    PubMed

    Lawrance, William; Banerji, Suneale; Day, Anthony J; Bhattacharjee, Shaumick; Jackson, David G

    2016-04-01

    The lymphatic endothelial receptor LYVE-1 has been implicated in both uptake of hyaluronan (HA) from tissue matrix and in facilitating transit of leukocytes and tumor cells through lymphatic vessels based largely onin vitrostudies with recombinant receptor in transfected fibroblasts. Curiously, however, LYVE-1 in lymphatic endothelium displays little if any binding to HAin vitro, and this has led to the conclusion that the native receptor is functionally silenced, a feature that is difficult to reconcile with its proposedin vivofunctions. Nonetheless, as we reported recently, LYVE-1 can function as a receptor for HA-encapsulated Group A streptococci and mediate lymphatic dissemination in mice. Here we resolve these paradoxical findings and show that the capacity of LYVE-1 to bind HA is strictly dependent on avidity, demanding appropriate receptor self-association and/or HA multimerization. In particular, we demonstrate the prerequisite of a critical LYVE-1 threshold density and show that HA binding may be elicited in lymphatic endothelium by surface clustering with divalent LYVE-1 mAbs. In addition, we show that cross-linking of biotinylated HA in streptavidin multimers or supramolecular complexes with the inflammation-induced protein TSG-6 enables binding even in the absence of LYVE-1 cross-linking. Finally, we show that endogenous HA on the surface of macrophages can engage LYVE-1, facilitating their adhesion and transit across lymphatic endothelium. These results reveal LYVE-1 as a low affinity receptor tuned to discriminate between different HA configurations through avidity and establish a new mechanistic basis for the functions ascribed to LYVE-1 in matrix HA binding and leukocyte traffickingin vivo. PMID:26823460

  2. 21 CFR 868.1575 - Gas collection vessel.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Gas collection vessel. 868.1575 Section 868.1575 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1575 Gas collection vessel....

  3. 21 CFR 868.1575 - Gas collection vessel.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Gas collection vessel. 868.1575 Section 868.1575 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1575 Gas collection vessel....

  4. 21 CFR 868.1575 - Gas collection vessel.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Gas collection vessel. 868.1575 Section 868.1575 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1575 Gas collection vessel....

  5. 76 FR 9550 - Proposed Information Collection; Comment Request; Northeast Region Vessel Identification Collection

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-18

    ... Region Vessel Identification Collection AGENCY: National Oceanic and Atmospheric Administration (NOAA... current information collection. Regulations at 50 CFR 648.8 and Sec. 697.8 require that owners of vessels... display the vessel's name and official number. The name and number must be of a specific size at...

  6. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation.

    PubMed

    Carrasco-Ramírez, Patricia; Greening, David W; Andrés, Germán; Gopal, Shashi K; Martín-Villar, Ester; Renart, Jaime; Simpson, Richard J; Quintanilla, Miguel

    2016-03-29

    Podoplanin (PDPN) is a transmembrane glycoprotein that plays crucial roles in embryonic development, the immune response, and malignant progression. Here, we report that cells ectopically or endogenously expressing PDPN release extracellular vesicles (EVs) that contain PDPN mRNA and protein. PDPN incorporates into membrane shed microvesicles (MVs) and endosomal-derived exosomes (EXOs), where it was found to colocalize with the canonical EV marker CD63 by immunoelectron microscopy. We have previously found that expression of PDPN in MDCK cells induces an epithelial-mesenchymal transition (EMT). Proteomic profiling of MDCK-PDPN cells compared to control cells shows that PDPN-induced EMT is associated with upregulation of oncogenic proteins and diminished expression of tumor suppressors. Proteomic analysis of exosomes reveals that MDCK-PDPN EXOs were enriched in protein cargos involved in cell adhesion, cytoskeletal remodeling, signal transduction and, importantly, intracellular trafficking and EV biogenesis. Indeed, expression of PDPN in MDCK cells stimulated both EXO and MV production, while knockdown of endogenous PDPN in human HN5 squamous carcinoma cells reduced EXO production and inhibited tumorigenesis. EXOs released from MDCK-PDPN and control cells both stimulated in vitro angiogenesis, but only EXOs containing PDPN were shown to promote lymphatic vessel formation. This effect was mediated by PDPN on the surface of EXOs, as demonstrated by a neutralizing specific monoclonal antibody. These results contribute to our understanding of PDPN-induced EMT in association to tumor progression, and suggest an important role for PDPN in EV biogenesis and/or release and for PDPN-EXOs in modulating lymphangiogenesis. PMID:26893367

  7. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation

    PubMed Central

    Andrés, Germán; Gopal, Shashi K.; Martín-Villar, Ester; Renart, Jaime; Simpson, Richard J.; Quintanilla, Miguel

    2016-01-01

    Podoplanin (PDPN) is a transmembrane glycoprotein that plays crucial roles in embryonic development, the immune response, and malignant progression. Here, we report that cells ectopically or endogenously expressing PDPN release extracellular vesicles (EVs) that contain PDPN mRNA and protein. PDPN incorporates into membrane shed microvesicles (MVs) and endosomal-derived exosomes (EXOs), where it was found to colocalize with the canonical EV marker CD63 by immunoelectron microscopy. We have previously found that expression of PDPN in MDCK cells induces an epithelial-mesenchymal transition (EMT). Proteomic profiling of MDCK-PDPN cells compared to control cells shows that PDPN-induced EMT is associated with upregulation of oncogenic proteins and diminished expression of tumor suppressors. Proteomic analysis of exosomes reveals that MDCK-PDPN EXOs were enriched in protein cargos involved in cell adhesion, cytoskeletal remodeling, signal transduction and, importantly, intracellular trafficking and EV biogenesis. Indeed, expression of PDPN in MDCK cells stimulated both EXO and MV production, while knockdown of endogenous PDPN in human HN5 squamous carcinoma cells reduced EXO production and inhibited tumorigenesis. EXOs released from MDCK-PDPN and control cells both stimulated in vitro angiogenesis, but only EXOs containing PDPN were shown to promote lymphatic vessel formation. This effect was mediated by PDPN on the surface of EXOs, as demonstrated by a neutralizing specific monoclonal antibody. These results contribute to our understanding of PDPN-induced EMT in association to tumor progression, and suggest an important role for PDPN in EV biogenesis and/or release and for PDPN-EXOs in modulating lymphangiogenesis. PMID:26893367

  8. 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

  9. In vivo label-free monitoring microvascular and lymphatic vessel changes and dynamics during wound healing in mouse ear pinna using optical microangiography

    NASA Astrophysics Data System (ADS)

    Yousefi, Siavash; Wang, Ruikang K.

    2014-02-01

    Cutaneous wound healing consists of multiple overlapping phases starting with blood coagulation following incision of blood vessels. In this paper, we briefly review wound healing phases that were observed by utilizing optical microangiography (OMAG) to monitor healing process and dynamics of microcirculation system in a mouse ear pinna wound model. Mouse ear pinna is composed of two layers of skin separated by a layer of cartilage and because its total thickness is around 500 μm, can be utilized as an ideal model for optical imaging techniques. These skin layers are identical to human skin structure except for sweat ducts and glands. Microcirculatory system responds to the wound injury by recruiting collateral vessels to supply blood flow to hypoxic area. Also, lymphatic vessels play an important role in the immune response of the tissue and clearing waste from interstitial fluid.

  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. PMID:25636584

  11. Prognostic Significance of Lymphatic Vessel Density Detected by D2-40 and Its Relation to Claudin-4 Expression in Prostatic Adenocarcinoma.

    PubMed

    Radi, Dina A; Abd-Elazeem, Marwa A

    2016-05-01

    Background Lymphovascular invasion is an important pathway of metastatic spread and regional lymph node metastasis is the major prognostic factor in prostatic adenocarcinoma. D2-40 is used to identify the lymphatic vessels and to assess the lymphatic vessel density (LVD). Expression of claudin-4 may be related to invasion and progression of carcinoma cells in several primary tumors. Aim To evaluate intra- and peritumoral LVD through immunohistochemical expression of D2-40 in relation to claudin-4 expression and clinicopathological parameters in prostatic adenocarcinoma. Materials and Methods Immunohistochemical staining procedure was performed on 53 paraffin-embedded blocks of radical prostatectomy specimens for prostatic adenocarcinoma using anti D2-40 and claudin-4 antibodies. Sections were evaluated for mean LVD in intratumoral and peritumoral tissues assessed by D2-40 expression. Results LVD in intratumoral tissues was significantly lower compared with peritumoral areas (P = .0001). Peritumoral mean LVD was significantly higher in cases with lymphovascular invasion (P = .041) and in cases with positive lymph node metastasis (P = .003) than intratumoral mean LVD. High claudin-4 expression was significantly correlated with high tumor grade (P = .0001), lymphovascular invasion (P = .006), and positive lymph node metastasis (P = .004). High claudin-4 expression was significantly associated with increased mean LVD in peritumoral tissues. Conclusion Increased peritumoral mean LVD in prostatic adenocarcinoma is associated with lymphovascular invasion and positive lymph node metastasis. High claudin-4 expression is associated with high tumor grade, lymphocascular invasion, positive lymph node metastasis, and high mean peritumoral LVD suggesting that D2-40 and claudin-4 may represent different mechanisms of lymphatic vessel invasion with both biomarkers is related to poor prognosis. PMID:26464161

  12. Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity.

    PubMed

    Savetsky, Ira L; Albano, Nicholas J; Cuzzone, Daniel A; Gardenier, Jason C; Torrisi, Jeremy S; García Nores, Gabriela D; Nitti, Matthew D; Hespe, Geoffrey E; Nelson, Tyler S; Kataru, Raghu P; Dixon, J Brandon; Mehrara, Babak J

    2015-11-01

    Obesity is a major risk factor for inflammatory dermatologic diseases, including atopic dermatitis and psoriasis. In addition, recent studies have shown that obesity impairs lymphatic function. As the lymphatic system is a critical regulator of inflammatory reactions, we tested the hypothesis that obesity-induced lymphatic dysfunction is a key regulator of cutaneous hypersensitivity reactions in obese mice. We found that obese mice have impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity. In addition, obese mice displayed heightened dermatitis responses to inflammatory skin stimuli, resulting in both higher peak inflammation and a delayed clearance of inflammatory responses. Injection of recombinant vascular endothelial growth factor-C remarkably increased lymphangiogenesis, lymphatic function, and lymphatic endothelial cell expression of chemokine (C-C motif) ligand 21, while decreasing inflammation and expression of inducible nitrous oxide synthase. These changes resulted in considerably decreased dermatitis responses in both lean and obese mice. Taken together, our findings suggest that obesity-induced changes in the lymphatic system result in an amplified and a prolonged inflammatory response. PMID:26176761

  13. 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.

  14. 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

  15. 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 ...

  16. 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 Kurklinsky AK, Rooke TW. ...

  17. 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.

  18. Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics

    PubMed Central

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

    2014-01-01

    Objective This study investigated the roles of the H1 and H2 histamine receptors, nitric oxide (NO) synthase, and soluble guanylate (sGC) cyclase in histamine-induced modulation of rat mesenteric collecting lymphatic pumping. Methods Isolated rat mesenteric collecting lymphatics were treated with 1–100 μM histamine. Histamine receptors were blocked with either the H1 antagonist mepyramine or the H2 antagonist cimetidine. The role of NO/sGC signaling was tested using the arginine analog L-NAME, the sGC inhibitor ODQ, and sodium nitroprusside (SNP) as a positive control. Results Histamine applied at 100 μM decreased tone and contraction frequency (CF) of isolated rat mesenteric collecting lymphatics. Pharmacologic blockade of either H1 or H2 histamine receptors significantly inhibited the response to histamine. Pretreatment with ODQ, but not L-NAME, completely inhibited the histamine-induced decrease in tone. ODQ pretreatment also significantly inhibited SNP-induced lymphatic relaxation. Conclusions H1 and H2 histamine receptors are both involved in histamine-induced relaxation of rat mesenteric collecting lymphatics. NO synthesis does not appear to contribute to the histamine-induced response. However, sGC is critical for the histamine-induced decrease in tone and contributes to the drop in CF. PMID:24702851

  19. 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. PMID:26822093

  20. Development of the lymphatic system: new questions and paradigms.

    PubMed

    Semo, Jonathan; Nicenboim, Julian; Yaniv, Karina

    2016-03-15

    The lymphatic system is a blind-ended network of vessels that plays important roles in mediating tissue fluid homeostasis, intestinal lipid absorption and the immune response. A profound understanding of the development of lymphatic vessels, as well as of the molecular cues governing their formation and morphogenesis, might prove essential for our ability to treat lymphatic-related diseases. The embryonic origins of lymphatic vessels have been debated for over a century, with a model claiming a venous origin for the lymphatic endothelium being predominant. However, recent studies have provided new insights into the origins of lymphatic vessels. Here, we review the molecular mechanisms controlling lymphatic specification and sprouting, and we discuss exciting findings that shed new light on previously uncharacterized sources of lymphatic endothelial cells. PMID:26980792

  1. Aberrant Lymphatic Endothelial Progenitors in Lymphatic Malformation Development

    PubMed Central

    Wu, June K.; Kitajewski, Christopher; Reiley, Maia; Keung, Connie H.; Monteagudo, Julie; Andrews, John P.; Liou, Peter; Thirumoorthi, Arul; Wong, Alvin

    2015-01-01

    Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs. PMID:25719418

  2. Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis.

    PubMed

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

    2016-03-01

    Postnatal 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

  3. 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

  4. 78 FR 77430 - Proposed Information Collection; Comment Request; Foreign Fishing Vessel Permits, Vessel, and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-23

    ... Fishing Vessel Permits, Vessel, and Gear Identification, and Reporting Requirements AGENCY: National....C. 1801 et seq.; MSA), to foreign fishing vessels fishing or operating in U.S. waters. MSA and associated regulations at 50 CFR Part 600 requires applications for the permits, vessels and certain gear...

  5. 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

  6. [Lymphatic endothelium in certain conditions].

    PubMed

    Nimaev, V V; Liubasrskiĭ, M S; Shevela, A I

    2013-01-01

    Presented herein is a review of the literature data concerning the structural and functional peculiarities of the endothelium of the lymphatic and blood vessels. The authors consider the current state of the art of the problem regarding dysfunction of lymphatic endothelium dysfunctions developing in various diseases, as well as in the process of ontogenesis, pointing out an important role of impaired processes of lymphangiogenesis, underlying the development of diseases of the lymphatic system. The authors also assess administration of quercetine in treatment for chronic venous insufficiency, followed by suggesting a possible mechanism of its positive action consisting ina decrease in the oedema at early stages of lymphoedema. PMID:23901429

  7. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation

    PubMed Central

    Boscolo, Elisa; Coma, Silvia; Luks, Valerie L.; Greene, Arin; Klagsbrun, Michael; Warman, Matthew L.; Bischoff, Joyce

    2014-01-01

    Lymphatic malformations (LM) are characterized by abnormal formation of lymphatic vessels and tissue overgrowth. The lymphatic vessels present in LM lesions may become blocked and enlarged as lymphatic fluid collects, forming a mass or cyst. Lesions are typically diagnosed during childhood, and are often disfiguring and life threatening. Available treatments consist of sclerotherapy, surgical removal and therapies to diminish complications. We isolated lymphatic endothelial cells (LM-LEC) from a surgically removed microcystic LM lesion. LM-LEC and normal human dermal-LEC (HD-LEC) expressed endothelial (CD31, VE-Cadherin) as well as lymphatic endothelial (Podoplanin, PROX1, LYVE1)-specific markers. Targeted gene sequencing analysis in patient-derived LM-LEC revealed the presence of two mutations in class I phosphoinositide 3-kinases (PI3K) genes. One is an inherited, premature stop codon in the PI3K regulatory subunit PIK3R3. The second is a somatic missense mutation in the PI3K catalytic subunit PIK3CA; this mutation has been found in association with overgrowth syndromes and cancer growth. LM-LEC exhibited angiogenic properties: both cellular proliferation and sprouting in collagen were significantly increased compared to HD-LEC. AKT-Thr308 was constitutively hyper-phosphorylated in LM-LEC. Treatment of LM-LEC with PI3-Kinase inhibitors Wortmannin and LY294 decreased cellular proliferation and prevented the phosphorylation of AKT-Thr308 in both HD-LEC and LM-LEC. Treatment with the mTOR inhibitor rapamycin also diminished cellular proliferation, sprouting and AKT phosphorylation, but only in LM-LEC. Our results implicate disrupted PI3K-AKT signaling in LEC isolated from a human lymphatic malformation lesion. PMID:25424831

  8. 76 FR 65206 - Agency Information Collection Activities: Small Vessel Reporting System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-20

    ... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Small Vessel... Vessel Reporting System (SVRS). This request for comment is being made pursuant to the Paperwork... concerning the following information collection: Title: Small Vessel Reporting System. OMB Number: Will...

  9. 76 FR 39114 - Agency Information Collection Activities: Vessel Entrance or Clearance Statement

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-05

    ... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Vessel Entrance or... concerning the Vessel Entrance or Clearance Statement (CBP Form 1300). This request for comment is being made... document CBP is soliciting comments concerning the following information collection: Title: Vessel...

  10. 33 CFR 187.105 - What information on titled vessels must be collected and what may be collected?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false What information on titled vessels must be collected and what may be collected? 187.105 Section 187.105 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY VESSEL IDENTIFICATION SYSTEM Information to be Collected by...

  11. 33 CFR 187.105 - What information on titled vessels must be collected and what may be collected?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false What information on titled vessels must be collected and what may be collected? 187.105 Section 187.105 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY VESSEL IDENTIFICATION SYSTEM Information to be Collected by...

  12. [Lymphoscintigraphic exploration in the limbs lymphatic disease].

    PubMed

    Baulieu, Françoise; Lorette, Gérard; Baulieu, Jean-Louis; Vaillant, Loïc

    2010-12-01

    Lymphoscintigraphy is based upon the physiological transport of small radioactive particles injected into interstitium toward lymphatic vessels and nodes. Lymphoscintigraphy directly investigates lymphatic system while other methods (ultrasounds, CT, MRI) investigate tissular consequences of lymphatic disease. The scintigraphic procedure has to be standardized in order to be reproducible. Lymphatic vessels, lymphatic nodes and interstitium are systematically analysed. Interpretation is visual and qualitative. Multiple abnormalities can be observed. However, none of them can consistently differentiate between primary and secondary lymphedema. Differential diagnosis is usually obtained by taking together clinical and lymphoscintigraphic data. By providing informations about lymphatic component and physiopathology of edema, lymphoscintigraphy contributes to the management of lymphedema. Hybrid imaging is a new imaging modality of edema. Recently used, it combines functional (scintigraphy) and anatomical (CT) data and seems to be able to provide further informations. PMID:20863652

  13. Lymphatic Filariasis

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Parasites - Lymphatic Filariasis Note: Javascript is disabled or is ... this? Submit Button Information For: Travelers Related Links Parasites A-Z Index Parasites Glossary Neglected Tropical Diseases ...

  14. Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging

    PubMed Central

    Nelson, Tyler S.; Akin, Ryan E.; Weiler, Michael J.; Kassis, Timothy; Kornuta, Jeffrey A.

    2014-01-01

    The ability to quantify collecting vessel function in a minimally invasive fashion is crucial to the study of lymphatic physiology and the role of lymphatic pump function in disease progression. Therefore, we developed a highly sensitive, minimally invasive research platform for quantifying the pumping capacity of collecting lymphatic vessels in the rodent tail and forelimb. To achieve this, we have integrated a near-infrared lymphatic imaging system with a feedback-controlled pressure cuff to modulate lymph flow. After occluding lymphatic flow by inflating a pressure cuff on the limb or tail, we gradually deflate the cuff while imaging flow restoration proximal to the cuff. Using prescribed pressure applications and automated image processing of fluorescence intensity levels in the vessels, we were able to noninvasively quantify the effective pumping pressure (Peff, pressure at which flow is restored after occlusion) and vessel emptying rate (rate of fluorescence clearance during flow occlusion) of lymphatics in the rat. To demonstrate the sensitivity of this system to changes in lymphatic function, a nitric oxide (NO) donor cream, glyceryl trinitrate ointment (GTNO), was applied to the tails. GTNO decreased Peff of the vessels by nearly 50% and the average emptying rate by more than 60%. We also demonstrate the suitability of this approach for acquiring measurements on the rat forelimb. Thus, this novel research platform provides the first minimally invasive measurements of Peff and emptying rate in rodents. This experimental platform holds strong potential for future in vivo studies that seek to evaluate changes in lymphatic health and disease. PMID:24430884

  15. Increased Detection of Lymphatic Vessel Invasion by D2-40 (Podoplanin) in Early Breast Cancer: Possible Influence on Patient Selection for Accelerated Partial Breast Irradiation

    SciTech Connect

    Debald, Manuel; Poelcher, Martin; Flucke, Uta; Walgenbach-Bruenagel, Gisela

    2010-07-15

    Purpose: Several international trials are currently investigating accelerated partial breast irradiation (APBI) for patients with early-stage breast cancer. According to existing guidelines, patients with lymphatic vessel invasion (LVI) do not qualify for APBI. D2-40 (podoplanin) significantly increases the frequency of LVI detection compared with conventional hematoxylin and eosin (HE) staining in early-stage breast cancer. Our purpose was to retrospectively assess the hypothetical change in management from APBI to whole breast radiotherapy with the application of D2-40. Patients and Methods: Immunostaining with D2-40 was performed on 254 invasive breast tumors of 247 patients. The following criteria were used to determine the eligibility for APBI: invasive ductal adenocarcinoma of {<=}3 cm, negative axillary node status (N0), and unifocal disease. Of the 247 patients, 74 with available information concerning LVI, as detected by D2-40 immunostaining and routine HE staining, formed our study population. Results: Using D2-40, our results demonstrated a significantly greater detection rate (p = .031) of LVI compared with routine HE staining. LVI was correctly identified by D2-40 (D2-40-positive LVI) in 10 (13.5%) of 74 tumors. On routine HE staining, 4 tumors (5.4%) were classified as HE-positive LVI. Doublestaining of these specimens with D2-40 unmasked false-positive LVI status in 2 (50%) of the 4 tumors. According to the current recommendations for APBI, immunostaining with D2-40 would have changed the clinical management from APBI to whole breast radiotherapy in 8 (10.8%) of 74 patients and from whole breast radiotherapy to APBI in 2 patients (2.7%). Conclusion: These data support the implementation of D2-40 immunostaining in the routine workup to determine a patient's eligibility for APBI.

  16. 76 FR 12339 - Proposed Information Collection; Comment Request; Southwest Region Vessel Identification...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-07

    ... Region Vessel Identification Requirements AGENCY: National Oceanic and Atmospheric Administration (NOAA... renewal of a current information collection. Regulations at 50 CFR 660.704 require that all vessels with... United States (U.S.) West Coast Highly Migratory Species Fisheries display the vessel's official...

  17. 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

  18. The Lymphatic System in Disease Processes and Cancer Progression.

    PubMed

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

    2016-07-11

    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

  19. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life.

    PubMed

    Hess, Paul R; Rawnsley, David R; Jakus, Zoltán; Yang, Yiqing; Sweet, Daniel T; Fu, Jianxin; Herzog, Brett; Lu, MinMin; Nieswandt, Bernhard; Oliver, Guillermo; Makinen, Taija; Xia, Lijun; Kahn, Mark L

    2014-01-01

    Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life. PMID:24292710

  20. 33 CFR 187.103 - What information must be collected to identify a vessel?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false What information must be collected to identify a vessel? 187.103 Section 187.103 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY VESSEL IDENTIFICATION SYSTEM Information to be Collected by Participating States § 187.103...

  1. 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

  2. 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. PMID:23640588

  3. 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. PMID:27088921

  4. 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

  5. 76 FR 82314 - Agency Information Collection Activities: Small Vessel Reporting System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-30

    ... published in the Federal Register (76 FR 65206) on October 20, 2011, allowing for a 60- day comment period... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Small Vessel... accordance with the Paperwork Reduction Act: the Small Vessel Reporting System (SVRS). CBP is proposing...

  6. 75 FR 3245 - Agency Information Collection Activities: Aircraft/Vessel Report (Form I-92)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-20

    ... published in the Federal Register (74 FR 54839) on October 23, 2009, allowing for a 60-day comment period... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Aircraft/Vessel... approval in accordance with the Paperwork Reduction Act: Aircraft/ Vessel Report (Form I-92). This is...

  7. VEGF Pathways in the Lymphatics of Healthy and Diseased Heart.

    PubMed

    Dashkevich, Alexey; Hagl, Christian; Beyersdorf, Friedhelm; Nykänen, Antti I; Lemström, Karl B

    2016-01-01

    Cardiac lymphatic system is a rare focus of the modern cardiovascular research. Nevertheless, the growing body of evidence is depicting lymphatic endothelium as an important functional unit in healthy and diseased myocardium. Since the discovery of angiogenic VEGF-A in 1983 and lymphangiogenic VEGF-C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. Tissue adaptation to several stimuli such as hypoxia, pathogen invasion, degenerative process and inflammation often involves coordinated changes in both blood and lymphatic vessels. As lymphatic vessels are involved in the initiation and resolution of inflammation and regulation of tissue edema, VEGF family members may have important roles in myocardial lymphatics in healthy and in cardiac disease. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel effects first in normal myocardium and then in cardiac disease. PMID:26190445

  8. 78 FR 58286 - Proposed Information Collection; Comment Request; Western Region Vessel Monitoring System and Pre...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-23

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE National Oceanic and Atmospheric Administration Proposed Information Collection; Comment Request; Western Region Vessel Monitoring System and Pre-Trip Reporting Requirements AGENCY: National Oceanic...

  9. Lymphatic endothelial regulation, lymphoedema, and lymph node metastasis.

    PubMed

    Karkkainen, Marika J; Alitalo, Kari

    2002-02-01

    Vascular endothelial growth factor receptor-3 (VEGFR-3) mediates lymphatic endothelial cell (LEC) growth, migration, and survival by binding VEGF-C and VEGF-D. Recent studies have revealed new regulators of the lymphatic endothelium, such as the transcription factor Prox1, and the cell surface proteins podoplanin and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). Furthermore, the isolation of LECs now allows detailed molecular studies of the factors regulating the lymphatic vasculature. These studies are aimed at targeting the lymphatic vasculature in the treatment of various diseases, such as tumour metastasis and lymphoedema. PMID:11969367

  10. Improved computer-assisted analysis of the global lymphatic network in human cervical tissues.

    PubMed

    Balsat, Cédric; Signolle, Nicolas; Goffin, Frédéric; Delbecque, Katty; Plancoulaine, Benoit; Sauthier, Philippe; Samouëlian, Vanessa; Béliard, Aude; Munaut, Carine; Foidart, Jean-Michel; Blacher, Silvia; Noël, Agnès; Kridelka, Frédéric

    2014-06-01

    Lymphatic dissemination is a key event in cervical cancer progression and related tumor lymphatic markers are viewed as promising prognostic factor of nodal extension. However, validating such parameters requires an objective characterization of the lymphatic vasculature. Here, we performed a global analysis of the lymphatic network using a new computerized method applied on whole uterine cervical digital images. Sixty-eight cases of cervical neoplasia (12 CIN3, 10 FIGO stage 1A and 46 stage IB1) and 10 cases of normal cervical tissue were reacted with antibodies raised against D2-40, D2-40/p16 and D2-40/Ki67. Immunostained structures were automatically detected on whole slides. The lymphatic vessel density (D2-40), proliferating lymphatic vessel density (D2-40/ki67) and spatial lymphatic distribution in respect to the adjacent epithelium were assessed from normal cervix to early cervical cancer and correlated with lymphovascular space invasion and lymph node status. Prominent lymphatic vessel density and proliferating lymphatic vessel density are detected under the transformation zone of benign cervix and no further increase is noted during cancer progression. Notably, a shift of lymphatic vessel distribution toward the neoplastic edges is detected. In IB1 cervical cancer, although intra- and peritumoral lymphatic vessel density are neither correlated with lymphovascular space invasion nor with lymph node metastasis, a specific spatial distribution with more lymphatic vessels in the vicinity of tumor edges is predictive of lymphatic dissemination. Herein, we provide a new computerized method suitable for an innovative detailed analysis of the lymphatic network. We show that the transformation zone of the benign cervix acts as a baseline lymphangiogenic niche before the initiation of neoplastic process. During cancer progression, this specific microenvironment is maintained with lymphatic vessels even in closer vicinity to tumor cells. PMID:24309324

  11. 76 FR 59711 - Agency Information Collection Activities; Vessel Entrance or Clearance Statement

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-27

    ... information collection was previously published in the Federal Register (76 FR 39114) on July 5, 2011... SECURITY U.S. Customs And Border Protection Agency Information Collection Activities; Vessel Entrance or Clearance Statement AGENCY: U.S. Customs and Border Protection, Department of Homeland Security. ACTION:...

  12. 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

  13. 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. PMID:27357637

  14. 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

  15. Hepatic lymphatics: anatomy and related diseases.

    PubMed

    Pupulim, Lawrence F; Vilgrain, Valérie; Ronot, Maxime; Becker, Christoph D; Breguet, Romain; Terraz, Sylvain

    2015-08-01

    The liver normally produces a large amount of lymph. It is estimated that between 25% and 50% of the lymph received by the thoracic duct comes from the liver. In normal conditions, hepatic lymphatics are not depicted on cross-sectional imaging. They are divided in lymphatics of deep system (lymphatics following the hepatic veins and the portal tract) and those of superficial system (convex surface and inferior surface). A variety of diseases may affect hepatic lymphatics and in general they manifest as lymphedema, lymphatic mass, or cystic lesions. Abnormal distended lymphatics are especially seen in periportal spaces as linear hypoattenuations on CT or strong linear hyperintensities on heavily T2-weighted MR imaging. Lymphatic tumor spread as in lymphoma and lymphangitic carcinomatosis manifests as periportal masses and regional lymph node enlargement. Lymphatic disruption after trauma or surgery is depicted as perihepatic fluid collections of lymph (lymphocele). Lymphatic malformation such as lymphangioma is seen on imaging as cystic spaces of variable size. PMID:25579171

  16. Tissue contribution to the mechanical features of diaphragmatic initial lymphatics

    PubMed Central

    Moriondo, Andrea; Boschetti, Federica; Bianchin, Francesca; Lattanzio, Simone; Marcozzi, Cristiana; Negrini, Daniela

    2010-01-01

    The role of the mechanical properties of the initial lymphatic wall and of the surrounding tissue in supporting lymph formation and/or progression was studied in six anaesthetized, neuromuscularly blocked and mechanically ventilated rats. After mid-sternal thoracotomy, submesothelial initial lymphatics were identified on the pleural diaphragmatic surface through stereomicroscopy. An ‘in vivo’ lymphatic segment was prepared by securing two surgical threads around the vessel at a distance of ∼2.5 mm leaving the vessel in place. Two glass micropipettes were inserted into the lumen, one for intraluminar injections of 4.6 nl saline boluses and one for hydraulic pressure (Plymph) recording. The compliance of the vessel wall (Clymph) was calculated as the slope of the plot describing the change in segment volume as a function of the post-injection Plymph changes. Two superficial lymphatic vessel populations with a significantly different Clymph (6.7 ± 1.6 and 1.5 ± 0.4 nl mmHg−1 (mean ± s.e.m.), P < 0.001) were identified. In seven additional rats, the average elastic modulus of diaphragmatic tissue strips was determined by uniaxial tension tests to be 1.7 ± 0.3 MPa. Clymph calculated for an initial lymphatic completely surrounded by isotropic tissue was 0.068 nl mmHg−1, i.e. two orders of magnitude lower than in submesothelial lymphatics. Modelling of stress distribution in the lymphatic wall suggests that compliant vessels may act as reservoirs accommodating large absorbed fluid volumes, while lymphatics with stiffer walls serve to propel fluid through the lumen of the lymphatic vessel by taking advantage of the more efficient mechanical transmission of tissue stresses to the lymphatic lumen. PMID:20724369

  17. Retrograde Lymphatic Spread of Esophageal Cancer

    PubMed Central

    Oshiro, Hisashi; Osaka, Yoshiaki; Tachibana, Shingo; Aoki, Takaya; Tsuchiya, Takayoshi; Nagao, Toshitaka

    2015-01-01

    Abstract The concept of the retrograde lymphatic spread of cancer cells appears to account for a subset of the essential mechanisms of cancer metastasis in various organs. However, no adequate data currently exist to illustrate the pathology of the retrograde lymphatic metastasis of cancer cells in human bodies. To shed light on this phenomenon, we report a case of a 63-year-old Japanese man who underwent an esophagectomy and lymph node dissection for early-stage esophageal cancer. The patient's clinical information was evaluated by board-certified surgeons and internists. Surgically excised materials were histopathologically evaluated by attending pathologists. Postoperative pathological examination revealed that the patient's tumor was a well-differentiated squamous cell carcinoma with negative surgical margins (T1N0M0, stage I). Apart from the primary lesion, a single lymphatic vessel invasion was found between the lamina propria and lamina muscularis of the esophagus where intralymphatic cancer cells had spread against the direction of backflow prevention valves and skipped beyond these valves without destroying them. The present case demonstrated that the retrograde lymphatic spread of cancer cells can occur in valve-equipped lymphatic vessels. Our study may not only provide a scientific basis for the concept of retrograde lymphatic metastasis but also explain a portion of the complexities associated with the lymphogenous metastasis of esophageal cancer. PMID:26166121

  18. The lymphatic system. Some surgical considerations.

    PubMed

    Glenn, W W

    1981-08-01

    This article on the lymphatics was undertaken for three reasons: The first is to recount the story of the rediscovery of these vessels in the 17th century and briefly review the subsequent events leading up to our present knowledge of the lymphatic system. The second is to emphasize the role of the lymphatics in maintaining extracellular fluid balance, in the removal of protein, fat, and other substances of large molecular size from the tissue spaces, and in the circulation of the lymphocytes from their germinal centers and storage depots to all parts of the body via lymphaticovenous connections. The third reason is to suggest that the responsibility for maintaining the transport function of the lymphatics properly belongs to the vascular surgeon. PMID:7020649

  19. 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

  20. 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.

  1. Patterns of lymphatic drainage from the skin in patients with melanoma.

    PubMed

    Uren, Roger F; Howman-Giles, Robert; Thompson, John F

    2003-04-01

    An essential prerequisite for a successful sentinel lymph node biopsy (SLNB) procedure is an accurate map of the pattern of lymphatic drainage from the primary tumor site in each patient. In melanoma patients, mapping requires high-quality lymphoscintigraphy, which can identify the actual lymphatic collecting vessels as they drain into the sentinel lymph nodes. Small-particle radiocolloids are needed to achieve this goal, and imaging protocols must be adapted to ensure that all true sentinel nodes, including those in unexpected locations, are found in every patient. Clinical prediction of lymphatic drainage from the skin is not possible. The old clinical guidelines based on Sappey's lines therefore should be abandoned. Patterns of lymphatic drainage from the skin are highly variable from patient to patient, even from the same area of the skin. Unexpected lymphatic drainage from the skin of the back to sentinel nodes in the triangular intermuscular space and, in some patients, through the posterior body wall to sentinel nodes in the para-aortic, paravertebral, and retroperitoneal areas has been found. Lymphatic drainage from the head and neck frequently involves sentinel nodes in multiple node fields and can occur from the base of the neck up to nodes in the occipital or upper cervical areas or from the scalp down to nodes at the neck base, bypassing many node groups. The sentinel node is not always found in the nearest node field and is best defined as "any lymph node receiving direct lymphatic drainage from a primary tumor site." Lymphatic drainage can occur from the upper limb to sentinel nodes above the axilla. Drainage to the epitrochlear region from the hand and arm as well as to the popliteal region from the foot and leg is more common than was previously thought. Interval nodes, which lie along the course of a lymphatic vessel between a lesion site and a recognized node field, are not uncommon, especially in the trunk. Drainage across the midline of the body

  2. 78 FR 64523 - Agency Information Collection Activities: Vessel Entrance or Clearance Statement

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-29

    ... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Vessel Entrance or Clearance Statement AGENCY: U.S. Customs and Border Protection (CBP), Department of Homeland Security... comments to U.S. Customs and Border Protection, Attn: Tracey Denning, Regulations and Rulings, Office...

  3. 78 FR 77139 - Agency Information Collection Activities: Small Vessel Reporting System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

    ... published in the Federal Register (78 FR 61378) on October 3, 2013, allowing for a 60-day comment ] period... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Small Vessel Reporting System AGENCY: U.S. Customs and Border Protection, Department of Homeland Security. ACTION:...

  4. 78 FR 61378 - Agency Information Collection Activities: Small Vessel Reporting System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-03

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF HOMELAND SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Small Vessel Reporting System AGENCY: U.S. Customs and Border Protection, Department of Homeland Security. ACTION:...

  5. 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. PMID:26443964

  6. Pkd1 regulates lymphatic vascular morphogenesis during development

    PubMed Central

    Coxam, Baptiste; Sabine, Amélie; Bower, Neil I.; Smith, Kelly A.; Pichol-Thievend, Cathy; Skoczylas, Renae; Astin, Jonathan W.; Frampton, Emmanuelle; Jaquet, Muriel; Crosier, Philip S.; Parton, Robert G.; Harvey, Natasha L.; Petrova, Tatiana V.; Schulte-Merker, Stefan; Francois, Mathias; Hogan, Benjamin M.

    2016-01-01

    Lymphatic vessels arise during development through sprouting of precursor cells from veins, which is regulated by well-studied signaling and transcriptional mechanisms. Less well understood is the ongoing elaboration of vessels to form a network. This involves cell polarisation, coordinated migration, adhesion, mixing, regression and cell shape rearrangements. We identified a zebrafish mutant, lymphatic and cardiac defects 1 (lyc1), with reduced lymphatic vessel development. We found a mutation in polycystic kidney disease 1a to be responsible for the phenotype. PKD1 is the most frequently mutated gene in autosomal dominant polycystic kidney disease (ADPKD). Initial sprouting of lymphatic precursors is normal in lyc1 mutants, but ongoing migration fails. Loss of Pkd1 in mice also has no effect on sprouting of precursors but leads to failed morphogenesis of the subcutaneous lymphatic network. Individual lymphatic endothelial cells display defective polarity, elongation and adherens junctions. This work identifies a highly selective and unexpected role for Pkd1 in lymphatic vessel morphogenesis during development. PMID:24767999

  7. Platelets: covert regulators of lymphatic development.

    PubMed

    Bertozzi, Cara C; Hess, Paul R; Kahn, Mark L

    2010-12-01

    The field of platelet biology has rapidly expanded beyond the classical role of platelets in preventing blood loss and orchestrating clot formation. Despite the lack of transcriptional ability of these anuclear cell fragments, platelet function is now thought to encompass such diverse contexts as tissue repair, immune activation, primary tumor formation, and metastasis. Recent studies from multiple groups have turned the spotlight on an exciting new role for platelets in the formation of lymphatic vessels during embryonic development. Genetic experiments demonstrate that podoplanin, a transmembrane protein expressed on lymphatic endothelial cells, engages the platelet C-type lectin-like receptor 2 (CLEC-2) when exposed to blood, leading to SYK-SLP-76-dependent platelet activation. When components of this pathway are disrupted, aberrant vascular connections form, resulting in blood-lymphatic mixing. Furthermore, platelet-null embryos manifest identical blood-lymphatic mixing. The identification of platelets as the critical cell type mediating blood-lymphatic vascular separation raises new questions in our understanding of lymphatic development and platelet biology. PMID:21071706

  8. Lymphatic endothelial differentiation in pulmonary lymphangioleiomyomatosis cells.

    PubMed

    Davis, Jennifer M; Hyjek, Elizabeth; Husain, Aliya N; Shen, Le; Jones, Jennifer; Schuger, Lucia A

    2013-08-01

    Pulmonary lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm affecting almost exclusively women of childbearing age. LAM belongs to the family of perivascular epithelioid cell tumors, characterized by spindle and epithelioid cells with smooth muscle and melanocytic differentiation. LAM cells infiltrate the lungs, producing multiple, bilateral lesions rich in lymphatic channels and forming cysts, leading to respiratory insufficiency. Here we used antibodies against four lymphatic endothelial markers-podoplanin (detected by D2-40), prospero homeobox 1 (PROX1), vascular endothelial growth factor receptor 3 (VEGFR-3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1)-to determine whether LAM cells show lymphatic differentiation. Twelve of 12 diagnostic biopsy specimens (early-stage LAM) and 19 of 19 explants (late-stage LAM) showed immunopositivity for D2-40 in most neoplastic cells. PROX1, VEGFR-3, and LYVE1 immunoreactivity varied from scarce in the early stage to abundant in the late stage. Lymphatic endothelial, smooth muscle, and melanocytic markers were partially co-localized. These findings indicate that lymphatic endothelial differentiation is a feature of LAM and provide evidence of a previously unidentified third lineage of differentiation in this neoplasm. This study has implications for the histological diagnosis of LAM, the origin of the neoplastic cells, and potential future treatment with drugs targeting lymphangiogenesis. PMID:23609227

  9. 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. PMID:23643778

  10. Quantitative imaging of lymphatic function with liposomal indocyanine green.

    PubMed

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

    2010-09-15

    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 toward 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-IR 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, whereas a decreased flow pattern was seen in mice with a higher lymph node tumor burden. This new method will likely facilitate quantitative studies of lymphatic function in preclinical investigations and may also have potential for imaging of lymphedema or improved sentinel lymph detection in cancer. PMID:20823159

  11. Lymphatic disorders after renal transplantation: new insights for an old complication

    PubMed Central

    Ranghino, Andrea; Segoloni, Giuseppe Paolo; Lasaponara, Fedele; Biancone, Luigi

    2015-01-01

    In renal transplanted patients, lymphoceles and lymphorrhea are well-known lymphatic complications. Surgical damage of the lymphatics of the graft during the procurement and of the lymphatic around the iliac vessels of the recipients has been associated with development of lymphatic complications. However, lymphatic complications may be related to medical factors such as diabetes, obesity, blood coagulation abnormalities, anticoagulation prophylaxis, high dose of diuretics, delay in graft function and immunosuppressive drugs. Consistently, immunosuppression regimens based on the use of mTOR inhibitors, especially in association with steroids and immediately after transplantation, has been associated with a high risk to develop lymphocele or lymphorrhea. In addition, several studies have demonstrated the association between rejection episodes and lymphatic complications. However, before the discovery of reliable markers of lymphatic vessels, the pathogenic mechanisms underlining the development of lymphatic complications during rejection and the influence of mTOR inhibitors remained not fully understood. The recent findings on the lymphatic systems of either native or transplanted kidneys together with the advances achieved on lymphangiogenesis shared some lights on the pathogenesis of lymphatic complications after renal transplantation. In this review, we describe the surgical and medical causes of lymphatic complications focusing on the rejection and immunosuppressive drugs as causes of lymphatic complications. PMID:26413290

  12. 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.

  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. MDA—Lymphatic Filariasis

    PubMed Central

    2014-01-01

    Lymphatic filariasis is one of the neglected tropical diseases. It is estimated that 120 million people are currently infected in 73 countries where filariasis is endemic. Lymphatic filariasis is a leading cause of chronic disability worldwide, including of 15 million people who have lymphoedema (elephantiasis) and 25 million men who have hydrocoele. PMID:25425947

  15. Electric current-induced lymphatic activation.

    PubMed

    Kajiya, Kentaro; Matsumoto-Okazaki, Yuko; Sawane, Mika; Fukada, Kaedeko; Takasugi, Yuya; Akai, Tomonori; Saito, Naoki; Mori, Yuichiro

    2014-12-01

    The lymphatic system in skin plays important roles in drainage of wastes and in the afferent phase of immune response. We previously showed that activation of vascular endothelial growth factor receptor (VEGFR), specifically the VEGFC/VEGFR-3 pathway, attenuates oedema and inflammation by promoting lymphangiogenesis, suggesting a protective role of lymphatic vessels against skin inflammation. However, it remains unknown how physical stimuli promote lymphatic function. Here, we show that lymphatic endothelial cells (LECs) are activated by direct-current (DC) electrical stimulation, which induced extension of actin filaments of LECs, increased calcium influx into LECs, and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK). An inhibitor of focal adhesion kinase, which plays a role in cellular adhesion and motility, diminished the DC-induced extension of F-actin and abrogated p38 phosphorylation. Time-lapse imaging revealed that pulsed-DC stimulation promoted proliferation and migration of LECs. Overall, these results indicate that electro-stimulation activates lymphatic function by activating p38 MAPK. PMID:25308203

  16. 76 FR 52317 - Proposed Information Collection; Comment Request; Northwest Region Vessel Identification...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-22

    ... Region Vessel Identification Requirements AGENCY: National Oceanic and Atmospheric Administration (NOAA... depends significantly on regulatory compliance. The vessel identification requirement is essential to facilitate enforcement. The ability to link fishing or other activity to the vessel owner or operator...

  17. 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.

  18. Lymph transport in rat mesenteric lymphatics experiencing edemagenic stress

    PubMed Central

    Rahbar, Elaheh; Akl, Tony; Coté, Gerard L.; Moore, James E.; Zawieja, David C.

    2014-01-01

    Objective To assess lymphatic flow adaptations to edema, we evaluated lymph transport function in rat mesenteric lymphatics under normal and edemagenic conditions in situ. Methods Twelve rats were infused with saline (intravenous infusion, 0.2 ml/min/100g body weight) to induce edema. We intravitally measured mesenteric lymphatic diameter and contraction frequency, as well as immune cell velocity and density before, during and after infusion. Results A 10-fold increase in lymph velocity (0.1–1 mm/s) and a 6-fold increase in flow rate (0.1–0.6 μL/min), were observed post-infusion, respectively. There were also increases in contraction frequency and fractional pump flow 1-minute post-infusion. Time-averaged wall shear stress increased 10 fold post-infusion to nearly 1.5 dynes/cm2. Similarly, maximum shear stress rose from 5 dynes/cm2 to 40 dynes/cm2. Conclusions Lymphatic vessels adapted to edemagenic stress by increasing lymph transport. Specifically, the increases in lymphatic contraction frequency, lymph velocity, and shear stress were significant. Lymph pumping increased post-infusion, though changes in lymphatic diameter were not statistically significant. These results indicate that edemagenic conditions stimulate lymph transport via increases in lymphatic contraction frequency, lymph velocity and flow. These changes, consequently, resulted in large increases in wall shear stress, which could then activate NO pathways and modulate lymphatic transport function. PMID:24397756

  19. Lymphatic Invasion as a Prognostic Biomarker in Primary Cutaneous Melanoma

    PubMed Central

    Xu, Xiaowei; Gimotty, Phyllis A.; Guerry, DuPont; Karakousis, Giorgos; Elder, David E.

    2016-01-01

    Melanoma has a propensity for lymph node metastasis. However, the incidence of lymphatic invasion detected by histology alone in primary melanoma is disproportionately low in comparison to the incidence of positive sentinel lymph nodes (SLN). With the discovery of lymphatic endothelial cell markers, such as podoplanin and LYVE-1, lymphatic vessels can be reliably detected in formalin-fixed paraffin-embedded (FFPE) tissues. There is a now consensus that lymphatic invasion detected by immunohistochemical stains in primary melanoma is much more common than previously reported by histological examination alone. Immunohistochemical stains show that lymphangiogenesis and lymphatic invasion in primary melanoma may occur intratumorally or peritumorally, and lymphatic invasion is common across the range of tumor thicknesses in primary vertical growth phase (VGP) melanomas. A number of studies have shown that lymphatic invasion in primary melanoma is associated with a positive sentinel lymph node biopsy and a worse clinical outcome. Although not currently a part of the standard of care for staging of melanoma, the detection of lymphatic invasion in primary melanoma using immunohistochemical markers may be helpful in planning of therapy in some cases and may find a routine role in primary melanoma microscopic attributes in future. PMID:24258984

  20. 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

  1. 76 FR 54738 - Proposed Information Collection; Comment Request; Atlantic Highly Migratory Species Vessel and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-02

    ... Highly Migratory Species Vessel and Gear Marking AGENCY: National Oceanic and Atmospheric Administration... their vessels. Flotation devices and high- flyers attached to certain fishing gears must also be marked with the vessel's number to identify the vessel to which the gear belongs. These requirements...

  2. Semaphorin3A, Neuropilin-1, and PlexinA1 Are Required for Lymphatic Valve Formation

    PubMed Central

    Bouvrée, Karine; Brunet, Isabelle; del Toro, Raquel; Gordon, Emma; Prahst, Claudia; Cristofaro, Brunella; Mathivet, Thomas; Xu, Yunling; Soueid, Jihane; Fortuna, Vitor; Miura, Nayoki; Aigrot, Marie-Stéphane; Maden, Charlotte H.; Ruhrberg, Christiana; Thomas, Jean Léon; Eichmann, Anne

    2013-01-01

    Rationale The lymphatic vasculature plays a major role in fluid homeostasis, absorption of dietary lipids, and immune surveillance. Fluid transport depends on the presence of intraluminal valves within lymphatic collectors. Defective formation of lymphatic valves leads to lymphedema, a progressive and debilitating condition for which curative treatments are currently unavailable. How lymphatic valve formation is regulated remains largely unknown. Objective We investigated if the repulsive axon guidance molecule Semaphorin3A (Sema3A) plays a role in lymphatic valve formation. Methods and Results We show that Sema3A mRNA is expressed in lymphatic vessels and that Sema3A protein binds to lymphatic valves expressing the Neuropilin-1 (Nrp1) and PlexinA1 receptors. Using mouse knockout models, we show that Sema3A is selectively required for lymphatic valve formation, via interaction with Nrp1 and PlexinA1. Sema3a−/− mice exhibit defects in lymphatic valve formation, which are not due to abnormal lymphatic patterning or sprouting, and mice carrying a mutation in the Sema3A binding site of Nrp1, or deficient for Plxna1, develop lymphatic valve defects similar to those seen in Sema3a−/− mice. Conclusions Our data demonstrate an essential direct function of Sema3A-Nrp1-PlexinA1 signaling in lymphatic valve formation. PMID:22723296

  3. Lymphatic complications after vascular interventions

    PubMed Central

    Obara, Andrzej; Maruszynski, Marek; Witkowski, Adam; Dąbrowski, Maciej; Chmielak, Zbigniew

    2014-01-01

    Introduction Lymphorrhea due to classical and mini-invasive surgical interventions on femoral and popliteal arteries is a serious hindrance to patient treatment. Depending on the experience of a particular center, the incidence and frequency of this type of complication may constitute a serious clinical problem. While the level of lymphorrhea intensity and its duration result in certain foreseeable consequences, their treatment can be a time-consuming and multistep procedure. Aim To compare different types of vascular interventions with lymphorrhea occurrence. Material and methods The authors conducted a retrospective analysis of lymphatic complications based on the material collected between 2005 and 2012 at the Department of Vascular and Endovascular Surgery of the Military Institute of Medicine in Warsaw and in the Department of Interventional Cardiology and Angiology of the Institute of Cardiology in Anin, Warsaw, in 2009–2012. Results Maintaining due thoroughness when dissecting tissues and treating the cutting line in this area with ligatures and tissue puncture are the most reliable methods of minimizing the risk of lymphatic leakage after surgical procedures performed in a classical way. The lymphatic complication under analysis is far less likely to occur when procedures are performed as planned and an endovascular technique is used – statistical significance p < 0.05. Minimally invasive and fully percutaneous procedures performed via needle puncture, including the use of the fascial closure technique to close the femoral artery, eliminate the likelihood of the occurrence of this vascular complication – statistical significance was found with p value less than 0.05. Conclusions We concluded that in every case by minimizing the vascular approach we protected the patient against lymphatic complications. PMID:25337168

  4. Lymphatics and the breast

    MedlinePlus Videos and Cool Tools

    ... 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. ...

  5. Preservation of data collected onboard an ocean-going research vessel

    NASA Astrophysics Data System (ADS)

    De Bruin, T.

    2012-12-01

    This presentation focuses on the experiences with managing and preserving the data collected onboard the Dutch ocean-going Research Vessel Pelagia. The Pelagia is the largest RV in the fleet of the Royal Netherlands Institute for Sea Research (NIOZ) and she conducts multidisciplinary research in the Atlantic and Indian Oceans. The Pelagia carries a whole suite of sensors, measuring parameters ranging from ocean depth, sea surface temperature and salinity to wind speed and - direction. These sensors are automatically operated while the ship is underway. The meteorological sensors, for instance, have been obtained from the Royal Netherlands Meteorological Office (KNMI), making the Pelagia the first Dutch VOSCLIM vessel. Calibration and quality assurance of these sensors and underway measurements will be discussed. All observational activities, including automated underway measurements and all deployments of measuring instruments into the sea, are recorded by an event logger system. Much experience was gained with an in-house developed event logger. Two years ago, this system was replaced by a system developed by Ifremer, fitting into an international trend towards improved standardisation and increased efficiency. This international trend is also exemplified by recent developments within the European Eurofleets and the American R2R projects. The experiences with these event logger systems will be presented, as well as a vision of an unified system.

  6. 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

  7. 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. PMID:26009246

  8. Assessment of lymphatic contractile function following manual lymphatic drainage using near-infrared fluorescence imaging

    PubMed Central

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

    2011-01-01

    Objective To investigate the feasibility of assessing the efficacy of manual lymphatic drainage (MLD), a method for lymphedema (LE) management, using near-infrared (NIR) fluorescence imaging. Design Exploratory pilot study. Setting Primary care unit. Intervention Indocyanine green of 25 μg in 0.1 cc each was injected intradermally in bilateral arms or legs of subjects. Diffused excitation light illuminated the limbs and NIR fluorescence images were collected using custom-built imaging systems. The subjects received MLD therapy, and imaging was performed pre- and post- therapy. Participants Ten subjects (age 18 – 68) diagnosed with Grade I or II LE and 12 normal control subjects (age 22 – 59). Main outcome measures Apparent lymph velocities and the periods between lymphatic propulsion events were computed from fluorescence images. The data collected pre- and post- MLD were compared and evaluated for differences. Results By comparing the pre- MLD lymphatic contractile function against post- MLD lymphatic function, our results show that the average apparent lymph velocity increased in both the symptomatic (+23%) and asymptomatic (+25%) limbs of LE subjects and in the control limbs (+28%) of normal subjects. The average lymphatic propulsion period decreased in the symptomatic (−9%) and asymptomatic (−20%) limbs of LE subjects, as well as in the control limbs (−23%). Conclusions We demonstrated that NIR fluorescence imaging could be used to quantify immediate benefits of lymphatic contractile function following MLD. PMID:21530723

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

    PubMed Central

    Escobedo, Noelia; Proulx, Steven T.; Karaman, Sinem; Dillard, Miriam E.; Johnson, Nicole; Detmar, Michael; Oliver, Guillermo

    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

  10. 77 FR 16209 - Proposed Information Collection; Comment Request; Permitting, Vessel Identification, and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-20

    ...; Permitting, Vessel Identification, and Reporting Requirements for the Pelagic Squid Jig Fishery in the... Regulations require that owners of vessels fishing for, or landing, pelagic squid in the western...

  11. 76 FR 22676 - Proposed Information Collection; Comment Request; Foreign Fishing Vessel Permit Applications

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-22

    ... Fishing Vessel Permit Applications AGENCY: National Oceanic and Atmospheric Administration (NOAA... regulations at 50 CFR 600, Subpart F, provide for the issuance of fishing permits to foreign vessels. The... directed foreign fishing, participation in joint ventures with United States (U.S.) vessels,...

  12. Immunopathogenesis of lymphatic filarial disease1

    PubMed Central

    Babu, Subash; Nutman, Thomas B.

    2012-01-01

    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). PMID:23053393

  13. 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.

  14. Cardiac lymphatics are heterogeneous in origin and respond to injury

    PubMed Central

    Klotz, Linda; Norman, Sophie; Vieira, Joaquim Miguel; Masters, Megan; Rohling, Mala; Dubé, Karina N.; Bollini, Sveva; Matsuzaki, Fumio; Carr, Carolyn A.; Riley, Paul R.

    2015-01-01

    The lymphatic vasculature is a blind-ended network crucial for tissue fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. In contrast, we reveal here that cardiac lymphatic vessels have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple cre-lox based lineage tracing revealed a potential contribution from the hemogenic endothelium during development and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction (MI) promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury. PMID:25992544

  15. 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.

  16. 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.

  17. Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.

    PubMed

    Dashkevich, A; Raissadati, A; Syrjälä, S O; Zarkada, G; Keränen, M A I; Tuuminen, R; Krebs, R; Anisimov, A; Jeltsch, M; Leppänen, V-M; Alitalo, K; Nykänen, A I; Lemström, K B

    2016-04-01

    Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia-reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection. PMID:26689983

  18. Integrin Alpha-9 Mediates Lymphatic Valve Formation in Corneal Lymphangiogenesis

    PubMed Central

    Altiok, Eda; Ecoiffier, Tatiana; Sessa, Roberto; Yuen, Don; Grimaldo, Sammy; Tran, Colin; Li, David; Rosner, Michael; Lee, Narae; Uede, Toshimitsu; Chen, Lu

    2015-01-01

    Purpose We recently reported that corneal lymphatic vessels develop integrin alpha-9 (Itga-9)-positive valves during inflammatory lymphangiogenesis. The purpose of this study was to further investigate the role of Itga-9 in corneal lymphatic valve formation in vivo and lymphatic endothelial cell (LEC) functions in vitro. Methods Standard murine suture placement model was used to study the effect of Itga-9 blockade on lymphatic valve formation in vivo using Itga-9 neutralizing antibody. Whole-mount corneas were harvested for immunofluorescent microscopic analysis. Additionally, human LEC culture system was used to examine the effect of Itga-9 gene knockdown on cell functions using small interfering RNAs (siRNAs). Results Itga-9 blockade in vivo significantly reduced the number of lymphatic valves formed in the inflamed cornea. Moreover, Itga-9 gene knockdown in human LECs suppresses cell functions of proliferation, adhesion, migration, and tube formation. Conclusions Itga-9 is critically involved in corneal lymphatic valve formation. Further investigation of the Itga-9 pathway may provide novel strategies to treat lymphatic-related diseases occurring both inside and outside the eye. PMID:26431485

  19. Evaluation of Data-Logging Transducer to Passively Collect Pressure Vessel p/T History

    NASA Technical Reports Server (NTRS)

    Wnuk, Stephen P.; Le, Son; Loew, Raymond A.

    2013-01-01

    Pressure vessels owned and operated by NASA are required to be regularly certified per agency policy. Certification requires an assessment of damage mechanisms and an estimation of vessel remaining life. Since detail service histories are not typically available for most pressure vessels, a conservative estimate of vessel pressure/temperature excursions is typically used in assessing fatigue life. This paper details trial use of a data-logging transducer to passively obtain actual pressure and temperature service histories of pressure vessels. The approach was found to have some potential for cost savings and other benefits in certain cases.

  20. 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

  1. Class 3 semaphorins negatively regulate dermal lymphatic network formation

    PubMed Central

    Uchida, Yutaka; James, Jennifer M.; Suto, Fumikazu; Mukouyama, Yoh-suke

    2015-01-01

    ABSTRACT The development of a patterned lymphatic vascular network is essential for proper lymphatic functions during organ development and homeostasis. Here we report that class 3 semaphorins (SEMA3s), SEMA3F and SEMA3G negatively regulate lymphatic endothelial cell (LEC) growth and sprouting to control dermal lymphatic network formation. Neuropilin2 (NRP2) functions as a receptor for SEMA3F and SEMA3G, as well as vascular endothelial growth factor C (VEGFC). In culture, Both SEMA3F and SEMA3G inhibit VEGFC-mediated sprouting and proliferation of human dermal LECs. In the developing mouse skin, Sema3f is expressed in the epidermis and Sema3g expression is restricted to arteries, whereas their receptor Nrp2 is preferentially expressed by lymphatic vessels. Both Sema3f;Sema3g double mutants and Nrp2 mutants exhibit increased LEC growth in the skin. In contrast, Sema3f;Sema3g double mutants display increased lymphatic branching, while Nrp2 mutants exhibit reduced lymphatic branching. A targeted mutation in PlexinA1 or PlexinA2, signal transducers forming a receptor complex with NRP2 for SEMA3s, exhibits an increase in LEC growth and lymphatic branching as observed in Sema3f;Sema3g double mutants. Our results provide the first evidence that SEMA3F and SEMA3G function as a negative regulator for dermal lymphangiogenesis in vivo. The reciprocal phenotype in lymphatic branching between Sema3f;Sema3g double mutants and Nrp2 mutants suggest a complex NRP2 function that regulates LEC behavior both positively and negatively, through a binding with VEGFC or SEMA3s. PMID:26319580

  2. Class 3 semaphorins negatively regulate dermal lymphatic network formation.

    PubMed

    Uchida, Yutaka; James, Jennifer M; Suto, Fumikazu; Mukouyama, Yoh-Suke

    2015-01-01

    The development of a patterned lymphatic vascular network is essential for proper lymphatic functions during organ development and homeostasis. Here we report that class 3 semaphorins (SEMA3s), SEMA3F and SEMA3G negatively regulate lymphatic endothelial cell (LEC) growth and sprouting to control dermal lymphatic network formation. Neuropilin2 (NRP2) functions as a receptor for SEMA3F and SEMA3G, as well as vascular endothelial growth factor C (VEGFC). In culture, Both SEMA3F and SEMA3G inhibit VEGFC-mediated sprouting and proliferation of human dermal LECs. In the developing mouse skin, Sema3f is expressed in the epidermis and Sema3g expression is restricted to arteries, whereas their receptor Nrp2 is preferentially expressed by lymphatic vessels. Both Sema3f;Sema3g double mutants and Nrp2 mutants exhibit increased LEC growth in the skin. In contrast, Sema3f;Sema3g double mutants display increased lymphatic branching, while Nrp2 mutants exhibit reduced lymphatic branching. A targeted mutation in PlexinA1 or PlexinA2, signal transducers forming a receptor complex with NRP2 for SEMA3s, exhibits an increase in LEC growth and lymphatic branching as observed in Sema3f;Sema3g double mutants. Our results provide the first evidence that SEMA3F and SEMA3G function as a negative regulator for dermal lymphangiogenesis in vivo. The reciprocal phenotype in lymphatic branching between Sema3f;Sema3g double mutants and Nrp2 mutants suggest a complex NRP2 function that regulates LEC behavior both positively and negatively, through a binding with VEGFC or SEMA3s. PMID:26319580

  3. 76 FR 78615 - Proposed Information Collection; Comment Request; Permitting, Vessel Identification, and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-19

    ...; Permitting, Vessel Identification, and Reporting Requirements for Deepwater Shrimp Fisheries in the Western... deepwater shrimp (Heterocarpus spp.), or land these species in ports, in the western Pacific region...

  4. Automated system for measurement, collection and processing of hydrometeorological data aboard scientific research vessels of the GUGMS (SIGMA-s)

    NASA Technical Reports Server (NTRS)

    Borisenkov, Y. P.; Fedorov, O. M.

    1974-01-01

    A report is made on the automated system known as SIGMA-s for the measurement, collection, and processing of hydrometeorological data aboard scientific research vessels of the Hydrometeorological Service. The various components of the system and the interfacing between them are described, as well as the projects that the system is equipped to handle.

  5. Crafting glass vessels: current research on the ancient glass collections in the Freer Gallery of Art, Washington, D.C.

    NASA Astrophysics Data System (ADS)

    Nagel, Alexander; McCarthy, Blythe; Bowe, Stacy

    Our knowledge of glass production in ancient Egypt has been well augmented by the publication of recently excavated materials and glass workshops, but also by more recent materials analysis, and experiments of modern glass-makers attempting to reconstruct the production process of thin-walled coreformed glass vessels. From the mounting of a prefabricated core to the final glass product our understanding of this profession has much improved. The small but well preserved glass collection of the Freer Gallery of Art in Washington, D.C. is a valid tool for examining and studying the technology and production of ancient Egyptian core formed glass vessels. Charles Lang Freer (1854-1919) acquired most of the material from Giovanni Dattari in Cairo in 1909. Previously the glass had received only limited discussion, suggesting that most of these vessels were produced in the 18th Dynasty in the 15th and 14th centuries BCE, while others date from the Hellenistic period and later. In an ongoing project we conducted computed radiography in conjunction with qualitative x-ray fluorescence analysis on a selected group of vessels to understand further aspects of the ancient production process. This paper will provide an overview of our recent research and present our data-gathering process and preliminary results. How can the examinations of core formed glass vessels in the Freer Gallery contribute to our understanding of ancient glass production and technology? By focusing on new ways of looking at old assumptions using the Freer Gallery glass collections, we hope to increase understanding of the challenges of the production process of core-vessel technology as represented by these vessels.

  6. Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer's Disease?

    PubMed

    Louveau, Antoine; Da Mesquita, Sandro; Kipnis, Jonathan

    2016-09-01

    Lymphatic vasculature drains interstitial fluids, which contain the tissue's waste products, and ensures immune surveillance of the tissues, allowing immune cell recirculation. Until recently, the CNS was considered to be devoid of a conventional lymphatic vasculature. The recent discovery in the meninges of a lymphatic network that drains the CNS calls into question classic models for the drainage of macromolecules and immune cells from the CNS. In the context of neurological disorders, the presence of a lymphatic system draining the CNS potentially offers a new player and a new avenue for therapy. In this review, we will attempt to integrate the known primary functions of the tissue lymphatic vasculature that exists in peripheral organs with the proposed function of meningeal lymphatic vessels in neurological disorders, specifically multiple sclerosis and Alzheimer's disease. We propose that these (and potentially other) neurological afflictions can be viewed as diseases with a neuro-lympho-vascular component and should be therapeutically targeted as such. PMID:27608759

  7. 78 FR 40436 - Proposed Information Collection; Comment Request; Mandatory Shrimp Vessel and Gear...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-05

    ... Shrimp Vessel and Gear Characterization Survey AGENCY: National Oceanic and Atmospheric Administration... Marine Fisheries Service (NMFS) manages the shrimp fishery in the waters of the Gulf of Mexico under the Shrimp Fishery Management Plan (FMP). The regulations for the Gulf Shrimp Vessel and...

  8. 77 FR 36998 - Proposed Information Collection; Comment Request; Mandatory Shrimp Vessel and Gear...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ... Shrimp Vessel and Gear Characterization Survey AGENCY: National Oceanic and Atmospheric Administration... Marine Fisheries Service (NMFS) manages the shrimp fishery in the waters of the Gulf of Mexico under the Shrimp Fishery Management Plan (FMP). The regulations for the Gulf Shrimp Vessel and...

  9. 77 FR 26513 - Proposed Information Collection; Comment Request; Southeast Region Vessel Monitoring System (VMS...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-04

    ... Region Vessel Monitoring System (VMS) and Related Requirements AGENCY: National Oceanic and Atmospheric... of Mexico under the Reef Fish Fishery Management Plan (FMP). The vessel monitoring system (VMS... habitat or spawning aggregations, or to reduce fishing pressure in areas that are heavily fished....

  10. Low-cost microcontroller platform for studying lymphatic biomechanics in vitro

    PubMed Central

    Kornuta, Jeffrey A.; Nipper, Matthew E.; Dixon, J. Brandon

    2012-01-01

    The pumping innate to collecting lymphatic vessels routinely exposes the endothelium to oscillatory wall shear stress and other dynamic forces. However, studying the mechanical sensitivity of the lymphatic endothelium remains a difficult task due to limitations of commercial or custom systems to apply a variety of time-varying stresses in vitro. Current biomechanical in vitro testing devices are very expensive, limited in capability, or highly complex; rendering them largely inaccessible to the endothelial cell biology community. To address these short-comings, the authors propose a reliable, low-cost platform for augmenting the capabilities of commercially available pumps to produce a wide variety of flow rate waveforms. In particular, the Arduino Uno, a microcontroller development board, is used to provide open-loop control of a digital peristaltic pump using precisely-timed serial commands. In addition, the flexibility of this platform is further demonstrated through its support of a custom-built cell-straining device capable of producing oscillatory strains with varying amplitudes and frequencies. Hence, this microcontroller development board is shown to be an inexpensive, precise, and easy-to-use tool for supplementing in vitro assays to quantify the effects of biomechanical forces on lymphatic endothelial cells. PMID:23178036

  11. 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. PMID:26418772

  12. The meningeal lymphatic system: a route for HIV brain migration?

    PubMed

    Lamers, Susanna L; Rose, Rebecca; Ndhlovu, Lishomwa C; Nolan, David J; Salemi, Marco; Maidji, Ekaterina; Stoddart, Cheryl A; McGrath, Michael S

    2016-06-01

    Two innovative studies recently identified functional lymphatic structures in the meninges that may influence the development of HIV-associated neurological disorders (HAND). Until now, blood vessels were assumed to be the sole transport system by which HIV-infected monocytes entered the brain by bypassing a potentially hostile blood-brain barrier through inflammatory-mediated semi-permeability. A cascade of specific chemokine signals promote monocyte migration from blood vessels to surrounding brain tissues via a well-supported endothelium, where the cells differentiate into tissue macrophages capable of productive HIV infection. Lymphatic vessels on the other hand are more loosely organized than blood vessels. They absorb interstitial fluid from bodily tissues where HIV may persist and exchange a variety of immune cells (CD4(+) T cells, monocytes, macrophages, and dendritic cells) with surrounding tissues through discontinuous endothelial junctions. We propose that the newly discovered meningeal lymphatics are key to HIV migration among viral reservoirs and brain tissue during periods of undetectable plasma viral loads due to suppressive combinational antiretroviral therapy, thus redefining the migration process in terms of a blood-lymphatic transport system. PMID:26572785

  13. 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. PMID:26077718

  14. Light microscopy of the lymphatics of the human atrial wall and lymphatic drainage of supraventricular pacemakers.

    PubMed

    Elisková, M; Eliska, O

    1989-01-01

    After injection of Indian ink stained 2% gelatine in 42 human hearts the lymph drainage of the regions of supraventricular cardiac pacemakers and the patterns of the lymphatic vascular bed in the atrial wall were studied. From the sites of the pacemakers the lymph is drained into the tracheobronchial nodes in 100%. Only two of those regions are drained through additional pathways, namely the SAN region into the anterior mediastinal node situated at the azygos vein and the coronary sinus area into the anterior mediastinal lateropericardiac nodes. In the cleared specimens as microscopically the epicardial lymph vessels produce polygonal superficial network; oblique anastomoses of that network run into the deeper layers of subepicardial tissue where they join with deep irregular lymphatic network. Deep subepicardial lymph vessels are often accompanied by veins and nerves. The course of most of myocardial lymph vessels follows the position of muscle cells. In the connective septa these vessels join to form larger trunks and open into the subepicardial vessels. PMID:2475557

  15. Lymphatic function is required prenatally for lung inflation at birth.

    PubMed

    Jakus, Zoltán; Gleghorn, Jason P; Enis, David R; Sen, Aslihan; Chia, Stephanie; Liu, Xi; Rawnsley, David R; Yang, Yiqing; Hess, Paul R; Zou, Zhiying; Yang, Jisheng; Guttentag, Susan H; Nelson, Celeste M; Kahn, Mark L

    2014-05-01

    Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants. PMID:24733830

  16. Potential application of in vivo imaging of impaired lymphatic duct to evaluate the severity of pressure ulcer in mouse model

    NASA Astrophysics Data System (ADS)

    Kasuya, Akira; Sakabe, Jun-Ichi; Tokura, Yoshiki

    2014-02-01

    Ischemia-reperfusion (IR) injury is a cause of pressure ulcer. However, a mechanism underlying the IR injury-induced lymphatic vessel damage remains unclear. We investigated the alterations of structure and function of lymphatic ducts in a mouse cutaneous IR model. And we suggested a new method for evaluating the severity of pressure ulcer. Immunohistochemistry showed that lymphatic ducts were totally vanished by IR injury, while blood vessels were relatively preserved. The production of harmful reactive oxygen species (ROS) was increased in injured tissue. In vitro study showed a high vulnerability of lymphatic endothelial cells to ROS. Then we evaluated the impaired lymphatic drainage using an in vivo imaging system for intradermally injected indocyanine green (ICG). The dysfunction of ICG drainage positively correlated with the severity of subsequent cutaneous changes. Quantification of the lymphatic duct dysfunction by this imaging system could be a useful strategy to estimate the severity of pressure ulcer.

  17. 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

  18. Plasticity of Blood- and Lymphatic Endothelial Cells and Marker Identification

    PubMed Central

    Keuschnigg, Johannes; Karinen, Sirkku; Auvinen, Kaisa; Irjala, Heikki; Mpindi, John-Patrick; Kallioniemi, Olli; Hautaniemi, Sampsa; Jalkanen, Sirpa; Salmi, Marko

    2013-01-01

    The distinction between lymphatic and blood vessels is biologically fundamental. Here we wanted to rigorously analyze the universal applicability of vascular markers and characteristics of the two widely used vascular model systems human microvascular endothelial cell line-1 (HMEC-1) and telomerase-immortalized microvascular endothelial cell line (TIME). Therefore we studied the protein expression and functional properties of the endothelial cell lines HMEC-1 and TIME by flow cytometry and in vitro flow assays. We then performed microarray analyses of the gene expression in these two cell lines and compared them to primary endothelial cells. Using bioinformatics we then defined 39 new, more universal, endothelial-type specific markers from 47 primary endothelial microarray datasets and validated them using immunohistochemistry with normal and pathological tissues. We surprisingly found that both HMEC-1 and TIME are hybrid blood- and lymphatic cells. In addition, we discovered great discrepancies in the previous identifications of blood- and lymphatic endothelium-specific genes. Hence we identified and validated new, universally applicable vascular markers. Summarizing, the hybrid blood-lymphatic endothelial phenotype of HMEC-1 and TIME is indicative of plasticity in the gene expression of immortalized endothelial cell lines. Moreover, we identified new, stable, vessel-type specific markers for blood- and lymphatic endothelium, useful for basic research and clinical diagnostics. PMID:24058540

  19. VEGF165 Stimulates Vessel Density and Vessel Diameter Differently in Angiogenesis and Lymphangiogenesis

    NASA Technical Reports Server (NTRS)

    Parsons-Wingerter, Patricia; Radhakrishnan, Krishnan; DiCorleto, Paul E.; Leontiev, Dmitry; Anand-Apte, Bela; Albarran, Brian; Farr, Andrew G.

    2005-01-01

    Vascular endothelial growth factor-165 (VEGF(sub 165)) stimulated angiogenesis in the quail chorioallantoic membrane (CAM) by vessel expansion from the capillary network. However, lymphangiogenesis was stimulated by the filopodial guidance of tip cells located on blind-ended lymphatic sprouts. As quantified by fractal/generational branching analysis using the computer code VESGEN, vascular density increased maximally at low VEGF concentrations, and vascular diameter increased most at high VEGF concentrations. Increased vascular density and diameter were statistically independent events (r(sub s), -0.06). By fluorescence immunohistochemistry of VEGF receptors VEGFR-1 and VEGFR-2, alpha smooth muscle actin ((alpha) SMA) and a vascular/lymphatic marker, VEGF(sub 165) increased the density and diameter of sprouting lymphatic vessels guided by tip cells (accompanied by the dissociation of lymphatics from blood vessels). Isolated migratory cells expressing (alpha)SMA were recruited to blood vessels, whereas isolated cells expressing VEGFR-2 were recruited primarily to lymphatics. In conclusion, VEGF(sub 165) increased lymphatic vessel density by lymphatic sprouting, but increased blood vessel density by vascular expansion from the capillary network.

  20. 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

  1. 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

  2. In vivo albumin labeling and lymphatic imaging.

    PubMed

    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 ((18)F-AlF-NEB) and Evans blue (EB) dye. After local injection, both (18)F-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 (18)F-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 (18)F-AlF-NEB and EB has great potential for clinical application to map sentinel LNs and provide intraoperative guidance. PMID:25535368

  3. New Model of Macrophage Acquisition of the Lymphatic Endothelial Phenotype

    PubMed Central

    Ran, Sophia

    2012-01-01

    Background 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. Methodology/Principal Findings 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. Conclusions/Significance 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

  4. Dextran sulfate sodium-induced acute colitis impairs dermal lymphatic function in mice

    PubMed Central

    Agollah, Germaine D; Wu, Grace; Peng, Ho-Lan; Kwon, Sunkuk

    2015-01-01

    AIM: To investigate whether dermal lymphatic function and architecture are systemically altered in dextran sulfate sodium (DSS)-induced acute colitis. METHODS: 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. RESULTS: 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

  5. Nonmalignant Adult Thoracic Lymphatic Disorders.

    PubMed

    Itkin, Maxim; McCormack, Francis X

    2016-09-01

    The thoracic lymphatic disorders are a heterogeneous group of uncommon conditions that are associated with thoracic masses, interstitial pulmonary infiltrates, and chylous complications. Accurate diagnosis of the thoracic lymphatic disorders has important implications for the newest approaches to management, including embolization and treatment with antilymphangiogenic drugs. New imaging techniques to characterize lymphatic flow, such as dynamic contrast-enhanced magnetic resonance lymphangiogram, are redefining approaches to disease classification and therapy. PMID:27514588

  6. Monitoring contractile dermal lymphatic activity following uniaxial mechanical loading.

    PubMed

    Gray, R J; Worsley, P R; Voegeli, D; Bader, D L

    2016-09-01

    It is proposed that direct mechanical loading can impair dermal lymphatic function, contributing to the causal pathway of pressure ulcers. The present study aims to investigate the effects of loading on human dermal lymphatic vessels. Ten participants were recruited with ages ranging from 24 to 61 years. Participants had intradermal Indocyanine Green injections administrated between left finger digits. Fluorescence was imaged for 5min sequences with an infra-red camera prior to lymph vessel loading, immediately after axial loading (60mmHg) and following a recovery period. Image processing was employed to defined transient lymph packets and compare lymph function between each test phase. The results revealed that between 1-8 transient events (median=4) occurred at baseline, with a median velocity of 8.1mm/sec (range 4.1-20.1mm/sec). Immediately post-loading, there was a significant (p<0.05) reduction in velocity (median=6.4, range 2.2-13.5mm/sec), although the number of transient lymph packages varied between participants. During the recovery period the number (range 1-7) and velocity (recovery median=9.6mm/sec) of transient packets were largely restored to basal values. The present study revealed that some individuals present with impaired dermal lymphatic function immediately after uniaxial mechanical loading. More research is needed to investigate the effects of pressure and shear on lymphatic vessel patency. PMID:27245749

  7. Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node

    PubMed Central

    Srinivasan, Swetha; Vannberg, Fredrik O.; Dixon, J. Brandon

    2016-01-01

    It is well documented that cells secrete exosomes, which can transfer biomolecules that impact recipient cells’ functionality in a variety of physiologic and disease processes. The role of lymphatic drainage and transport of exosomes is as yet unknown, although the lymphatics play critical roles in immunity and exosomes are in the ideal size-range for lymphatic transport. Through in vivo near-infrared (NIR) imaging we have shown that exosomes are rapidly transported within minutes from the periphery to the lymph node by lymphatics. Using an in vitro model of lymphatic uptake, we have shown that lymphatic endothelial cells actively enhanced lymphatic uptake and transport of exosomes to the luminal side of the vessel. Furthermore, we have demonstrated a differential distribution of exosomes in the draining lymph nodes that is dependent on the lymphatic flow. Lastly, through endpoint analysis of cellular distribution of exosomes in the node, we identified macrophages and B-cells as key players in exosome uptake. Together these results suggest that exosome transfer by lymphatic flow from the periphery to the lymph node could provide a mechanism for rapid exchange of infection-specific information that precedes the arrival of migrating cells, thus priming the node for a more effective immune response. PMID:27087234

  8. Oxazolone-Induced Contact Hypersensitivity Reduces Lymphatic Drainage but Enhances the Induction of Adaptive Immunity

    PubMed Central

    Aebischer, David; Willrodt, Ann-Helen; Halin, Cornelia

    2014-01-01

    Contact hypersensitivity (CHS) induced by topical application of haptens is a commonly used model to study dermal inflammatory responses in mice. Several recent studies have indicated that CHS-induced skin inflammation triggers lymphangiogenesis but may negatively impact the immune-function of lymphatic vessels, namely fluid drainage and dendritic cell (DC) migration to draining lymph nodes (dLNs). On the other hand, haptens have been shown to exert immune-stimulatory activity by inducing DC maturation. In this study we investigated how the presence of pre-established CHS-induced skin inflammation affects the induction of adaptive immunity in dLNs. Using a mouse model of oxazolone-induced skin inflammation we observed that lymphatic drainage was reduced and DC migration from skin to dLNs was partially compromised. At the same time, a significantly stronger adaptive immune response towards ovalbumin (OVA) was induced when immunization had occurred in CHS-inflamed skin as compared to uninflamed control skin. In fact, immunization with sterile OVA in CHS-inflamed skin evoked a delayed-type hypersensitivity (DTH) response comparable to the one induced by conventional immunization with OVA and adjuvant in uninflamed skin. Striking phenotypic and functional differences were observed when comparing DCs from LNs draining uninflamed or CHS-inflamed skin. DCs from LNs draining CHS-inflamed skin expressed higher levels of co-stimulatory molecules and MHC molecules, produced higher levels of the interleukin-12/23 p40 subunit (IL-12/23-p40) and more potently induced T cell activation in vitro. Immunization experiments revealed that blockade of IL-12/23-p40 during the priming phase partially reverted the CHS-induced enhancement of the adaptive immune response. Collectively, our findings indicate that CHS-induced skin inflammation generates an overall immune-stimulatory milieu, which outweighs the potentially suppressive effect of reduced lymphatic vessel function. PMID:24911791

  9. Determining the combined effect of the lymphatic valve leaflets and sinus on resistance to forward flow.

    PubMed

    Wilson, John T; van Loon, Raoul; Wang, Wei; Zawieja, David C; Moore, James E

    2015-10-15

    The lymphatic system is vital to a proper maintenance of fluid and solute homeostasis. Collecting lymphatics are composed of actively contracting tubular vessels segmented by bulbous sinus regions that encapsulate bi-leaflet check valves. Valve resistance to forward flow strongly influences pumping performance. However, because of the sub-millimeter size of the vessels with flow rates typically <1 ml/h and pressures of a few cmH2O, resistance is difficult to measure experimentally. Using a newly defined idealized geometry, we employed an uncoupled approach where the solid leaflet deflections of the open valve were computed and lymph flow calculations were subsequently performed. We sought to understand: 1) the effect of sinus and leaflet size on the resulting deflections experienced by the valve leaflets and 2) the effects on valve resistance to forward flow of the fully open valve. For geometries with sinus-to-root diameter ratios >1.39, the average resistance to forward flow was 0.95×10(6)[g/(cm4 s)]. Compared to the viscous pressure drop that would occur in a straight tube the same diameter as the upstream lymphangion, valve leaflets alone increase the pressure drop up to 35%. However, the presence of the sinus reduces viscous losses, with the net effect that when combined with leaflets the overall resistance is less than that of the equivalent continuing straight tube. Accurately quantifying resistance to forward flow will add to the knowledge used to develop therapeutics for treating lymphatic disorders and may eventually lead to understanding some forms of primary lymphedema. PMID:26315921

  10. 76 FR 26705 - Proposed Information Collection; Comment Request; Commercial Fishing Vessel Cost and Earnings...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-09

    ... Environmental Policy Act, Executive Order 12866 and the Regulatory Flexibility Act. The Social Sciences Branch (SSB) of the NMFS, Northeast Fisheries Science Center (NEFSC) is responsible for estimating the economic and social impacts of fishery management actions. Lack of information on vessel operating...

  11. 76 FR 3151 - Agency Information Collection Activities: Record of Vessel Foreign Repair or Equipment Purchase

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-19

    ... Foreign Repair or Equipment Purchase AGENCY: U.S. Customs and Border Protection (CBP), Department of... requirement concerning the Record of Vessel Foreign Repair or Equipment Purchase (CBP Form 226). This request... request for Office of Management and Budget (OMB) approval. All comments will become a matter of...

  12. 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

  13. Consequences of intravascular lymphatic valve properties: a study of contraction timing in a multi-lymphangion model.

    PubMed

    Bertram, Christopher D; Macaskill, Charlie; Davis, Michael J; Moore, James E

    2016-04-01

    The observed properties of valves in collecting lymphatic vessels include transmural pressure-dependent bias to the open state and hysteresis. The bias may reduce resistance to flow when the vessel is functioning as a conduit. However, lymphatic pumping implies a streamwise increase in mean pressure across each valve, suggesting that the bias is then potentially unhelpful. Lymph pumping by a model of several collecting lymphatic vessel segments (lymphangions) in series, which incorporated these properties, was investigated under conditions of adverse pressure difference while varying the refractory period between active muscular contractions and the inter-lymphangion contraction delay. It was found that many combinations of the timing parameters and the adverse pressure difference led to one or more intermediate valves remaining open instead of switching between open and closed states during repetitive contraction cycles. Cyclic valve switching was reliably indicated if the mean pressure in a lymphangion over a cycle was higher than that in the lymphangion upstream, but either lack of or very brief valve closure could cause mean pressure to be lower downstream. Widely separated combinations of refractory period and delay time were found to produce the greatest flow-rate for a given pressure difference. The efficiency of pumping was always maximized by a long refractory period and lymphangion contraction starting when the contraction of the lymphangion immediately upstream was peaking. By means of an ex vivo experiment, it was verified that intermediate valves in a chain of pumping lymphangions can remain open, while the lymphangions on either side of the open valve continue to execute contractions. PMID:26747501

  14. Lymphatic drainage from the eye: A new target for therapy.

    PubMed

    Yucel, Yeni; Gupta, Neeru

    2015-01-01

    Lowering intraocular pressure (IOP) has been central to glaucoma care for over a century. In order to prevent sight loss from disease, there has been considerable focus on medical and surgical methods to improve fluid drainage from the eye. In spite of this, our understanding of exactly how aqueous humor leaves the eye is not complete. Recently, lymphatic vessels have been discovered in the human uvea, with studies showing lymphatic fluid outflow in several models, in addition to evidence for their pharmacological enhancement. The presence of a lymphatic outflow system points to an exciting, expanded understanding of how fluid and particulate materials such as proteins move out of the eye, and how IOP may be regulated. We coin the term "uveolymphatic pathway"-to reflect a comprehensive and compelling new target for glaucoma and an exciting opportunity for future investigations to better understand the eye in health and disease. PMID:26497791

  15. Evaluation of the Influence of Marine Vessel Emissions Plumes on Measurements Collected at the Amphitrite Point Coastal Background Site

    NASA Astrophysics Data System (ADS)

    Iannone, R.; Jones, K.; Schiller, C. L.; Ainslie, B.; Macdonald, A. M.; Mihele, C.; Vingarzan, R.

    2014-12-01

    A marine boundary layer air quality monitoring site was established on the west coast of Vancouver Island at Amphitrite Point in May 2010. The main objectives for the site were to (1) determine background air pollutant concentrations and trends, (2) support air quality modelling validation and development, (3) complement the high elevation background monitoring site at Whistler and other regional monitoring initiatives, and (4) conduct chemical process studies in the marine boundary layer. During the initial evaluations of the collected data (e.g., O3, PM2.5, NOx, and SO2) and its comparison to other marine background sites, periods were observed that are clearly representative of background air, continental background air, and those clearly influenced by ship and boat traffic in the region.On the basis that the individual pollutants observed are closely related to emissions observed by underway marine vessels, certain observational periods in the collected dataset were associated with ship plumes. Utilizing the data provided by marine vessel movements, CALPUFF emission inputs were generated for dispersion modelling of ship pollutants. CALPUFF model output data were subsequently compared to measured data in order to better characterize impacts from marine vessel traffic.

  16. The Glymphatic-Lymphatic Continuum: Opportunities for Osteopathic Manipulative Medicine.

    PubMed

    Hitscherich, Kyle; Smith, Kyle; Cuoco, Joshua A; Ruvolo, Kathryn E; Mancini, Jayme D; Leheste, Joerg R; Torres, German

    2016-03-01

    The brain has long been thought to lack a lymphatic drainage system. Recent studies, however, show the presence of a brain-wide paravascular system appropriately named the glymphatic system based on its similarity to the lymphatic system in function and its dependence on astroglial water flux. Besides the clearance of cerebrospinal fluid and interstitial fluid, the glymphatic system also facilitates the clearance of interstitial solutes such as amyloid-β and tau from the brain. As cerebrospinal fluid and interstitial fluid are cleared through the glymphatic system, eventually draining into the lymphatic vessels of the neck, this continuous fluid circuit offers a paradigm shift in osteopathic manipulative medicine. For instance, manipulation of the glymphatic-lymphatic continuum could be used to promote experimental initiatives for nonpharmacologic, noninvasive management of neurologic disorders. In the present review, the authors describe what is known about the glymphatic system and identify several osteopathic experimental strategies rooted in a mechanistic understanding of the glymphatic-lymphatic continuum. PMID:26927910

  17. Immunology of lymphatic filariasis

    PubMed Central

    Babu, Subash; Nutman, Thomas B.

    2013-01-01

    The immune responses to filarial parasites encompass a complex network of innate and adaptive cells whose interaction with the parasite underlies a spectrum of clinical manifestations. The predominant immunological feature of lymphatic filariasis is an antigen - specific Th2 response and an expansion of IL-10 producing CD4+ T cells that is accompanied by a muted Th1 response. This antigen specific T cell hypo-responsiveness appears to be crucial for the maintenance of the sustained, long-standing infection often with high parasite densities. While the correlates of protective immunity to lymphatic filariasis are still incompletely understood, primarily due to the lack of suitable animal models to study susceptibility, it is clear that T cells and to a certain extent B cells are required for protective immunity. Host immune responses, especially CD4+ T cell responses clearly play a role in mediating pathological manifestations of LF, including lymphedema, hydrocele and elephantiasis. The main underlying defect in the development of clinical pathology appears to be a failure to induce T cell hypo-responsiveness in the face of antigenic stimulation. Finally, another intriguing feature of filarial infections is their propensity to induce bystander effects on a variety of immune responses, including responses to vaccinations, allergens and to other infectious agents. The complexity of the immune response to filarial infection therefore provides an important gateway to understanding the regulation of immune responses to chronic infections, in general. PMID:24134686

  18. Is lymphatic status related to regression of inflammation in Crohn's disease?

    PubMed Central

    Tonelli, Francesco; Giudici, Francesco; Liscia, Gadiel

    2012-01-01

    AIM: To investigate the status of the lymphatic vessels in the small bowel affected by Crohn’s disease (CD) at the moment of surgery. METHODS: During the period January 2011-June 2011, 25 consecutive patients affected by CD were operated on in our Institution. During surgery, Patent Blue V was injected subserosally and the way it spread along the subserosa of the intestinal wall, through the mesenterial layers towards the main lymphatic collectors and eventually to the lymph nodes was observed and recorded. Since some patients had been undergone strictureplasty at previous surgery, we also examined the status of intestinal lymph vessels after previous strictureplasties. The same procedure was performed in a control group of 5 patients affected by colorectal cancer. Length of lesions, caliber, maximal thickness of the diseased intestinal wall, thickness of the wall at injection site and thickness of the mesentery were evaluated at surgery. RESULTS: We observed three features after the injection of Patent Blue V in the intestinal loops: (1) Macroscopically healthy terminal ileum of patients with CD or colon cancer showed thin lymphatic vessels linearly directed toward the mesentery; (2) In mild lesions in which the intestinal wall did not reach 8 mm of thickness, we observed short, wide and tortuous lymphatic vessels directed longitudinally along the intestinal axis toward disease-free areas and then transversally toward the mesentery; and (3) Injection in the severely affected lesions, that had a thickness of the intestinal wall over 10 mm, did not show any feature of lymphatic vessels at least on the subserosal surface. There was a correlation between the thickness of the parietal wall and the severity of the lymphatic alterations. Normal lymphatic vessels were observed at previous strictureplasties in the presence of complete regression of the inflammation. CONCLUSION: Injection of Patent Blue V in the intestinal wall could help distinguish healthy tracts of the

  19. 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

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

    PubMed

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

    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

  1. Altered lymphatic function and architecture in salt-induced hypertension assessed by near-infrared fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Kwon, Sunkuk; Agollah, Germaine D.; Chan, Wenyaw; Sevick-Muraca, Eva M.

    2012-08-01

    The lymphatic system plays an important role in maintaining the fluid homeostasis between the blood vascular and interstitial tissue compartment and there is recent evidence that its transport capabilities may regulate blood pressure in salt-induced hypertension. Yet, there is little known how the lymphatic contractile function and architecture responds to dietary salt-intake. Thus, we longitudinally characterized lymphatic contractile function and vessel remodeling noninvasively using dynamic near-infrared fluorescence imaging in animal models of salt-induced hypertension. The lymphatics of mice and rats were imaged following intradermal injection of indocyanine green to the ear tip or the base of the tail before and during two weeks of either a high salt diet (HSD) or normal chow. Our noninvasive imaging data demonstrated dilated lymphatic vessels in the skin of mice and rats on a HSD as compared to their baseline levels. In addition, our dynamic imaging results showed increased lymphatic contraction frequency in HSD-fed mice and rats. Lymphatic contractile function and vessel remodeling occurs in response to salt-induced hypertension suggesting a possible role for the lymphatics in the regulation of vascular blood pressure.

  2. Pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis in tumor lymphangiogenesis and lymphatic metastasis.

    PubMed

    Wang, Jingwen; Huang, Yuhong; Zhang, Jun; Wei, Yuanyi; Mahoud, Salma; Bakheet, Ahmed Musa Hago; Wang, Li; Zhou, Shuting; Tang, Jianwu

    2016-10-01

    Precondition for tumor lymphatic metastasis is that tumor cells induce formation of original and newborn lymphatic vessels and invade surrounding lymphatic vessels in tumor stroma, while some pathway-related molecules play an important role in mechanisms associated with proliferation and migration of lymphatic endothelial cells (LECs) and tumor cells. In lymphangiogenesis and lymphatic metastasis, the pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis, such as Furin-like enzyme, CNTN1, Prox1, LYVE-1, Podoplanin, SOX18, SDF1 and CXCR4, are direct constitutors as a portion of VEGFC/D-VEGFR3/NRP2 axis, and their biological activities rely on this ligand-receptor system. These axis-related signal molecules could gradually produce waterfall-like cascading effects, mediate differentiation and maturation of LECs, remodel original and neonatal lymphatic vessels, as well as ultimately promote tumor cell chemotaxis, migration, invasion and metastasis to lymphoid tracts. This review summarizes the structure and function features of pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis, the expression changes of these molecules in different anatomic organs or histopathologic types or development stages of various tumors, the characteristics of transduction, implementation, integration of signal networks, the interactive effects on biological behaviors between tumor cells and lymphatic endothelial cells, and their molecular mechanisms and significances in tumor lymphangiogenesis and lymphatic metastasis. PMID:27527412

  3. 76 FR 16611 - Proposed Information Collection; Comment Request; Socio-Economic Surveys of Vessel Owners, Permit...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-24

    ... information on crew, wage calculation systems, individual and community well-being, fishing practices, job satisfaction, job opportunities, and attitudes toward fisheries management. SSB intends to collect these...

  4. 76 FR 15989 - Agency Information Collection Activities: Record of Vessel Foreign Repair or Equipment Purchase

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-22

    ... proposed information collection was previously published in the Federal Register (76 FR 3151) on January 19... Repair or Equipment Purchase AGENCY: U.S. Customs and Border Protection, Department of Homeland Security... submitting the following information collection request to the Office of Management and ] Budget (OMB)...

  5. Hyaluroan-regulated lymphatic permeability through S1P receptors is crucial for cancer metastasis.

    PubMed

    Yu, Mengsi; He, Pingqing; Liu, Yiwen; He, Yiqing; Du, Yan; Wu, Man; Zhang, Guoliang; Yang, Cuixia; Gao, Feng

    2015-01-01

    Disruption of cancer lymphatic vessel barrier function occurs has been reported to involve in cancer lymphatic metastasis. Hyaluronan (HA), a major glycosaminoglycan component of the extracellular matrix, is associated with cancer metastasis. We investigated the effect of high/low molecular weight hyaluronan (HMW-HA/LMW-HA) on regulation of barrier function and tight junctions in cancer lymphatic endothelial cell (LEC) monolayer. Results showed that LMW-HA increased the permeability of cancer LEC monolayers and induced disruption of Zonula Occludens-1 (ZO-1)-mediated intercellular tight junction and actin stress fiber formation. HMW-HA treatment decreased permeability in cancer LEC monolayers and cortical actin ring formation. As reported, sphingosine 1-phosphate (S1P) receptors are involved in vascular integrity. After silencing of lymphatic vessel endothelial hyaluronan receptor (LYVE-1), upregulation of S1P receptors (S1P1 and S1P3) induced by HMW-HA/LMW-HA were inhibited, respectively. With S1P3 silenced, the disruption of ZO-1 as well as stress fiber formation and the ROCK1/RhoA signaling pathway induced by LMW-HA was not observed in cancer LEC. These results suggested that S1P receptors may play an important role in HMW-HA-/LMW-HA-mediated regulation of cancer lymphatic vessel integrity, which might be the initial step of cancer lymphatic metastasis and a useful intervention of cancer progression. PMID:25428387

  6. Dual-channel in-situ optical imaging system for quantifying lipid uptake and lymphatic pump function.

    PubMed

    Kassis, Timothy; Kohan, Alison B; Weiler, Michael J; Nipper, Matthew E; Cornelius, Rachel; Tso, Patrick; Dixon, J Brandon

    2012-08-01

    Nearly all dietary lipids are transported from the intestine to venous circulation through the lymphatic system, yet the mechanisms that regulate this process remain unclear. Elucidating the mechanisms involved in the functional response of lymphatics to changes in lipid load would provide valuable insight into recent implications of lymphatic dysfunction in lipid related diseases. Therefore, we sought to develop an in situ imaging system to quantify and correlate lymphatic function as it relates to lipid transport. The imaging platform provides the capability of dual-channel imaging of both high-speed bright-field video and fluorescence simultaneously. Utilizing post-acquisition image processing algorithms, we can quantify correlations between vessel pump function, lymph flow, and lipid concentration of mesenteric lymphatic vessels in situ. All image analysis is automated with customized LabVIEW virtual instruments; local flow is measured through lymphocyte velocity tracking, vessel contraction through measurements of the vessel wall displacement, and lipid uptake through fluorescence intensity tracking of an orally administered fluorescently labelled fatty acid analogue, BODIPY FL C16. This system will prove to be an invaluable tool for scientists studying intestinal lymphatic function in health and disease, and those investigating strategies for targeting the lymphatics with orally delivered drugs to avoid first pass metabolism. PMID:23224192

  7. Dual-channel in-situ optical imaging system for quantifying lipid uptake and lymphatic pump function

    NASA Astrophysics Data System (ADS)

    Kassis, Timothy; Kohan, Alison B.; Weiler, Michael J.; Nipper, Matthew E.; Cornelius, Rachel; Tso, Patrick; Brandon Dixon, J.

    2012-08-01

    Nearly all dietary lipids are transported from the intestine to venous circulation through the lymphatic system, yet the mechanisms that regulate this process remain unclear. Elucidating the mechanisms involved in the functional response of lymphatics to changes in lipid load would provide valuable insight into recent implications of lymphatic dysfunction in lipid related diseases. Therefore, we sought to develop an in situ imaging system to quantify and correlate lymphatic function as it relates to lipid transport. The imaging platform provides the capability of dual-channel imaging of both high-speed bright-field video and fluorescence simultaneously. Utilizing post-acquisition image processing algorithms, we can quantify correlations between vessel pump function, lymph flow, and lipid concentration of mesenteric lymphatic vessels in situ. All image analysis is automated with customized LabVIEW virtual instruments; local flow is measured through lymphocyte velocity tracking, vessel contraction through measurements of the vessel wall displacement, and lipid uptake through fluorescence intensity tracking of an orally administered fluorescently labelled fatty acid analogue, BODIPY FL C16. This system will prove to be an invaluable tool for scientists studying intestinal lymphatic function in health and disease, and those investigating strategies for targeting the lymphatics with orally delivered drugs to avoid first pass metabolism.

  8. Dual-channel in-situ optical imaging system for quantifying lipid uptake and lymphatic pump function

    PubMed Central

    Kassis, Timothy; Kohan, Alison B.; Weiler, Michael J.; Nipper, Matthew E.; Cornelius, Rachel; Tso, Patrick

    2012-01-01

    Abstract. Nearly all dietary lipids are transported from the intestine to venous circulation through the lymphatic system, yet the mechanisms that regulate this process remain unclear. Elucidating the mechanisms involved in the functional response of lymphatics to changes in lipid load would provide valuable insight into recent implications of lymphatic dysfunction in lipid related diseases. Therefore, we sought to develop an in situ imaging system to quantify and correlate lymphatic function as it relates to lipid transport. The imaging platform provides the capability of dual-channel imaging of both high-speed bright-field video and fluorescence simultaneously. Utilizing post-acquisition image processing algorithms, we can quantify correlations between vessel pump function, lymph flow, and lipid concentration of mesenteric lymphatic vessels in situ. All image analysis is automated with customized LabVIEW virtual instruments; local flow is measured through lymphocyte velocity tracking, vessel contraction through measurements of the vessel wall displacement, and lipid uptake through fluorescence intensity tracking of an orally administered fluorescently labelled fatty acid analogue, BODIPY FL C16. This system will prove to be an invaluable tool for scientists studying intestinal lymphatic function in health and disease, and those investigating strategies for targeting the lymphatics with orally delivered drugs to avoid first pass metabolism. PMID:23224192

  9. Spleen and Lymphatic System

    MedlinePlus

    ... destroy damaged cells. How It Works Carrying Away Waste Lymph fluid drains into tiny vessels called lymph ... crowd out healthy cells and may cause tumors (solid growths) in other parts of the body. Splenomegaly ( ...

  10. Dual origin of avian lymphatics.

    PubMed

    Wilting, Jörg; Aref, Yama; Huang, Ruijin; Tomarev, Stanislav I; Schweigerer, Lothar; Christ, Bodo; Valasek, Petr; Papoutsi, Maria

    2006-04-01

    The earliest signs of the lymphatic vascular system are the lymph sacs, which develop adjacent to specific embryonic veins. It has been suggested that sprouts from the lymph sacs form the complete lymphatic vascular system. We have studied the origin of the jugular lymph sacs (JLS), the dermal lymphatics and the lymph hearts of avian embryos. In day 6.5 embryos, the JLS is an endothelial-lined sinusoidal structure. The lymphatic endothelial cells (LECs) stain (in the quail) positive for QH1 antibody and soybean agglutinin. As early as day 4, the anlagen of the JLS can be recognized by their Prox1 expression. Prox1 is found in the jugular section of the cardinal veins, and in scattered cells located in the dermatomes along the cranio-caudal axis and in the splanchnopleura. In the quail, such cells are positive for Prox1 and QH1. In the jugular region, the veins co-express the angiopoietin receptor Tie2. Quail-chick-chimera studies show that the peripheral parts of the JLS form by integration of cells from the paraxial mesoderm. Intra-venous application of DiI-conjugated acetylated low-density lipoprotein into day 4 embryos suggests a venous origin of the deep parts of the JLS. Superficial lymphatics are directly derived from the dermatomes, as shown by dermatome grafting. The lymph hearts in the lumbo-sacral region develop from a plexus of Prox1-positive lymphatic capillaries. Both LECs and muscle cells of the lymph hearts are of somitic origin. In sum, avian lymphatics are of dual origin. The deep parts of the lymph sacs are derived from adjacent veins, the superficial parts of the JLS and the dermal lymphatics from local lymphangioblasts. PMID:16457798

  11. Near infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute vs. chronic phases of arthritis in mice

    PubMed Central

    Zhou, Quan; Wood, Ronald; Schwarz, Edward M.; Wang, Yong-Jun; Xing, Lianping

    2010-01-01

    Objective Development of an in vivo imaging method to assess lymphatic draining function in the K/B×N mouse model of inflammatory arthritis. Methods Indocyanine green (ICG), a near-infrared (NIR) fluorescent dye, was injected intradermally into the footpad of wild-type mice, the limb was illuminated with an 806 nm NIR laser, and the movement of ICG from the injection site to the draining popliteal lymph node (PLN) was recorded with a CCD camera. ICG-NIR images were analyzed to obtain 5 measures of lymphatic function across time. K/B×N arthritic mice and control non-arthritic littermates were imaged at one-month of age when acute joint inflammation commenced, and repeated at 3 months when joint inflammation became chronic. Lymphangiogenesis in PLNs was assessed by immunochemistry. Results ICG and its transport within lymphatic vessels were readily visualized and quantitative measures derived. During the acute phase of arthritis, the lymphatic vessels were dilated with increased ICG signal intensity and lymphatic pulses, and PLNs became fluorescent quickly. During the chronic phase, new lymphatic vessels were present near the foot. However, ICG appearance in lymphatic vessels was delayed. The size and area of PLN lymphatic sinuses progressively increased in the K/B×N mice. Conclusion ICG-NIR lymphatic imaging is a valuable method to assess the lymphatic draining function in mice with inflammatory arthritis. ICG-NIR imaging of K/B×N mice identified two distinct lymphatic phenotypes during the acute and chronic phase of inflammation. This technique can be used to assess new therapies for lymphatic disorders. PMID:20309866

  12. Development of Blood and Lymphatic Endothelial Cells in Embryonic and Fetal Human Skin.

    PubMed

    Schuster, Christopher; Mildner, Michael; Botta, Albert; Nemec, Lucas; Rogojanu, Radu; Beer, Lucian; Fiala, Christian; Eppel, Wolfgang; Bauer, Wolfgang; Petzelbauer, Peter; Elbe-Bürger, Adelheid

    2015-09-01

    Blood and lymphatic vessels provide nutrients for the skin and fulfill important homeostatic functions, such as the regulation of immunologic processes. In this study, we investigated the development of blood and lymphatic endothelial cells in prenatal human skin in situ using multicolor immunofluorescence and analyzed angiogenic molecules by protein arrays of lysates and cell culture supernatants. We found that at 8 to 10 weeks of estimated gestational age, CD144(+) vessels predominantly express the venous endothelial cell marker PAL-E, whereas CD144(+)PAL-E(-) vessels compatible with arteries only appear at the end of the first trimester. Lymphatic progenitor cells at 8 weeks of estimated gestational age express CD31, CD144, Prox1, and temporary PAL-E. At that developmental stage not all lymphatic progenitor cells express podoplanin or Lyve-1, which are acquired with advancing gestational age in a stepwise fashion. Already in second-trimester human skin, the phenotype of blood and lymphatic vessels roughly resembles the one in adult skin. The expression pattern of angiogenic molecules in lysates and cell culture supernatants of prenatal skin did not reveal the expected bent to proangiogenic molecules, indicating a complex regulation of angiogenesis during ontogeny. In summary, this study provides enticing new insights into the development and phenotypic characteristics of the vascular system in human prenatal skin. PMID:26188132

  13. 76 FR 16610 - Proposed Information Collection; Comment Request; Pacific Islands Region Vessel and Gear...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-24

    ...The Department of Commerce, as part of its continuing effort to reduce paperwork and respondent burden, invites the general public and other Federal agencies to take this opportunity to comment on proposed and/or continuing information collections, as required by the Paperwork Reduction Act of...

  14. Dermal lymphatic dilation in a mouse model of alopecia areata.

    PubMed

    Sundberg, John P; Pratt, C Herbert; Silva, Kathleen A; Kennedy, Victoria E; Stearns, Timothy M; Sundberg, Beth A; King, Lloyd E; HogenEsch, Harm

    2016-04-01

    Mouse models of various types of inflammatory skin disease are often accompanied by increased dermal angiogenesis. The C3H/HeJ inbred strain spontaneously develops alopecia areata (AA), a cell mediated autoimmune disorder that can be controllably expanded using full thickness skin grafts to young unaffected mice. This provides a reproducible and progressive model for AA in which the vascularization of the skin can be examined. Mice receiving skin grafts from AA or normal mice were evaluated at 5, 10, 15, and 20 weeks after engraftment. Lymphatics are often overlooked as they are small slit-like structures above the hair follicle that resemble artifact-like separation of collagen bundles with some fixatives. Lymphatics are easily detected using lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) by immunohistochemistry to label their endothelial cells. Using LYVE1, there were no changes in distribution or numbers of lymphatics although they were more prominent (dilated) in the mice with AA. Lyve1 transcripts were not significantly upregulated except at 10 weeks after skin grafting when clinical signs of AA first become apparent. Other genes involved with vascular growth and dilation or movement of immune cells were dysregulated, mostly upregulated. These findings emphasize aspects of AA not commonly considered and provide potential targets for therapeutic intervention. PMID:26960166

  15. A tissue engineered model of the intestinal lacteal for evaluating lipid transport by lymphatics

    PubMed Central

    Dixon, J. Brandon; Raghunathan, Sandeep; Swartz, Melody A.

    2010-01-01

    Lacteals are the entry point of all dietary lipids into the circulation, yet little is known about the active regulation of lipid uptake by these lymphatic vessels, and there lacks in vitro models to study the lacteal – enterocyte interface. We describe an in vitro model of the human intestinal microenvironment containing differentiated Caco-2 cells and lymphatic endothelial cells (LECs). We characterize the model for fatty acid, lipoprotein, albumin, and dextran transport, and compare to qualitative uptake of fatty acids into lacteals in vivo. We demonstrate relevant morphological features of both cell types and strongly polarized transport of fatty acid in the intestinal-to-lymphatic direction. We found much higher transport rates of lipid than of dextran or albumin across the lymphatic endothelial monolayer, suggesting most lipid transport is active and intracellular. This was confirmed with confocal imaging of Bodipy, a fluorescent fatty acid, along with transmission electron microscopy. Since our model recapitulates crucial aspects of the in vivo lymphatic-enterocyte interface, it is useful for studying the biology of lipid transport by lymphatics and as a tool for screening drugs and nanoparticles that target intestinal lymphatics. PMID:19396808

  16. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2.

    PubMed

    Taher, Mahdi; Nakao, Shintaro; Zandi, Souska; Melhorn, Mark I; Hayes, K C; Hafezi-Moghadam, Ali

    2016-07-01

    The role of lymphatics in atherosclerosis is not yet understood. Here, we investigate lymphatic growth dynamics and marker expression in atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. The prolymphangiogenic growth factor, VEGF-C, was elevated in atherosclerotic aortic walls. Despite increased VEGF-C, we found that adventitial lymphatics regress during the course of formation of atherosclerosis (P < 0.01). Similar to lymphatic regression, the number of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1(+)) macrophages decreased in the aortic adventitia of apoE(-/-) mice with atherosclerosis (P < 0.01). Intimal lymphatics in the atherosclerotic lesions exhibited an atypical phenotype, with the expression of podoplanin and VEGF receptor 3 (VEGFR-3) but not of LYVE-1 and prospero homeobox protein 1. In the aortas of atherosclerotic animals, we found markedly increased soluble VEGFR-2. We hypothesized that the elevated soluble VEGFR-2 that was found in the aortas of apoE(-/-) mice with atherosclerosis binds to and diminishes the activity of VEGF-C. This trapping mechanism explains, despite increased VEGF-C in the atherosclerotic aortas, how adventitial lymphatics regress. Lymphatic regression impedes the drainage of lipids, growth factors, inflammatory cytokines, and immune cells. Insufficient lymphatic drainage could thus exacerbate atherosclerosis formation. Our study contributes new insights to previously unknown dynamic changes of adventitial lymphatics. Targeting soluble VEGFR-2 in atherosclerosis may provide a new strategy for the liberation of endogenous VEGF-C and the prevention of lymphatic regression.-Taher, M., Nakao, S., Zandi, S., Melhorn, M. I., Hayes, K. C., Hafezi-Moghadam, A. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2. PMID:27006449

  17. A Comparative Study of Adhesion of Melanoma and Breast Cancer Cells to Blood and Lymphatic Endothelium

    PubMed Central

    Safuan, Sabreena; Storr, Sarah J.; Patel, Poulam M.

    2012-01-01

    Abstract Background Lymphovascular invasion (LVI) is an important step in the metastatic cascade; tumor cell migration and adhesion to blood and lymphatic vessels is followed by invasion through the vessel wall and subsequent systemic spread. Although primary breast cancers and melanomas have rich blood vascular networks, LVI is predominately lymphatic in nature. Whilst the adhesion of tumor cells to blood endothelium has been extensively investigated, there is a paucity of information on tumor cell adhesion to lymphatic endothelium. Methods and Results Breast cancer (MDA-MB-231 and MCF7) and melanoma (MeWo and SKMEL-30) cell adhesion to lymphatic (hTERT-LEC and HMVEC dLy Neo) and blood (HUVEC and hMEC-1) endothelial cells were assessed using static adhesion assays. The effect of inflammatory conditions, tumor necrosis factor-α (TNF-α) stimulation of endothelial and tumor cells, on the adhesive process was also examined. In addition, the effects of TNF-α stimulation on tumor cell migration was investigated using haplotaxis (scratch wound) assays. Breast cancer and melanoma cells exhibited higher levels of adhesion to blood compared to lymphatic endothelial cells (p<0.001). TNF-α stimulation of endothelial cells, or of tumor cells alone, did not significantly alter tumor–endothelial cell adhesion or patterns. When both tumor and endothelial cells were stimulated with TNF-α, a significant increase in adhesion was observed (p<0.01), which was notably higher in the lymphatic cell models (p<0.001). TNF-α-stimulation of all tumor cell lines significantly increased their migration rate (p<0.01). Conclusions Results suggest that metastasis resultant from lymphatic vessel-tumor cell adhesion may be modulated by cytokine stimulation, which could represent an important therapeutic target in breast cancer and melanoma. PMID:23215743

  18. Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis.

    PubMed

    Sato, Hirokazu; Higashiyama, Masaaki; Hozumi, Hideaki; Sato, Shingo; Furuhashi, Hirotaka; Takajo, Takeshi; Maruta, Koji; Yasutake, Yuichi; Narimatsu, Kazuyuki; Yoshikawa, Kenichi; Kurihara, Chie; Okada, Yoshikiyo; Watanabe, Chikako; Komoto, Shunsuke; Tomita, Kengo; Nagao, Shigeaki; Miura, Soichiro; Hokari, Ryota

    2016-08-01

    Lymphatic failure is a histopathological feature of inflammatory bowel disease (IBD). Recent studies show that interaction between platelets and podoplanin on lymphatic endothelial cells (LECs) suppresses lymphangiogenesis. We aimed to investigate the role of platelets in the inflammatory process of colitis, which is likely to be through modulation of lymphangiogenesis. Lymphangiogenesis in colonic mucosal specimens from patients with IBD was investigated by studying mRNA expression of lymphangiogenic factors and histologically by examining lymphatic vessel (LV) densities. Involvement of lymphangiogenesis in intestinal inflammation was studied by administering VEGF-receptor 3 (VEGF-R3) inhibitors to the mouse model of colitis using dextran sulfate sodium and evaluating platelet migration to LVs. The inhibitory effect of platelets on lymphangiogenesis was investigated in vivo by administering antiplatelet antibody to the colitis mouse model and in vitro by coculturing platelets with lymphatic endothelial cells. Although mRNA expressions of lymphangiogenic factors such as VEGF-R3 and podoplanin were significantly increased in the inflamed mucosa of patients with IBD compared with those with quiescent mucosa, there was no difference in LV density between them. In the colitis model, VEGF-R3 inhibition resulted in aggravated colitis, decreased lymphatic density, and increased platelet migration to LVs. Administration of an antiplatelet antibody increased LV densities and significantly ameliorated colitis. Coculture with platelets inhibited proliferation of LECs in vitro. Our data suggest that despite elevated lymphangiogenic factors during colonic inflammation, platelet migration to LVs resulted in suppressed lymphangiogenesis, leading to aggravation of colitis by blocking the clearance of inflammatory cells. Modulating the interaction between platelets and LVs could be a new therapeutic means for treating IBD. PMID:27313177

  19. Therapeutic strategy for lower limb lymphedema and lymphatic fistula after resection of a malignant tumor in the hip joint region: a case report.

    PubMed

    Hara, H; Mihara, M; Hayashi, A; Kanemaru, M; Todokoro, T; Yamamoto, T; Iida, T; Hino, R; Koshima, I

    2014-03-01

    Lymphatic fistula complicating lymphedema is thought to occur due to communication between lymph vessels and the skin, which has yet to be shown objectively. The objective of this case report is to show the pathology and treatment using simultaneous lymphatic fistula resection and lymphatico-venous anastomosis (LVA). A 40-year-old woman underwent extended resection and total hip arthroplasty for primitive neuroectodermal tumor in the right proximal femur 23 years ago. Right lower limb lymphedema developed immediately after surgery and lymphatic fistula appeared in the posterior thigh. On ICG lymphography, lymph reflux toward the distal side dispersing in a fan-shape reticular pattern from the lymphatic fistula region was noted after intracutaneous injection of ICG into the foot. We performed simultaneous lymphatic fistula resection and of LVA. Pathological examination showed that the epidermis and stratum corneum of the healthy skin were lost in the lymphatic fistula region. Dilated lymph vessels were open in this region. The examinations provide the first objective evidence that the cause of lymphatic fistula may be lymph reflux from lymphatic stems to precollectors through lymphatic perforators. PMID:23908155

  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. 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.

  2. A Lymphatic dwelling filarioid nematode, Rumenfilaria andersoni (Filarioidea; Splendidofilariinae), is an emerging parasite in Finnish cervids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background-Recent studies revealed expansion of filarioid nematodes into the northern Finland. In addition to Setaria tundra, unidentified and very abundant filarioids, representing Rumenfilaria andersoni, were found inhabiting the lymphatic vessels of reindeer. Our study explores the biology and d...

  3. Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport

    PubMed Central

    Kvietys, Peter R.; Granger, D. Neil

    2010-01-01

    Two of the principal functions of intestinal lymphatics are to assist in 1) maintaining interstitial volume within relatively normal limits during alterations in capillary filtration (e.g., acute portal hypertension) and 2) removal of absorbed water and chylomicrons. The contribution of lymphatics to the prevention of interstitial over-hydration or dehydration during alterations in transcapillary filtration is similar in the small intestine and colon. While the lymphatics of the small intestine contribute substantially to the removal of absorbed water (particularly at low and moderate absorption rates), the contribution of colonic lymphatics to the removal of the fluid absorbate is negligible. This difference is attributed to the relative caliber and location of lymphatics in the mucosal layer of the small and large intestines. In the small intestine, large lacteals lie in close proximity to transporting epithelium, while colonic lymph vessels are rather sparse and confined to the basal portion of the mucosa. In the small intestine, the lymphatics assume a more important role in removing absorbed water during lipid absorption than during glucose absorption. PMID:20961304

  4. Integration of CD45-positive leukocytes into newly forming lymphatics of adult mice.

    PubMed

    Buttler, K; Lohrberg, M; Gross, G; Weich, H A; Wilting, J

    2016-06-01

    The embryonic origin of lymphatic endothelial cells (LECs) has been a matter of controversy since more than a century. However, recent studies in mice have supported the concept that embryonic lymphangiogenesis is a complex process consisting of growth of lymphatics from specific venous segments as well as the integration of lymphangioblasts into the lymphatic networks. Similarly, the mechanisms of adult lymphangiogenesis are poorly understood and have rarely been studied. We have recently shown that endothelial progenitor cells isolated from the lung of adult mice have the capacity to form both blood vessels and lymphatics when grafted with Matrigel plugs into the skin of syngeneic mice. Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel plugs. We observed a striking co-localization of CD45(+) leukocytes with the developing lymphatics. Numerous CD45(+) cells expressed the LEC marker podoplanin and were obviously integrated into the lining of lymphatic capillaries. This indicates that, similar to inflammation-induced lymphangiogenesis in man, circulating CD45(+) cells of adult mice are capable of initiating lymphangiogenesis and of adopting a lymphvasculogenic cellular differentiation program. The data are discussed in the context of embryonic and inflammation-induced lymphangiogenesis. PMID:26748643

  5. Lymphangiogenesis and expression of specific molecules as lymphatic endothelial cell markers.

    PubMed

    Kato, Seiji; Shimoda, Hiroshi; Ji, Rui-Cheng; Miura, Masahiro

    2006-06-01

    In recent years, several functional molecules specifically expressed and localized in lymphatic endothelial cells, such as 5'-nucleotidase, lymphatic vessel endothelial receptor-1, vascular endothelial growth factor receptor-3, podoplanin and Prox-1, have been identified. The discovery of the lymphatic endothelial cell markers facilitated detailed analysis of the nature and structural organization of the lymphatic vessels and their growth (lymphangiogenesis). As a result, over the past few years, advances have been made in understanding the cellular and molecular aspects of physiological lymphangiogenesis and tumor-induced lymphangiogenesis. The biology of lymphangiogenesis, particularly the mechanism of its regulation, is very important in understanding the formation of the lymphatic system as a biological regulation system transporting tissue fluid and wandering cells, including lymphocytes, and disease involving lymphangiogenesis. The understanding of the molecular mechanism of lymphangiogenesis and the elucidation of the development of normal and pathological tissues are expected to lead to the development of therapy for intractable diseases, such as malignant tumors and lymphedema. PMID:16800291

  6. Optimization of monoclonal antibody delivery via the lymphatics: the dose dependence

    SciTech Connect

    Steller, M.A.; Parker, R.J.; Covell, D.G.; Holton, O.D. 3d.; Keenan, A.M.; Sieber, S.M.; Weinstein, J.N.

    1986-04-01

    After interstitial injection in mice, antibody molecules enter local lymphatic vessels, flow with the lymph to regional lymph nodes, and bind to target antigens there. Compared with i.v. administration, delivery via the lymphatics provides a more efficient means for localizing antibody in lymph nodes. An IgG2a (36-7-5) directed against the murine class I major histocompatibility antigen H-2Kk has proved useful for studying the pharmacology of lymphatic delivery. At very low doses, most of the antibody remains at the injection site in Kk-positive animals. As the dose is progressively increased, most effective labeling occurs first in nodes proximal to the injection site and then in the next group of nodes along the lymphatic chain. At higher doses, antibody overflows the lymphatic system and enters the blood-stream via the thoracic duct and other lymphatic-venous connections. Once in the blood, antibody is rapidly cleared, apparently by binding to Kk-bearing cells. These findings indicate that the single-pass distribution of monoclonal antibodies in the lymphatics can be strongly dose dependent, a principle which may be of clinical significance in the improvement of immunolymphoscintigraphic imaging, especially with antibodies directed against normal and malignant lymphoid cells. Monoclonal antibodies directed against normal cell types in the lymph node may be useful for assessing the integrity of lymphatic chains by immunolymphoscintigraphy or, more speculatively, for altering the status of regional immune function. The results presented here indicate that a low or intermediate antibody dose may optimize the signal:noise ratio for imaging. In Kk-negative animals, the percentage of dose taken up in the major organs was essentially independent of the dose administered; there was no evidence for saturable sites of nonspecific binding.

  7. Lymphatic endothelial mCLCA1 is a ligand for leukocyte LFA-1 and Mac-1

    PubMed Central

    Furuya, Momoko; Kirschbaum, Sara B.; Paulovich, Amanda; Pauli, Bendicht U.; Zhang, Heidi; Alexander, Jonathan S.; Farr, Andrew G.; Ruddell, Alanna

    2012-01-01

    The lymphatic circulation mediates drainage of fluid and cells from the periphery through lymph nodes, facilitating immune detection of lymph-borne foreign antigens. The 10.1.1 monoclonal antibody recognizes a lymphatic endothelial antigen, here purified by antibody affinity chromatography. SDS-PAGE and mass spectrometry identified mCLCA1 as the 10.1.1 antigen, a 90 kD cell surface protein expressed in lymphatic endothelium and stromal cells of spleen and thymus. The 10.1.1 antibody affinity chromatography also purified LFA-1, an integrin that mediates leukocyte adhesion to endothelium. This mCLCA1-LFA-1 interaction has functional consequences, as lymphocyte adhesion to lymphatic endothelium was blocked by 10.1.1 antibody bound to endothelium, or by LFA-1 antibody bound to lymphocytes. Lymphocyte adhesion was increased by cytokine treatment of lymphatic endothelium, in association with increased expression of ICAM-1, an endothelial surface protein that is also a ligand for LFA-1. By contrast, mCLCA1 expression and the relative contribution of mCLCA1 to lymphocyte adhesion were unaffected by cytokine activation, demonstrating that mCLCA1 and ICAM-1 interactions with LFA-1 are differentially regulated. mCLCA1 also bound to the LFA-1-related Mac-1 integrin that is preferentially expressed on leukocytes. mCLCA1-mediated adhesion of Mac-1- or LFA-1-expressing leukocytes to lymphatic vessels and lymph node lymphatic sinuses provides a new target for investigation of lymphatic involvement in leukocyte adhesion and trafficking during the immune response. PMID:20937843

  8. 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

  9. 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. PMID:26901813

  10. Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction.

    PubMed

    Moriondo, Andrea; Solari, Eleonora; Marcozzi, Cristiana; Negrini, Daniela

    2016-01-01

    Peripheral rat diaphragmatic lymphatic vessels, endowed with intrinsic spontaneous contractility, were in vivo filled with fluorescent dextrans and microspheres and subsequently studied ex vivo in excised diaphragmatic samples. Changes in diameter and lymph velocity were detected, in a vessel segment, during spontaneous lymphatic smooth muscle contraction and upon activation, through electrical whole-field stimulation, of diaphragmatic skeletal muscle fibers. During intrinsic contraction lymph flowed both forward and backward, with a net forward propulsion of 14.1 ± 2.9 μm at an average net forward speed of 18.0 ± 3.6 μm/s. Each skeletal muscle contraction sustained a net forward-lymph displacement of 441.9 ± 159.2 μm at an average velocity of 339.9 ± 122.7 μm/s, values significantly higher than those documented during spontaneous contraction. The flow velocity profile was parabolic during both spontaneous and skeletal muscle contraction, and the shear stress calculated at the vessel wall at the highest instantaneous velocity never exceeded 0.25 dyne/cm(2). Therefore, we propose that the synchronous contraction of diaphragmatic skeletal muscle fibers recruited at every inspiratory act dramatically enhances diaphragmatic lymph propulsion, whereas the spontaneous lymphatic contractility might, at least in the diaphragm, be essential in organizing the pattern of flow redistribution within the diaphragmatic lymphatic circuit. Moreover, the very low shear stress values observed in diaphragmatic lymphatics suggest that, in contrast with other contractile lymphatic networks, a likely interplay between intrinsic and extrinsic mechanisms be based on a mechanical and/or electrical connection rather than on nitric oxide release. PMID:26519032

  11. Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination.

    PubMed Central

    de Waal, R. M.; van Altena, M. C.; Erhard, H.; Weidle, U. H.; Nooijen, P. T.; Ruiter, D. J.

    1997-01-01

    Cutaneous melanoma has an initial preference for lymphatic spread. Remarkably, melanoma progression toward this metastasizing phenotype is accompanied by intense blood vessel angiogenesis (hemangiogenesis), but lymphangiogenesis, the formation of new lymph vessels in the tumor, has never been reported. To investigate how primary melanoma cells interact with the existing lymphatic microvasculature, and whether lymphangiogenesis occurs, an immunostaining was developed that differentially decorates blood and lymph vessels in frozen tissue sections. The density and distribution of both these vessel types in and around thin (< or = 1.5 mm) and thick (> or = 1.5 mm) primary melanoma lesions and in normal and uninvolved skin were determined. Although especially in thick melanoma lesions a significant increase in blood vessel density was observed, lymphatic density remained unaltered, showing that lymphangiogenesis did not occur. Morphological analysis indicated, however, that melanoma progression is accompanied by a sequence of events that involves hemangiogenesis supporting tumor expansion, especially in the vertical growth phase. Often, stromal sepia are formed around the blood capillaries in the tumor neovasculature protecting them from invasion. Lymph vessels inside the tumor were infrequently observed. However, subepidermal lymph vessels often seemed to be entrapped and penetrated by the expanding tumor mass. In this way, hemangiogenesis, as the driving force behind tumor expansion, might indirectly increase the chance of lymphatic invasion in the absence of lymphangiogenesis. This model explains the paradox that, although melanoma metastasis seems to require angiogenesis, a consistent relation of prognosis with blood capillary density in primary cutaneous melanoma is lacking. Images Figure 1 Figure 2 Figure 3 PMID:9176389

  12. Who discovered the lymphatic system.

    PubMed

    Chikly, B

    1997-12-01

    The 17th century saw several emerging and almost simultaneous discoveries in the field of lymphology by Asselli, Pecquet, Bartholin and possibly Joliffe. However, Olof Rudbeck (1630-1708) of Sweden, a true scientific genius, who mastered botany, chemistry, physics, mathematics, astronomy, music, drawing, architecture and engineering, and became the Rector of the Faculty of Upsala, was probably the first anatomist to consider correctly the lymphatic circulation as an integrated system of the whole body. PMID:9476250

  13. Methods for effective fluorophore injection and imaging of lymphatics in small animals

    NASA Astrophysics Data System (ADS)

    DSouza, Alisha V.; Marra, Kayla A.; Gunn, Jason R.; Samkoe, Kimberley S.; Tichauer, Kenneth M.; Pogue, Brian W.

    2016-03-01

    Morbidity and complexity involved in lymph node staging via surgical resection and biopsy calls for staging techniques that are less invasive. While visible blue dyes are commonly used in locating sentinel lymph nodes, since they follow tumor-draining lymphatic vessels, they do not provide a metric to evaluate presence of cancer. An area of active research is to use fluorescent dyes to assess tumor burden of sentinel and secondary lymph nodes. The goal of this work was to successfully perform fluorescence imaging of IRDye®680RD in the lymphatics, in a repeatable manner.

  14. TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.

    PubMed

    Pang, M-F; Georgoudaki, A-M; Lambut, L; Johansson, J; Tabor, V; Hagikura, K; Jin, Y; Jansson, M; Alexander, J S; Nelson, C M; Jakobsson, L; Betsholtz, C; Sund, M; Karlsson, M C I; Fuxe, J

    2016-02-11

    Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells. PMID:25961925

  15. OCULAR LYMPHATICS: STATE-OF-THE-ART REVIEW

    PubMed Central

    Chen, L.

    2015-01-01

    Research involving the lymphatic system has experienced an exponential progression during the past decade largely because of advancement of modern technology and discovery of several lymphatic specific molecules. The eye provides an excellent site for lymphatic studies due to its accessible location and the unique feature of tissue heterogeneity – while some tissues are lymphatic-rich, others are lymphatic-free or -inducible. This review provides an update on our current understanding of ocular lymphatics and possible associated eye diseases. PMID:19725271

  16. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance.

    PubMed

    Zolla, Valerio; Nizamutdinova, Irina Tsoy; Scharf, Brian; Clement, Cristina C; Maejima, Daisuke; Akl, Tony; Nagai, Takashi; Luciani, Paola; Leroux, Jean-Christophe; Halin, Cornelia; Stukes, Sabriya; Tiwari, Sangeeta; Casadevall, Arturo; Jacobs, William R; Entenberg, David; Zawieja, David C; Condeelis, John; Fooksman, David R; Gashev, Anatoliy A; Santambrogio, Laura

    2015-08-01

    The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport. PMID:25982749

  17. Junb controls lymphatic vascular development in zebrafish via miR-182.

    PubMed

    Kiesow, Kristin; Bennewitz, Katrin; Miranda, Laura Gutierrez; Stoll, Sandra J; Hartenstein, Bettina; Angel, Peter; Kroll, Jens; Schorpp-Kistner, Marina

    2015-01-01

    JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli. Previously, JUNB was shown to act as a critical positive regulator of blood vessel development and homeostasis as well as a negative regulator of proliferation, inflammation and tumour growth. Here, we demonstrate that the oncogenic miR-182 is a novel JUNB target. Loss-of-function studies by morpholino-mediated knockdown and the CRISPR/Cas9 technology identify a novel function for both JUNB and its target miR-182 in lymphatic vascular development in zebrafish. Furthermore, we show that miR-182 attenuates foxo1 expression indicating that strictly balanced Foxo1 levels are required for proper lymphatic vascular development in zebrafish. In conclusion, our findings uncover with the Junb/miR-182/Foxo1 regulatory axis a novel key player in governing lymphatic vascular morphogenesis in zebrafish. PMID:26458334

  18. Junb controls lymphatic vascular development in zebrafish via miR-182

    PubMed Central

    Kiesow, Kristin; Bennewitz, Katrin; Miranda, Laura Gutierrez; Stoll, Sandra J.; Hartenstein, Bettina; Angel, Peter; Kroll, Jens; Schorpp-Kistner, Marina

    2015-01-01

    JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli. Previously, JUNB was shown to act as a critical positive regulator of blood vessel development and homeostasis as well as a negative regulator of proliferation, inflammation and tumour growth. Here, we demonstrate that the oncogenic miR-182 is a novel JUNB target. Loss-of-function studies by morpholino-mediated knockdown and the CRISPR/Cas9 technology identify a novel function for both JUNB and its target miR-182 in lymphatic vascular development in zebrafish. Furthermore, we show that miR-182 attenuates foxo1 expression indicating that strictly balanced Foxo1 levels are required for proper lymphatic vascular development in zebrafish. In conclusion, our findings uncover with the Junb/miR-182/Foxo1 regulatory axis a novel key player in governing lymphatic vascular morphogenesis in zebrafish. PMID:26458334

  19. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.

    PubMed

    Wiig, Helge; Schröder, Agnes; Neuhofer, Wolfgang; Jantsch, Jonathan; Kopp, Christoph; Karlsen, Tine V; Boschmann, Michael; Goss, Jennifer; Bry, Maija; Rakova, Natalia; Dahlmann, Anke; Brenner, Sven; Tenstad, Olav; Nurmi, Harri; Mervaala, Eero; Wagner, Hubertus; Beck, Franz-Xaver; Müller, Dominik N; Kerjaschki, Dontscho; Luft, Friedrich C; Harrison, David G; Alitalo, Kari; Titze, Jens

    2013-07-01

    The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function. PMID:23722907

  20. [ A comparative lympho-scintigraphic evaluation of manual lymphatic drainage and pressotherapy in edema of the arm following treatment of a breast tumor].

    PubMed

    Janbon, C; Ferrandez, J C; Vinot, J M; Serin, D

    1990-01-01

    Manual lymphatic drainage (MLD) and pressure-therapy are part of the therapeutical gears used in physiotherapy for reducing edema. The solution to the problem of the reduction fo lymphedema of the extremities rests with the evacuation of the liquid phase and the resorption of the stagnant proteins in the interstitial compartment not being collected by the lymphatic system. The injection of a 99 Technetium-labelled colloid substance provides a functional approach to the problem of lymphatic stasis. PMID:2212876

  1. Development of a Tissue-Engineered Lymphatic Graft Using Nanocomposite Polymer for the Treatment of Secondary Lymphedema.

    PubMed

    Kanapathy, Muholan; Kalaskar, Deepak; Mosahebi, Afshin; Seifalian, Alexander M

    2016-03-01

    Damage of the lymphatic vessels, commonly due to surgical resection for cancer treatment, leads to secondary lymphedema. Tissue engineering approach offers a possible solution to reconstruct this damage with the use of lymphatic graft to re-establish the lymphatic flow, hence preventing lymphedema. The aim of this study is to develop a tissue-engineered lymphatic graft using nanocomposite polymer and human dermal lymphatic endothelial cells (HDLECs). A nanocomposite polymer, the polyhedral oligomeric silsequioxane-poly(carbonate-urea)urethane (POSS-PCU), which has enhanced mechanical, chemical, and physical characteristics, was used to develop the lymphatic graft. POSS-PCU has been used clinically for the world's first synthetic trachea, lacrimal duct, and is currently undergoing clinical trial for coronary artery bypass graft. Two designs and fabrication methods were used to manufacture the conduits. The fabrication method, the mechanical and physical properties, as well as the hydraulic conductivity were tested. This is followed by in vitro cell culture analysis to test the cytocompatibility of HDLEC with the polymer surface. Using the casted extrusion method, the nanocomposite lymphatic graft demonstrates desirable mechanical property and hydraulic conductivity to re-establish the lymphatic flow. The conduit has high tensile strength (casted: 74.86 ± 5.74 MPa vs. coagulated: 31.33 ± 3.71 MPa; P < 0.001), favorable kink resistance, and excellent suture retention property (casted vs. coagulated, P < 0.05). Cytocompatibility study showed that the POSS-PCU scaffold supports the attachment and growth of HDLECs. This study demonstrates the feasibility of developing a tissue-engineered lymphatic graft using the nanocomposite polymer. It displays excellent mechanical property and cytocompatibility to HDLECs, offering much promise for clinical applications and as a new treatment option for secondary lymphedema. PMID:26517009

  2. Mechanoinduction of lymph vessel expansion

    PubMed Central

    Planas-Paz, Lara; Strilić, Boris; Goedecke, Axel; Breier, Georg; Fässler, Reinhard; Lammert, Eckhard

    2012-01-01

    In the mammalian embryo, few mechanical signals have been identified to influence organ development and function. Here, we report that an increase in the volume of interstitial or extracellular fluid mechanically induces growth of an organ system, that is, the lymphatic vasculature. We first demonstrate that lymph vessel expansion in the developing mouse embryo correlates with a peak in interstitial fluid pressure and lymphatic endothelial cell (LEC) elongation. In ‘loss-of-fluid' experiments, we then show that aspiration of interstitial fluid reduces the length of LECs, decreases tyrosine phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR3), and inhibits LEC proliferation. Conversely, in ‘gain-of-fluid' experiments, increasing the amount of interstitial fluid elongates the LECs, and increases both VEGFR3 phosphorylation and LEC proliferation. Finally, we provide genetic evidence that β1 integrins are required for the proliferative response of LECs to both fluid accumulation and cell stretching and, therefore, are necessary for lymphatic vessel expansion and fluid drainage. Thus, we propose a new and physiologically relevant mode of VEGFR3 activation, which is based on mechanotransduction and is essential for normal development and fluid homeostasis in a mammalian embryo. PMID:22157817

  3. The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine

    PubMed Central

    Mahadevan, Aparna; Welsh, Ian C.; Sivakumar, Aravind; Gludish, David W.; Shilvock, Abigail R.; Noden, Drew M.; Kurpios, Natasza A.

    2015-01-01

    SUMMARY The dorsal mesentery (DM) is the major conduit for blood and lymphatic vessels in the gut. The mechanisms underlying their morphogenesis are challenging to study and remain unknown. Here we show that arteriogenesis in the DM begins during gut rotation and proceeds strictly on the left side, dependent on the Pitx2 target gene Cxcl12. Although competent Cxcr4-positive angioblasts are present on the right, they fail to form vessels and progressively emigrate. Surprisingly, gut lymphatics also initiate in the left DM and arise only after – and dependent on – arteriogenesis, implicating arteries as drivers of gut lymphangiogenesis. Our data begin to unravel the origin of two distinct vascular systems and demonstrate how early L-R molecular asymmetries are translated into organ-specific vascular patterns. We propose a dual origin of gut lymphangiogenesis, where prior arterial growth is required to initiate local lymphatics that only subsequently connect to the vascular system. PMID:25482882

  4. The role of RNA interference in the developmental separation of blood and lymphatic vasculature

    PubMed Central

    2014-01-01

    Background Dicer is an RNase III enzyme that cleaves double stranded RNA and generates functional interfering RNAs that act as important regulators of gene and protein expression. Dicer plays an essential role during mouse development because the deletion of the dicer gene leads to embryonic death. In addition, dicer-dependent interfering RNAs regulate postnatal angiogenesis. However, the role of dicer is not yet fully elucidated during vascular development. Methods In order to explore the functional roles of the RNA interference in vascular biology, we developed a new constitutive Cre/loxP-mediated inactivation of dicer in tie2 expressing cells. Results We show that cell-specific inactivation of dicer in Tie2 expressing cells does not perturb early blood vessel development and patterning. Tie2-Cre; dicerfl/fl mutant embryos do not show any blood vascular defects until embryonic day (E)12.5, a time at which hemorrhages and edema appear. Then, midgestational lethality occurs at E14.5 in mutant embryos. The developing lymphatic vessels of dicer-mutant embryos are filled with circulating red blood cells, revealing an impaired separation of blood and lymphatic vasculature. Conclusion Thus, these results show that RNA interference perturbs neither vasculogenesis and developmental angiogenesis, nor lymphatic specification from venous endothelial cells but actually provides evidence for an epigenetic control of separation of blood and lymphatic vasculature. PMID:24690185

  5. Modelling the lymphatic system: challenges and opportunities

    PubMed Central

    Margaris, K. N.; Black, R. A.

    2012-01-01

    The lymphatic system is a vital part of the circulatory and immune systems, and plays an important role in homeostasis by controlling extracellular fluid volume and in combating infection. Nevertheless, there is a notable disparity in terms of research effort expended in relation to the treatment of lymphatic diseases in contrast to the cardiovascular system. While similarities to the cardiovascular system exist, there are considerable differences in their anatomy and physiology. This review outlines some of the challenges and opportunities for those engaged in modelling biological systems. The study of the lymphatic system is still in its infancy, the vast majority of the models presented in the literature to date having been developed since 2003. The number of distinct models and their variants are few in number, and only one effort has been made thus far to study the entire lymphatic network; elements of the lymphatic system such as the nodes, which act as pumps and reservoirs, have not been addressed by mathematical models. Clearly, more work will be necessary in combination with experimental verification in order to progress and update the knowledge on the function of the lymphatic system. As our knowledge and understanding of its function increase, new and more effective treatments of lymphatic diseases are bound to emerge. PMID:22237677

  6. Benign mesothelial cells in lymph nodes and lymphatic spaces associated with ascites.

    PubMed

    Pizzi, Marco; Valentini, Elisa; Galligioni, Alessandra; Cesaro, Sonia; Pontisso, Patrizia; Da Dalt, Gianfranco; Rugge, Massimo

    2016-07-01

    Intra-nodal mesothelial cells are assumed to be indicative of metastatic mesothelioma. The invasion of benign mesothelial cells into lymph nodes is an extraordinary complication of different (mostly inflammatory) disorders involving the serosal cavities. In a cirrhotic patient with recurrent ascites, this report describes the first case of mesothelial cell spreading into lymphatic vessels, coexisting with non-malignant inclusions of mesothelial cells in multiple abdominal lymph nodes. PMID:26696597

  7. Imaging Lymphatic System in Breast Cancer Patients with Magnetic Resonance Lymphangiography

    PubMed Central

    Lu, Qing; Hua, Jia; Kassir, Mohammad M.; Delproposto, Zachary; Dai, Yongming; Sun, Jingyi; Haacke, Mark; Hu, Jiani

    2013-01-01

    Objective To investigate the feasibility of gadolinium (Gd) contrast-enhanced magnetic resonance lymphangiography (MRL) in breast cancer patients within a typical clinical setting, and to establish a Gd-MRL protocol and identify potential MRL biomarkers for differentiating metastatic from non-metastatic lymph nodes. Materials and Methods 32 patients with unilateral breast cancer were enrolled and divided into 4 groups of 8 patients. Groups I, II, and III received 1.0, 0.5, and 0.3 ml of intradermal contrast; group IV received two 0.5 ml doses of intradermal contrast. MRL images were acquired on a 3.0 T system and evaluated independently by two radiologists for the number and size of enhancing lymph nodes, lymph node contrast uptake kinetics, lymph vessel size, and contrast enhancement patterns within lymph nodes. Results Group III patients had a statistically significant decrease in the total number of enhancing axillary lymph nodes and lymphatic vessels compared to all other groups. While group IV patients had a statistically significant faster time to reach the maximum peak enhancement over group I and II (by 3 minutes), there was no other statistically significant difference between imaging results between groups I, II, and IV. 27 out of 128 lymphatic vessels (21%) showed dilatation, and all patients with dilated lymphatic vessels were pathologically proven to have metastases. Using the pattern of enhancement defects as the sole criterion for identifying metastatic lymph nodes during Gd-MRL interpretation, and using histopathology as the gold standard, the sensitivity and specificity were estimated to be 86% and 95%, respectively. Conclusion Gd-MRL can adequately depict the lymphatic system, can define sentinel lymph nodes, and has the potential to differentiate between metastatic and non-metastatic lymph nodes in breast cancer patients. PMID:23861979

  8. MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis

    PubMed Central

    Wong, Hoi Leong Xavier; Jin, Guoxiang; Cao, Renhai; Zhang, Shuo; Cao, Yihai; Zhou, Zhongjun

    2016-01-01

    Lymphangiogensis is involved in various pathological conditions, such as arthritis and cancer metastasis. Although many factors have been identified to stimulate lymphatic vessel growth, little is known about lymphangiogenesis inhibitors. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) is an endogenous suppressor of lymphatic vessel growth. MT1-MMP-deficient mice exhibit spontaneous corneal lymphangiogenesis without concomitant changes in angiogenesis. Mice lacking MT1-MMP in either lymphatic endothelial cells or macrophages recapitulate corneal lymphangiogenic phenotypes observed in Mmp14−/− mice, suggesting that the spontaneous lymphangiogenesis is both lymphatic endothelial cells autonomous and macrophage associated. Mechanistically, MT1-MMP directly cleaves LYVE-1 on lymphatic endothelial cells to inhibit LYVE-1-mediated lymphangiogenic responses. In addition, MT1-MMP-mediated PI3Kδ signalling restrains the production of VEGF-C from prolymphangiogenic macrophages through repressing the activation of NF-κB signalling. Thus, we identify MT1-MMP as an endogenous inhibitor of physiological lymphangiogenesis. PMID:26926389

  9. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance

    PubMed Central

    Zolla, Valerio; Nizamutdinova, Irina Tsoy; Scharf, Brian; Clement, Cristina C; Maejima, Daisuke; Akl, Tony; Nagai, Takashi; Luciani, Paola; Leroux, Jean-Christophe; Halin, Cornelia; Stukes, Sabriya; Tiwari, Sangeeta; Casadevall, Arturo; Jacobs, William R; Entenberg, David; Zawieja, David C; Condeelis, John; Fooksman, David R; Gashev, Anatoliy A; Santambrogio, Laura

    2015-01-01

    The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic’s endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport. PMID:25982749

  10. Lymphatic Filariasis: Frequently Asked Questions (FAQs)

    MedlinePlus

    ... a parasitic disease caused by microscopic, thread-like worms. The adult worms only live in the human lymph system. The ... South America. You cannot get infected with the worms in the United States. How is lymphatic filariasis ...

  11. 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

  12. 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.

  13. Deep pulmonary lymphatics in immature lungs.

    PubMed

    Dickie, Renée; Cormack, Meredith; Semmler-Behnke, Manuela; Kreyling, Wolfgang G; Tsuda, Akira

    2009-09-01

    Recently, we found that the translocation of inhaled nanoparticles from the air space to secondary organs is age dependent and substantially greater in neonates than in adults (J Respir Crit Care Med 177: A48, 2008). One reason for this difference might be age-dependent differences in alveolar barrier integrity. Because the neonate lung is undergoing morphogenetic and fluid balance changes, we hypothesize that the alveolar barrier of developing lungs is more easily compromised and susceptible to foreign material influx than that of adult lungs. On the basis of these hypotheses, we predict that the postnatally developing lung is also more likely to allow the translocation of some materials from the air space to the lymphatic lumens. To test this idea, we intratracheally instilled methyl methacrylate into immature and adult lungs and compared lymphatic filling between these two age groups. Scanning electron microscopy of the resultant corrosion casts revealed peribronchial saccular and conduit lymphatic architecture. Deep pulmonary lymphatic casts were present on the majority (58.5%) of airways in immature lungs, but lymphatic casting in adult lungs, as anticipated, was much more infrequent (21.6%). Thus the neonate lung appears to be more susceptible than the adult lung to the passage of instilled methyl methacrylate from the air space into the lymphatics. We speculate that this could imply greater probability of translocation of other materials, such as nanoparticles, from the immature lung as well. PMID:19556455

  14. Label free in vivo laser speckle imaging of blood and lymph vessels

    NASA Astrophysics Data System (ADS)

    Kalchenko, Vyacheslav; Kuznetsov, Yuri; Meglinski, Igor; Harmelin, Alon

    2012-05-01

    The peripheral lymphatic vascular system is a part of the immune body system comprising a complex network of lymph vessels and nodes that are flowing lymph toward the heart. Traditionally the imaging of lymphatic vessels is based on the conventional imaging modalities utilizing contrast fluorescence materials. Given the important role of the lymphatic system there is a critical need for the development of noninvasive imaging technologies for functional quantitative diagnosis of the lymph vessels and lymph flow without using foreign chemicals. We report a label free methodology for noninvasive in vivo imaging of blood and lymph vessels, using long-exposure laser speckle imaging approach. This approach entails great promise in the noninvasive studies of tissues blood and lymph vessels distribution in vivo.

  15. Lymphatic endothelial cells actively regulate prostate cancer cell invasion.

    PubMed

    Shah, Tariq; Wildes, Flonne; Kakkad, Samata; Artemov, Dmitri; Bhujwalla, Zaver M

    2016-07-01

    Lymphatic vessels serve as the primary route for metastatic spread to lymph nodes. However, it is not clear how interactions between cancer cells and lymphatic endothelial cells (LECs), especially within hypoxic microenvironments, affect the invasion of cancer cells. Here, using an MR compatible cell perfusion assay, we investigated the role of LEC-prostate cancer (PCa) cell interaction in the invasion and degradation of the extracellular matrix (ECM) by two human PCa cell lines, PC-3 and DU-145, under normoxia and hypoxia, and determined the metabolic changes that occurred under these conditions. We observed a significant increase in the invasion of ECM by invasive PC-3 cells, but not poorly invasive DU-145 cells when human dermal lymphatic microvascular endothelial cells (HMVEC-dlys) were present. Enhanced degradation of ECM by PC-3 cells in the presence of HMVEC-dlys identified interactions between HMVEC-dlys and PCa cells influencing cancer cell invasion. The enhanced ECM degradation was partly attributed to increased MMP-9 enzymatic activity in PC-3 cells when HMVEC-dlys were in close proximity. Significantly higher uPAR and MMP-9 expression levels observed in PC-3 cells compared to DU-145 cells may be one mechanism for increased invasion and degradation of matrigel by these cells irrespective of the presence of HMVEC-dlys. Hypoxia significantly decreased invasion by PC-3 cells, but this decrease was significantly attenuated when HMVEC-dlys were present. Significantly higher phosphocholine was observed in invasive PC-3 cells, while higher glycerophosphocholine was observed in DU-145 cells. These metabolites were not altered in the presence of HMVEC-dlys. Significantly increased lipid levels and lipid droplets were observed in PC-3 and DU-145 cells under hypoxia reflecting an adaptive survival response to oxidative stress. These results suggest that in vivo, invasive cells in or near lymphatic endothelial cells are likely to be more invasive and degrade the ECM

  16. An in vivo antilymphatic screen in zebrafish identifies novel inhibitors of mammalian lymphangiogenesis and lymphatic-mediated metastasis.

    PubMed

    Astin, Jonathan W; Jamieson, Stephen M F; Eng, Tiffany C Y; Flores, Maria V; Misa, June P; Chien, Annie; Crosier, Kathryn E; Crosier, Philip S

    2014-10-01

    The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral step in the metastatic spread of tumor cells, first to the sentinel lymph nodes that surround the tumor and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use, and there is an important potential clinical niche for antilymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have antilymphatic activity. These include kaempferol, a natural product found in plants; leflunomide, an inhibitor of pyrimidine biosynthesis; and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Antilymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide, and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumor-associated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model, kaempferol administration was also associated with tumor deposits in the pancreas and diaphragm, and flunarizine was found to be tumorigenic. Although this screen revealed that zebrafish is a viable platform for the identification and development of mammalian antilymphatic compounds, it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumor context. PMID:25053822

  17. Artificial Lymphatic Drainage Systems for Vascularized Microfluidic Scaffolds

    PubMed Central

    Wong, Keith H. K.; Truslow, James G.; Khankhel, Aimal H.; Chan, Kelvin L. S.; Tien, Joe

    2012-01-01

    The formation of a stably perfused microvasculature continues to be a major challenge in tissue engineering. Previous work has suggested the importance of a sufficiently large transmural pressure in maintaining vascular stability and perfusion. Here we show that a system of empty channels that provides a drainage function analogous to that of lymphatic microvasculature in vivo can stabilize vascular adhesion and maintain perfusion rate in dense, hydraulically resistive fibrin scaffolds in vitro. In the absence of drainage, endothelial delamination increased as scaffold density increased from 6 mg/mL to 30 mg/mL and scaffold hydraulic conductivity decreased by a factor of twenty. Single drainage channels exerted only localized vascular stabilization, the extent of which depended on the distance between vessel and drainage as well as scaffold density. Computational modeling of these experiments yielded an estimate of 0.40–1.36 cm H2O for the minimum transmural pressure required for vascular stability. We further designed and constructed fibrin patches (0.8 by 0.9 cm2) that were perfused by a parallel array of vessels and drained by an orthogonal array of drainage channels; only with the drainage did the vessels display long-term stability and perfusion. This work underscores the importance of drainage in vascularization, especially when a dense, hydraulically resistive scaffold is used. PMID:23281125

  18. Monitoring of small lymphatics function under different impact on animal model by integrated optical imaging

    NASA Astrophysics Data System (ADS)

    Galanzha, Ekaterina I.; Tuchin, Valery V.; Chowdhury, Parimal; Zharov, Vladimir P.

    2004-08-01

    The digital transmission microscopy is very informative, noninvasive for vessels, simple and available method for studying and measuring lymph microvessels function in vivo. Rat mesentery can use as promising animal model of lymph microvessels in vivo. Such imaging system allowed visualizing the entire lymphangion (with input and output valves), its wall, lymphatic valves, lymph flow as well as single cells in flow; obtaining anew basic information on lymph microcirculation and quantitative data on lymphatic function including indexes of phasic contractions and valve function, the quantitative parameters of lymph-flow velocity. Rat mesentery is good model to create different types of lymphedemas in acute and chronic experiments. The obtained data revealed that significant edema started immediately after lymph node dissection in one-half of cases and was accompanied by lymphatic disturbances. The greatest degree of edema was found after 1 week. After 4 weeks, the degree of edema sometimes decreased, but functional lymphatic disturbances progressed. Nicotine had significant direct dose-dependent effect on microlymphatic function at the acute local application, but the same dose of this drug was not effect on microcirculation in chronic intoxication. Despite yielding interesting data, transmittance microscopy had some limitations when applied to microcirculation studies. The problems could be solved at the application of integrated measuring technique.

  19. The use of novel lymphatic endothelial cell-specific immunohistochemical markers to differentiate cutaneous angiosarcomas in dogs.

    PubMed

    Halsey, C H C; Worley, D R; Curran, K; Charles, J B; Ehrhart, E J

    2016-09-01

    Lymphangiosarcomas are uncommon vascular neoplasms that arise from lymphatic endothelial cells (LECs). They efface and replace normal subcutaneous tissue and are characterised by arborising, vascular channels lined by a single layer of pleomorphic endothelial cells and a paucity of erythrocytes. Lymphangiosarcomas are architecturally similar to hemangiosarcomas, a common malignancy of vascular origin arising from blood vascular endothelial cells. Common immunohistochemical markers for vascular endothelium, such as Factor VIII-related antigen (F8RA) and CD31, have traditionally been used to confirm the diagnosis of tumours of vascular origin. However, these markers fail to differentiate between lymphangiosarcoma and hemangiosarcoma, which often show overlapping morphologic features, disparate clinical behaviour and require different treatment modalities. Here we describe the use of two novel LEC-specific markers, lymphatic vessel endothelial receptor-1 (LYVE-1) and prospero-related homeobox gene-1 (PROX-1), to further differentiate between vascular tumours of lymphatic (lymphangiosarcoma) and blood (hemangiosarcoma) endothelial cell origin in the dog. PMID:24593773

  20. [Lymphatic malformations in the head and neck area].

    PubMed

    Wiegand, S; Werner, J A

    2016-02-01

    Lymphatic malformations are congenital malformations of the lymphatic system. They are mainly located in the head and neck area, and grow proportional to the patients' body growth. Depending on the morphology, it can be distinguished between macrocystic, microcystic and mixed lymphatic malformations. Due to their infiltrative growth, microcystic lymphatic malformations are particularly difficult to treat. Therapeutic approaches include conventional surgical resection, laser therapy, sclerotherapy and systemic drug therapies. PMID:26820157

  1. Clinical Feasibility of Noninvasive Visualization of Lymphatic Flow using Principles of Spin Labeling MRI: Implications for Lymphedema Assessment

    PubMed Central

    Rane, Swati; Donahue, Paula M. C.; Towse, Ted; Ridner, Sheila; Chappell, Michael; Jordi, John; Gore, John; Donahue, Manus J.

    2015-01-01

    Purpose To extend a commonly employed, noninvasive arterial spin labeling (ASL) MRI method for measuring blood flow to evaluate lymphatic flow. Materials and Methods All volunteers (n=12) provided informed consent in accordance with IRB and HIPAA regulations. Quantitative relaxation time (T1 and T2) measurements were made in extracted human lymphatic fluid at 3.0T. Guided by these parameters, an ASL MRI approach was adapted to measure lymphatic flow (flow-alternating-inversion-recovery lymphatic water labeling; 3×3×5 mm3) in healthy subjects (n=6; 30±1 yrs; recruitment duration=2 months). Lymphatic flow velocity was quantified by performing spin labeling measurements as a function of post-labeling delay time and measuring the time-to-peak of signal in axillary lymph nodes. Clinical feasibility was evaluated in Stage II lymphedema patients (n=3; 60yr/F, 43yr/F, 64yr/F) and control subjects with unilateral cuff-induced lymphatic stenosis (n=3; 31yr/M, 31yr/M, 35yr/F). Results T1 and T2 of lymphatic fluid at 3.0T were 3100±160 ms (range=2930-3210 ms; median=3200 ms) and 610±12 ms (range=598-618 ms; median=610 ms), respectively. Healthy lymphatic flow (afferent vessel to axillary node) velocity was found to be 0.61±0.13 cm/min (n=6). A reduction (P<0.005) in lymphatic flow velocity in the affected arms of patients and the affected arms of healthy subjects with manipulated cuff-induced flow reduction was observed. The ratio of unaffected to affected axilla lymphatic velocity (1.24±0.18) was significantly (P<0.005) higher than the Left/Right ratio in healthy subjects (0.91±0.18). Conclusion This work provides a foundation for clinical investigations whereby lymphedema etiogenesis and therapies may be interrogated without exogenous agents and with clinically available imaging equipment. PMID:23864103

  2. 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

  3. 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. PMID:27297208

  4. 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

  5. Role of lymphatics in removal of sheep lung surfactant lipid.

    PubMed

    Tarpey, M M; O'Brodovich, H M; Young, S L

    1983-04-01

    To study the role of lung lymphatics in the removal of surfactant lipid from the sheep lung, we injected [1-14C]palmitate intravenously into six animals previously fitted with a cannula draining the caudal mediastinal lymph node. Lung lymph was collected for 100 h after injection of radiolabel. We obtained alveolar lavage material through a tracheostomy in four other animals after intravenous injection of [9,10-3H]palmitate. We measured radioactivity at several time points in lipid extracts from lymph, lavage fluid, and lung tissue. Alveolar lavage disaturated phosphatidylcholine (DSPC) specific activity peaked at about 40 h and was reduced to 30% of this value by 82 h. About 2% of the injected radiolabel was incorporated into lung tissue lipids. Only 4% of the level of labeling achieved in lung tissue lipids was found in lung lymph lipid during 100 h of lymph collection. Sixty-three percent of radiolabel in lymph lipid was recovered in phospholipids, and 29% of phospholipid radiolabel was found in DSPC. The distribution of phosphorus and palmitate radiolabel in lung lymph phospholipid did not closely resemble that of surfactant lipid. No rise in lung lymph DSPC specific activity was observed following the peak in lavage specific activity. If surfactant lipid is removed from the alveolar compartment without extensive recycling, then we conclude that the lung lymphatics do not play a major role in the clearance of surfactant lipid from the alveolar surface. PMID:6687883

  6. Ginsenoside Rg1 enhances lymphatic transport of intrapulmonary silica via VEGF-C/VEGFR-3 signaling in silicotic rats.

    PubMed

    Yu, Jie; Mao, Lijun; Guan, Li; Zhang, Yanlin; Zhao, Jinyuan

    2016-03-25

    Ginsenoside Rg1, extracted mainly from Panax ginseng, has been shown to exert strong pro-angiogenic activities in vivo. But it is unclear whether ginsenoside Rg1 could promote lung lymphangiogenesis to improve lymphatic transport of intrapulmonary silica in silicotic rats. Here we investigated the effect of ginsenoside Rg1 on lymphatic transport of silica during experimental silicosis, and found that ginsenoside Rg1 treatment significantly raised the silicon content in tracheobronchial lymph nodes and serum to reduce the silicon level in lung interstitium, meanwhile increased pulmonary lymphatic vessel density by enhancing the protein and mRNA expressions of vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3). The stimulative effect of ginsenoside Rg1 on lymphatic transport of silica was actively correlated with its pro-lymphangiogenic identity. And VEGFR-3 inhibitor SAR131675 blocked these above effects of ginsenoside Rg1. These findings suggest that ginsenoside Rg1 exhibits good protective effect against lung burden of silica during experimental silicosis through improving lymphatic transport of intrapulmonary silica, which is potentially associated with the activation of VEGF-C/VEGFR-3 signaling pathway. PMID:26920056

  7. Personalized Therapy for Generalized Lymphatic Anomaly/Gorham-Stout Disease With a Combination of Sunitinib and Taxol

    PubMed Central

    Rössler, Jochen; Saueressig, Ulrich; Kayser, Gian; von Winterfeld, Moritz

    2015-01-01

    The recently revised ISSVA classification approved in Melbourne in April 2014 recognizes generalized lymphatic anomaly and lymphatic malformation in Gorham-Stout disease. The 2 entities can overlap in presentation, as both are characterized by destructive lymphatic vessel invasion of the axial skeleton and surrounding soft tissues. At least at present, no standard therapeutic options exist, and due to the rarity of the disease, no clinical trials are available. We present 2 patients, 1 with generalized lymphatic anomaly and 1 with lymphatic malformation in Gorham-Stout disease, with severe exacerbation during puberty. The first child presented in florid pulmonary failure and pleural effusion, the other with severe pain due to bone destruction of the pelvis and inability to walk. Both were treated using individualized protocols. The manuscript describes the rationale for choosing sunitinib in combination with low-dose (metronomic) taxol. Both patients experienced clinical and radiologic response without major toxicities, suggesting that patients with rare conditions may benefit from individualized, molecularly based therapies. PMID:26458155

  8. Transcription factor COUP-TFII is indispensable for venous and lymphatic development in zebrafish and Xenopus laevis

    SciTech Connect

    Aranguren, Xabier L.; Beerens, Manu; Vandevelde, Wouter; Dewerchin, Mieke; Carmeliet, Peter; Luttun, Aernout

    2011-06-24

    Highlights: {yields} COUP-TFII deficiency in zebrafish affects arterio-venous EC specification. {yields} COUP-TFII is indispensable for lymphatic development in zebrafish. {yields} COUP-TFII knockdown in Xenopus disrupts lymphatic EC differentiation and migration. {yields} COUP-TFII's role in EC fate decisions is evolutionary conserved. -- Abstract: Transcription factors play a central role in cell fate determination. Gene targeting in mice revealed that Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII, also known as Nuclear Receptor 2F2 or NR2F2) induces a venous phenotype in endothelial cells (ECs). More recently, NR2F2 was shown to be required for initiating the expression of Prox1, responsible for lymphatic commitment of venous ECs. Small animal models like zebrafish embryos and Xenopus laevis tadpoles have been very useful to elucidate mechanisms of (lymph) vascular development. Therefore, the role of NR2F2 in (lymph) vascular development was studied by eliminating its expression in these models. Like in mice, absence of NR2F2 in zebrafish resulted in distinct vascular defects including loss of venous marker expression, major trunk vessel fusion and vascular leakage. Both in zebrafish and Xenopus the development of the main lymphatic structures was severely hampered. NR2F2 knockdown significantly decreased prox1 expression in zebrafish ECs and the same manipulation affected lymphatic (L)EC commitment, migration and function in Xenopus tadpoles. Therefore, the role of NR2F2 in EC fate determination is evolutionary conserved.

  9. High-resolution geophysical data collected aboard the U.S. Geological Survey research vessel Rafael to supplement existing datasets from Buzzards Bay and Vineyard Sound, Massachusetts

    USGS Publications Warehouse

    Pendleton, Elizabeth A.; Andrews, Brian D.; Danforth, William W.; Foster, David S.

    2014-01-01

    Geophysical and geospatial data were collected in Buzzards Bay, in the shallow-water areas of Vineyard Sound, and in the nearshore areas off the eastern Elizabeth Islands and northern coast of Martha's Vineyard, Massachusetts, on the U.S. Geological Survey research vessel Rafael between 2007 and 2011, in a collaborative effort between the U.S. Geological Survey and the Massachusetts Office of Coastal Zone Management. This report describes results of this collaborative effort, which include mapping the geology of the inner shelf zone of the Elizabeth Islands and the sand shoals of Vineyard Sound and studying geologic processes that contribute to the evolution of this area. Data collected during these surveys include: bathymetry, acoustic backscatter, seismic-reflection profiles, sound velocity profiles, and navigation. The long-term goals of this project are (1) to provide high-resolution geophysical data that will support research on the influence of sea-level change and sediment supply on coastal evolution and (2) to inventory subtidal marine habitats and their distribution within the coastal zone of Massachusetts.

  10. 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.

  11. Nature's rheologists: Lymphatic endothelial cells control migration in response to shear stress

    NASA Astrophysics Data System (ADS)

    Fuller, Gerald; Dunn, Alex; Surya, Vinay

    2015-03-01

    Endothelial cells (ECs) line the inner surface of blood and lymphatic vessels and are sensitive to fluid flow as part of their physiological function. EC organization, migration and vessel development are profoundly influenced by shear stresses, with important implications in cardiovascular disease and tumor metastasis. How ECs sense fluid flow is a central and unanswered question in cardiovascular biology. We developed a high-throughput live-cell flow chamber that models the gradients in wall shear stress experienced by ECs in vivo. Live-cell imaging allows us to probe cellular responses to flow, most notably EC migration, which has a key role in vessel remodeling. We find that most EC subtypes, including ECs from the venous, arterial, and microvascular systems, migrate in the flow direction. In contrast, human lymphatic microvascular ECs (hLMVECs) migrate against flow and up spatial gradients in wall shear stress. Further experiments reveal that hLMVECs are sensitive to the magnitude, direction, and the local spatial gradients in wall shear stress. Lastly, recent efforts have aimed to link this directional migration to spatial gradients in cell-mediated small molecule emission that may be linked to the gradient in wall shear stress.

  12. b-FGF Induces Corneal Blood and Lymphatic Growth in a Spatially Distinct Pattern

    PubMed Central

    Hajrasouliha, Amir R.; Sadrai, Zahra; Chauhan, Sunil K.; Dana, Reza

    2013-01-01

    Purpose To study the spatial variances in ligand expression and angiogenic effect in response to the inflammatory response induced by b-FGF. Methods b-FGF micropellets (80ng) were implanted in the temporal side of the cornea of Balbc/c mice. On days 1, 3, and 7 blood (heme) and lymph-angiogenesis were observed by immunofluorescence staining of corneal flat mounts with LYVE-1 and CD31 to identify lymphatic and blood vessels, respectively. A second group of corneas were harvested for quantitative RT-PCR. Each cornea was divided in two different area defines as (i) pre-pellet area and (ii) opposite-pellet area. Expression of VEGF ligands were evaluated using Real-time PCR in each respective zone. Results Blood vessels grew into the cornea from the pre-pellet area while corneal lymphatic vessels grew from the opposite-pellet area toward the center of the cornea. VEGF-A was upregulated in the pre-pellet while VEGF-D expression was mostly observed in the opposite-pellet area. VEGF-C level increased simultaneously in both areas. Conclusion A single inducing factor, i.e., b-FGF, may simultaneously provoke heme-and lymph-angiogenesis in different locations of the cornea through differential expression of VEGF ligands. This distinctive spatial pattern should be considered while evaluating the corneal predilection for inflammation beyond that which is directly visible by slit lamp examination. PMID:22467003

  13. Antiedema effects of Siberian ginseng in humans and its molecular mechanism of lymphatic vascular function in vitro.

    PubMed

    Fukada, Kaedeko; Kajiya-Sawane, Mika; Matsumoto, Yuko; Hasegawa, Tatsuya; Fukaya, Yukitaka; Kajiya, Kentaro

    2016-07-01

    The lymphatic system in the skin plays a major role in tissue fluid homeostasis, in the afferent phase of the immune response, and in tumor metastasis. Although lymphangiogenic factors involved in embryonic development and the metastatic spread of tumor cells have been well studied, little is known about small-molecule compounds that activate lymphatic function, especially under physiological conditions. We hypothesized that the identification of a lymphatic-activating compound could provide a method for improving edema. Here, we show that Siberian ginseng (Eleutherococcus senticosus) and its component eleutheroside E induce phosphorylation of the endothelial-specific receptor Tie2 in vitro. The activation of Tie2 on lymphatic endothelial cells (LECs) is known to stabilize lymphatic vessels, so we examined the effects of Siberian ginseng on LECs. We found that Siberian ginseng induces the migration and cord formation of LECs. Permeability assays demonstrated that it stabilizes LECs by promoting the intercellular localization of vascular endothelial cadherin, which is an endothelium-specific cell-cell adhesion molecule involved in endothelial barrier function, and it induces the phosphorylation of endothelial nitric oxide synthase by LECs. These effects appear to be mediated by the activation of Tie2 in LECs. Finally, we investigated whether the consumption of Siberian ginseng powder improves edema in a 2-way, randomized, crossover study in 50 healthy female volunteers. Edema of the lower limbs was significantly attenuated at 2 and 4hours after ingestion as compared with the control group. Thus, we demonstrate that Siberian ginseng exerts its potent antiedema activity mainly by promoting lymphatic function. PMID:27333960

  14. Hyperplasia, de novo lymphangiogenesis, and lymphatic regression in mice with tissue-specific, inducible overexpression of murine VEGF-D.

    PubMed

    Lammoglia, Gabriela M; Van Zandt, Carolynn E; Galvan, Daniel X; Orozco, Jose L; Dellinger, Michael T; Rutkowski, Joseph M

    2016-08-01

    Lymphatic vessels modulate tissue fluid balance and inflammation and provide a conduit for endocrine and lipid transport. The growth of new lymphatic vessels in the adult, lymphangiogenesis, is predominantly mediated through vascular endothelial growth factor receptor-3 (VEGFR-3) signaling. We took advantage of the unique binding of murine VEGF-D specifically to VEGFR-3 and generated mice capable of inducible, tissue-specific expression of murine VEGF-D under a tightly-controlled tetracycline response element (TRE) promoter to stimulate adult tissue lymphangiogenesis. With doxycycline-activated expression, TRE-VEGF-D mouse crossed to mice with tissue-specific promoters for the lung [Clara cell secretory protein-reverse tetracycline transactivator (rtTA)] developed pulmonary lymphangiectasia. In the kidney, (kidney-specific protein-rtTA × TRE-VEGF-D) mice exhibited rapid lymphatic hyperplasia on induction of VEGF-D expression. Crossed with adipocyte-specific adiponectin-rtTA mice [Adipo-VEGF-D (VD)], chronic VEGF-D overexpression was capable of inducing de novo lymphangiogenesis in white adipose tissue and a massive expansion of brown adipose tissue lymphatics. VEGF-D expression in white adipose tissue also increased macrophage infiltration and tissue fibrosis in the tissue. Expression did not, however, measurably affect peripheral fluid transport, the blood vasculature, or basal metabolic parameters. On removal of the doxycycline stimulus, VEGF-D expression returned to normal, and the expanded adipose tissue lymphatics regressed in Adipo-VD mice. The inducible TRE-VEGF-D mouse thus provides a novel murine platform to study the adult mechanisms and therapies of an array of disease- and tissue-specific models of lymphangiogenesis. PMID:27342876

  15. Interstitial fluid, plasma protein, colloid, and leukocyte uptake into initial lymphatics.

    PubMed

    Ikomi, F; Hunt, J; Hanna, G; Schmid-Schönbein, G W

    1996-11-01

    Lymphatics serve to remove from the interstitium a range of materials, including plasma proteins, colloid materials, and cells. Lymph flow rates can be enhanced by periodic tissue compression or venous pressure elevation, but little is known to what degree enhancement of lymph flow affects material transport. The objective was to examine the uptake of plasma proteins, a colloidal perflubron emulsion (LA-11063, mean particle diameter = 0.34 micron), and leukocytes into lymphatics. Prenodal collecting lymphatics in the lower hindlimb of rabbits were cannulated with and without foot massage and after elevation of venous pressure (40 mmHg). The average lymph flow rates were elevated approximately 22-fold by the skin massage but only about threefold by venous pressure elevation. Lymph-to-plasma protein concentration ratio remained unchanged by the massage but decreased significantly after venous pressure elevation. Lymph colloid concentration and leukocyte counts were elevated on average 47 and 8.5 times, respectively, by foot massage, but both decreased after venous pressure elevation. These results suggest that skin movement by massage and elevation of the venous pressure lead to opposite lymph transport kinetics of protein, colloids, and cells. Massage is more effective to enhance material transport out of the interstitium into the initial lymphatics. PMID:8941530

  16. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis

    PubMed Central

    Lee, Esak; Fertig, Elana J.; Jin, Kideok; Sukumar, Saraswati; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Breast cancer metastasis involves lymphatic dissemination in addition to hematogenous spreading. Although stromal lymphatic vessels (LVs) serve as initial metastatic routes, roles of organ-residing LVs are under-investigated. Here we show that lymphatic endothelial cells (LECs), a component of LVs within pre-metastatic niches, are conditioned by triple-negative breast cancer (TNBC) cells to accelerate metastasis. LECs within the lungs and lymph nodes, conditioned by tumor-secreted factors express CCL5 that is not expressed either in normal LECs or cancer cells, and direct tumor dissemination into these tissues. Moreover, tumor-conditioned LECs promote angiogenesis in these organs, allowing tumor extravasation and colonization. Mechanistically, tumor cell-secreted IL6 causes Stat3 phosphorylation in LECs. This pStat3 induces HIF-1α and VEGF, and a pStat3-pc-Jun-pATF-2 ternary complex induces CCL5 expression in LECs. This study demonstrates anti-metastatic activities of multiple repurposed drugs, blocking a self-reinforcing paracrine loop between breast cancer cells and LECs. PMID:25178650

  17. Lymphatic spreading and lymphadenectomy for esophageal carcinoma

    PubMed Central

    Ji, Xiang; Cai, Jie; Chen, Yao; Chen, Long-Qi

    2016-01-01

    Esophageal carcinoma (EC) is a highly lethal malignancy with a poor prognosis. One of the most important prognostic factors in EC is lymph node status. Therefore, lymphadenectomy has been recognized as a key that influences the outcome of surgical treatment for EC. However, the lymphatic drainage system of the esophagus, including an abundant lymph-capillary network in the lamina propria and muscularis mucosa, is very complex with cervical, mediastinal and celiac node spreading. The extent of lymphadenectomy for EC has always been controversial because of the very complex pattern of lymph node spreading. In this article, published literature regarding lymphatic spreading was reviewed and the current lymphadenectomy trends for EC are discussed. PMID:26843917

  18. Sterile inflammation after lymph node transfer improves lymphatic function and regeneration

    PubMed Central

    Joseph, Walter J.; Aschen, Seth; Ghanta, Swapna; Cuzzone, Daniel; Albano, Nicholas; Gardenier, Jason; Savetsky, Ira; Torrisi, Jeremy; Mehrara, Babak J.

    2014-01-01

    Introduction Lymph node transplantation is a promising surgical technique for the treatment of lymphedema. However, while initial clinical results have been largely promising, inconsistent responses have been reported in some cases. While the cause of this inconsistency remains unknown, it is likely that impaired lymphangiogenesis and spontaneous regeneration of lymphatic vessels in the transplanted lymph nodes may be a contributing factor suggesting that development of novel techniques to augment lymphangiogenesis may be clinically useful. The aim of this study was therefore to determine if sterile inflammatory reactions can serve as a physiologic means of augmenting lymphangiogenesis in transplanted lymph nodes using a murine model. Methods We used our previously reported model of lymph node transfer to study the effect of sterile inflammation on lymphatic regeneration. Mice were divided into 3 groups: Group 1 animals served as controls and underwent lymphadenectomy followed by immediate lymph node transplantation without inflammation. Group 2 animals (inflammation before transfer) were transplanted with lymph nodes harvested from donor animals in which a sterile inflammatory reaction was induced in the ipsilateral donor limb using complete Freund’s adjuvant and ovalbumin (CFA/OVA). Group 3 animals (inflammation after transfer) were transplanted with lymph nodes and then inflammation was induced in the ipsilateral limb using CFA/OVA. Lymphatic function, lymphangiogenesis, and lymph node histology were examined 28 days after transplant and compared with normal lymph node. Results Animals that had sterile inflammation after transplantation (group 3) had significantly improved lymphatic function (>2 fold increase) as assessed by lymphoscintigraphy, increased peri-nodal lymphangiogenesis, and functional lymphatics as compared with no-inflammation or inflammation before transplant groups (p<0.01). In addition, inflammation after transplantation was associated a more

  19. 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

  20. 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

  1. Lymphangiography to Treat Postoperative Lymphatic Leakage: A Technical Review

    PubMed Central

    Lee, Edward Wolfgang; Ko, Heung Kyu; Park, Jihong; Kim, Soo Hwan; Sung, Kyu-Bo

    2014-01-01

    In addition to imaging the lymphatics and detecting various types of lymphatic leakage, lymphangiography is a therapeutic option for patients with chylothorax, chylous ascites, and lymphatic fistula. Percutaneous thoracic duct embolization, transabdominal catheterization of the cisterna chyli or thoracic duct, and subsequent embolization of the thoracic duct is an alternative to surgical ligation of the thoracic duct. In this pictorial review, we present the detailed technique, clinical applications, and complications of lymphangiography and thoracic duct embolization. PMID:25469083

  2. [Mediastinal lymphatic spread of bronchopulmonary cancer].

    PubMed

    Riquet, M

    1991-01-01

    The mediastinum may be divided into 4 zones divided by the tracheo-bronchial axis in which are situated the lymphatic chains involved in the lymphatic drainage of the lungs. In the upper right zone there are 2 chains which are frequently involved, the right paratracheal chain (PTD) and the tracho-oesophageal chain (TO) and 2 lymphatic chains which are less often involved, the superior right phrenic chain (PH Dt) and the lymphatic chain which crosses the Azygos vein (AZM). In the superior left zone are found 2 chains which are frequently infiltrated: The pre-aortic carotid chain (AO) and the left superior bronchial chain (BSG) and 2 chains which are more rarely involved: The left superior phrenic (PHG) and the chain which crosses the aorta (the minor aorta Azygos; AOmi). At the level of the right and left inferior zones are found important groups of lymphatic ganglia at the intratracheo-bronchial bifurcation (ITB) and of one other part of the tracheo-oesophageal axis, the juxta-oesophageal ganglia (OE) and those of the triangular ligament (LT). The lymph coming from the pulmonary segments crosses the ganglia (LN) of the segments of the lobe and of the hilum before reaching the mediastinum and then at the final stage the lymph nodes situated on the margins of the mediastinum considered as N3 in cancer assessment. This schema is not the rule. In less than 5% of cases the lymph may drain without any lymph node relay either to the subclavicular hollow or to the thoracic duct in the mediastinum. More frequently (in 20-35% cases according to the segment considered) the lymph returns directly to the mediastinum ganglia without relaying through the intrapulmonary ganglia. Finally there are those cases where only the perilobar LN are involved. In these cases it is not necessarily the LN of the lobe drained but sometimes of another pulmonary lobe. These direct paths (N2) confirmed in study of cancer, demand and justify the need for a systematic cure of mediastinal LN. It is

  3. 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).

  4. PKC activation increases Ca2+ sensitivity of permeabilized lymphatic muscle via myosin light chain 20 phosphorylation-dependent and -independent mechanisms

    PubMed Central

    Dougherty, Patrick J.; Nepiyushchikh, Zhanna V.; Chakraborty, Sanjukta; Wang, Wei; Davis, Michael J.; Zawieja, David C.

    2014-01-01

    The contractile activity of muscle cells lining the walls of collecting lymphatics is responsible for generating and regulating flow within the lymphatic system. Activation of PKC signaling contributes to the regulation of smooth muscle contraction by enhancing sensitivity of the contractile apparatus to Ca2+. It is currently unknown whether PKC signaling contributes to the regulation of lymphatic muscle contraction. We hypothesized that the activation of PKC signaling would increase the sensitivity of the lymphatic myofilament to Ca2+. To test this hypothesis, we determined the effects of PKC activation with phorbol esters [PMA or phorbol dibutyrate (PDBu)] on the contractile behavior of α-toxin-permeabilized rat mesenteric and cervical lymphatics or the thoracic duct. The addition of PMA or PDBu induced a significant increase in the contractile force of submaximally activated α-toxin-permeabilized lymphatic muscle independent of a change in intracellular Ca2+ concentration, and the Ca2+-force relationship of lymphatic muscle was significantly left shifted, indicating greater myofilament Ca2+ sensitivity. Phorbol esters increased the maximal rate of force development, whereas the rate of relaxation was reduced. Western blot and immunohistochemistry data indicated that the initial rapid increase in tension development after stimulation by PDBu was associated with myosin light chain (MLC)20 phosphorylation; however, the later, steady-state Ca2+ sensitization of permeabilized lymphatic muscle was not associated with increased phosphorylation of MLC20 at Ser19, 17-kDa C-kinase-potentiated protein phosphatase-1 inhibitor at Thr38, or caldesmon at Ser789. Thus, these data indicate that PKC-dependent Ca2+ sensitization of lymphatic muscle may involve MLC20 phosphorylation-dependent and -independent mechanism(s). PMID:24414065

  5. Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study

    PubMed Central

    2010-01-01

    Background Lymph node metastasis in endometrial cancer significantly decreases survival rate. Few data on the influence of intratumoral lymphatic microvessel density (LMVD) on survival in endometrial cancer are available. Our aim was to assess the intratumoral LMVD of endometrial carcinomas and to investigate its association with classical pathological factors, lymph node metastasis and survival. Methods Fifty-seven patients with endometrial carcinoma diagnosed between 2000 and 2008 underwent complete surgical staging and evaluation of intratumoral LMVD and other histologic variables. Lymphatic microvessels were identified by immunohistochemical staining using monoclonal antibody against human podoplanin (clone D2-40) and evaluated by counting the number of immunostained lymphatic vessels in 10 hot spot areas at 400× magnification. The LMVD was expressed by the mean number of vessels in these 10 hot spot microscopic fields. We next investigated the association of LMVD with the clinicopathologic findings and prognosis. Results The mean number of lymphatic vessels counted in all cases ranged between 0 and 4.7. The median value of mean LMVD was 0.5, and defined the cut-off for low and high LMVD. We identified low intratumoral LMVD in 27 (47.4%) patients and high LMVD in 30 (52.6%) patients. High intratumoral LMVD was associated with lesser miometrial and adnaexal infiltration, lesser cervical and peritoneal involvement, and fewer fatal cases. Although there was lower lymph node involvement among cases with high LMVD, the difference did not reach significance. No association was seen between LMVD and FIGO staging, histological type, or vascular invasion. On the other hand, low intratumoral LMVD was associated with poor outcome. Seventy-five percent of deaths occurred in patients with low intratumoral LMVD. Conclusion Our results show association of high intratumoral LMVD with features related to more localized disease and better outcome. We discuss the role of

  6. Du-Huo-Ji-Sheng-Tang Attenuates Inflammation of TNF-Tg Mice Related to Promoting Lymphatic Drainage Function

    PubMed Central

    Chen, Yan; Li, Jinlong; Li, Qiang; Wang, Tengteng; Xing, Lianping; Xu, Hao; Wang, Yongjun; Shi, Qi; Zhou, Quan; Liang, Qianqian

    2016-01-01

    To investigate whether Du-Huo-Ji-Sheng-Tang (DHJST) attenuate inflammation of RA related to lymphatic drainage function in vivo, we treated eight 3-month-old TNF-Tg mice with DHJST (12 g/kg) or the same volume of physiological saline once every day for 12 weeks, and 3-month-old WT littermates were used as negative control. After twelve weeks, we performed NIR-ICG imaging and found that DHJST increased the ICG clearance at the footpad and the pulse of efferent lymphatic vessel between popliteal lymph node and footpad. Histology staining at ankle joints showed that DHJST decreases synovial inflammation, bone erosion, cartilage erosion, and TRAP+ osteoclast area in TNF-Tg mice. Immunohistochemical staining by using anti-Lyve-1 and anti-podoplanin antibody showed that DHJST stimulated lymphangiogenesis in ankle joints of TNF-Tg mice. And zebrafish study suggested that DHJST promoted the formation of lymphatic thoracic duct. In conclusion, DHJST inhibits inflammation severity and promotes lymphangiogenesis and lymphatic drainage function of TNF-Tg mice. PMID:27239212

  7. Community-directed treatment of lymphatic filariasis in Kenya and its role in the national programmes for elimination of lymphatic filariasis.

    PubMed

    Wamae, Njeri; Njenga, Sammy M; Kisingu, Wilfred M; Muthigani, Pauline W; Kiiru, Karanja

    2006-01-01

    We conducted a prospective, cross-sectional study to examine and compare treatment coverage of lymphatic filariasis by the health system (HST) and a health system implemented, community-directed treatment for the control of lymphatic filariasis (ComDT / HS) in 44 randomly selected villages in coastal Kenya. Demographic information on the villages and peripheral health facilities to guide design and implementation was obtained from a situation analysis phase of this study. A series of interactive training sessions on basic biology of lymphatic filariasis, concept and philosophy of ComDT / HS were given to members of the District Health Management Team (DHMT), peripheral health staff, community leaders and community drug distributors (CDDs) prior to ivermectin distribution. An intensive sensitization process of the community by the trained peripheral health staff and community leaders followed before selection of the CDDs. Quantitative and qualitative data for evaluation of the study were collected by coverage surveys of randomly selected households, focus group discussions and interviews, immediately after the drug distribution. Treatment coverage of all eligible persons was 46.5 and 88 % in HST and ComDT/HS villages, respectively, P < 0.001. In comparing treatment coverage by the two study arms in relationship to the distance from a health facility, coverage among HST and not ComDT / HS villages was influenced by distance. In Kenya, ComDT / HS can effectively be implemented by the regular health system and can attain coverage levels compatible with the global filariasis elimination goal. PMID:17348745

  8. Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair

    PubMed Central

    Lee, Shin-Jeong; Park, Changwon; Lee, Ji Yoon; Kim, Sangsung; Kwon, Pil Jae; Kim, Woansang; Jeon, Yong Heui; Lee, Eugine; Yoon, Young-sup

    2015-01-01

    Human pluripotent stem cells (hPSCs) have emerged as an important source for cell therapy. However, to date, no studies demonstrated generation of purified hPSC-derived lymphatic endothelial cells (LECs) and tested their therapeutic potential in disease models. Here we sought to differentiate hPSCs into the LEC lineage, purify them with LEC markers, and evaluate their therapeutic effects. We found that an OP9-assisted culture system reinforced by addition of VEGF-A, VEGF-C, and EGF most efficiently generated LECs, which were then isolated via FACS-sorting with LYVE-1 and PODOPLANIN. These hPSC-derived LYVE-1+PODOPLANIN+cells showed a pure committed LEC phenotype, formed new lymphatic vessels, and expressed lymphangiogenic factors at high levels. These hPSC-derived LECs enhanced wound healing through lymphangiogenesis and lymphvasculogenesis. Here we report, for the first time, that LECs can be selectively isolated from differentiating hPSCs, and that these cells are potent for lymphatic vessel formation in vivo and wound healing. This system and the purified hPSC-derived LECs can serve as a new platform for studying LEC development as well as for cell therapy. PMID:26066093

  9. Lymphatic drainage and CTV in pancreatic carcinoma.

    PubMed

    Morganti, Alessio G; Cellini, Numa; Mattiucci, Gian Carlo; Macchia, Gabriella; Smaniotto, Daniela; Luzi, Stefano; Balducci, Mario; Deodato, Francesco; Valentini, Vincenzo; Trodella, Lucio

    2003-01-01

    CTV definition in exclusive or adjuvant radiation therapy of pancreatic carcinoma is essentially based on the opinion of "expert" authors and on the knowledge of lymphatic pathways. The subject has been widely debated. Radiotherapy treatments of the entire upper abdomen (liver and pancreatic region), pancreas and lymph node stations, to volumes focused on macroscopic tumor only, have been proposed. Carcinoma of exocrine pancreas is characterized by the frequent, early appearance of metastasis via the lymphatic route. Most commonly involved lymph node stations include those of the celiac trunk, superior mesenteric, peripancreatic, lumboaortic lymph nodes, those of the hepatic portal (the latter in particular for pancreatic head tumors) and of the hilum of spleen (the latter in particular for pancreatic tail tumors). The possible multicentricity of pancreatic carcinoma, most likely due to intraductal spread, should lead to the inclusion in the CTV of the entire pancreatic parenchyma. This should be considered also for the frequent perineural intra- or extrapancreatic spread of pancreatic carcinoma present also in small tumors (T1). In extrapancreatic spread the retropancreatic adipose tissue should be included in the CTV at least at the GTV level. At the present state of knowledge, in the absence of pattern of failure analysis and of comparison of different treatment approaches, in terms of the definition of volumes of interest, CTV definitions which include lymphatic drainage stations, most part of pancreatic parenchyma and retropancreatic adipose tissue seem justified especially in treatments for cure. In palliation, the CTV may be limited to the GTV and the adipose tissue behind it. PMID:15018319

  10. Nitric oxide formation by lymphatic bulb and valves is a major regulatory component of lymphatic pumping

    PubMed Central

    Gasheva, Olga Yu.; Zawieja, David C.

    2011-01-01

    Microscopic lymphatics produce nitric oxide (NO) during contraction as flow shear activates the endothelial cells. The valve leaflets and bulbous valve housing contain a large amount of endothelial nitric oxide synthase (eNOS) due both to many endothelial cells and increased expression of eNOS. Direct NO measurements indicate the valve area has a 30–50% higher NO concentration ([NO]) than tubular regions although both regions generate equivalent relative increases in [NO] with each contraction. We hypothesize that 1) the greater eNOS and [NO] of the bulb region would have greater effects to lower pumping activity of the overall lymphatic than occurs in tubular regions and 2), the elevated [NO] in the bulb region may be because of high NO production in the valve leaflets that diffuses to the wall of the bulb. Measurement of [NO] with a micropipette inside the lymphatic bulb revealed the valve leaflets generate ∼50% larger [NO] than the bulb wall in the in vivo rat mesenteric lymphatics. The valves add NO to the lymph that quickly diffuses to the bulb wall. Bradykinin locally released iontophoretically from a micropipette on both bulbs and tubes increased the [NO] in a dose-dependent manner up to ∼50%, demonstrating agonist activation of the NO pathway. However, pumping output determined by contraction frequency and stroke volume decreased much more for the bulb than tubular areas in response to the bradykinin. In effect, NO generation by the bulb area and its valves limits the pumped flow of the total lymphatic by lowering frequency and stroke volume of individual contractions. PMID:21890688

  11. Lymphatic Filariasis in Children in Haiti.

    PubMed

    Byrne, Sharon K; Collins, Shonta D

    2015-01-01

    Using available evidence and astute assessment skills, nurses and advanced practice nurses, as members of an inter-professional team, were able to assess, diagnose, and initiate treatment for a child with lymphatic filariasis within a global health practice setting. The lessons learned during health outreach trips to an underserved commune of Port-au-Prince, Haiti can promote an understanding of appropriate nursing practice related to this parasitic infection. They can also assist nursing students, nurse practitioner students, and faculties as members of a medical outreach team to promote sustainability which is a benchmark of nursing leadership in global health. PMID:26121754

  12. Lymphatic filariasis: A view at pathological diversity

    PubMed Central

    Mahalingashetti, Prashant Basavaraj; Subramanian, Ramaswamy Anikode; Jayker, Sushan Shweta; Vijay, A

    2014-01-01

    Filariasis is traditionally diagnosed following screening of peripheral smear for microfilaria. Clinically lymphatic filariasis mimics the common local diseases. Thus, it is plausible to observe this parasitic infection in histological sections. We encountered three such cases, which displayed diverse patterns of immune response. Presence of both dead and viable worm at the same foci suggests that such immune response could be the result of parasitic death. Histological features such as endothelial injury and granulomatous response attests to the role of Wolbachia bacteria in influencing tissue response. PMID:25250237

  13. 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

  14. Evaluation of the use of surrogate tissues for calculating radiation dose to lymphatic nodes from external photon beams

    PubMed Central

    Lamart, Stephanie; Moroz, Brian E.; Lee, Choonsik

    2013-01-01

    Lymphatic node chains of the human body are particularly difficult to realistically model in computational human phantoms. In the absence of a lymphatic node model, researchers have used the following surrogate tissues to calculate the radiation dose to the lymphatic nodes: blood vessels, muscle and the combination of the muscle and adipose tissues. In the present work, the authors investigated whether and in which extent the use of different surrogate tissues is appropriate to assess the lymph node dose, using a realistic model of lymphatic nodes that the authors recently reported. Using a Monte Carlo radiation transport method coupled with the adult male hybrid phantom that included the lymph node model, the air kerma-to-absorbed dose conversion coefficients (Gy Gy−1) to the lymph nodes and other tissues used as surrogates for external photon beams of 15 discrete energies (0.015–10 MeV) were computed using the following six idealised geometries: anterior–posterior (AP), posterior–anterior (PA), right lateral, left lateral, rotational and isotropic. To validate the results of this study, the lymph node dose calculated here was compared with the dose published by the International Commission on Radiological Protection for the adult male reference phantom. The lymph node dose conversion coefficients with the values calculated for the blood vessels, muscle, adipose tissue and the combination of muscle and adipose tissues were then compared. It was found that muscle was the best estimator for the lymph nodes, with a dose difference averaged across energies >0.08 MeV of <8 % in all irradiation geometries excluding the AP and PA geometries for which the blood vessels were found to be the best estimator. In conclusion, muscle and blood vessels may preferably be used as surrogate tissues in the absence of lymphatic nodes in a given voxel phantom. For energies <0.08 MeV, for which the authors observed a difference of up to 30-fold, an explicit lymph node model may

  15. Lymphatic Specific Disruption in the Fine Structure of Heparan Sulfate Inhibits Dendritic Cell Traffic and Functional T Cell Responses in the Lymph Node

    PubMed Central

    Yin, Xin; Johns, Scott C.; Kim, Daniel; Mikulski, Zbigniew; Salanga, Catherina L.; Handel, Tracy M.; Macal, Mónica; Zúñiga, Elina I.; Fuster, Mark M.

    2014-01-01

    Dendritic cells (DC) are potent antigen-presenting cells essential for initiating adaptive immunity. Following pathogen exposure, trafficking of DC to lymph nodes (LN) through afferent lymphatic vessels constitutes a crucial step in the execution of their functions. The mechanisms regulating this process, however, are poorly understood, although the involvement of certain chemokines in this process has recently been reported. Herein, we demonstrate that genetically altering the fine structure (N-sulfation) of heparan sulfate specifically in mouse lymphatic endothelium significantly reduces DC trafficking to regional lymph nodes in vivo. Moreover, this alteration had the unique functional consequence of reducing CD8+ T cell proliferative responses in draining lymph nodes in an ovalbumin immunization model. Mechanistic studies suggested that lymphatic endothelial heparan sulfate regulates multiple steps during DC trafficking, including optimal presentation of chemokines on the surface of DC, thus acting as a co-receptor that may function “in trans” to mediate chemokine-receptor binding. This study not only identifies novel glycan-mediated mechanisms that regulate lymphatic DC trafficking, but also validates the fine structure of lymphatic-vascular specific heparan sulfate as a novel molecular target for strategies aiming to modulate DC behavior and/or alter pathologic T cell responses in lymph nodes. PMID:24493818

  16. Reactor vessel stud thread protector

    SciTech Connect

    Gasparro, M.R.

    1989-04-04

    This patent describes a stud thread protector for a nuclear reactor pressure vessel. The vessel has a removable closure head, the closure head being sealingly engaged with the pressure vessel by a plurality of stud bolts, an upper end thereof having a threaded section for threadingly engaging a nut and a vertical bore being disposed within the stud bolt. The stud thread protector encloses the exposed upper portion of the bolt and associated nut projecting above the closure head. The reactor vessel stud thread protector is comprised of: a tubular wall portion being opened at its lower end and substantially closed at its upper end; a drip pan associated with the outer surface of the protector, the drip pan being disposed radially inwardly with respect to the outer periphery of the vessel head, whereby the drip pan collects any fluid being emitted from the reactor vessel; and means for fastening the stud thread protector to an associated stud.

  17. CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin

    PubMed Central

    Hou, Wei-Hsien; Liu, I-Hua; Tsai, Cheng C.; Johnson, Frank E.; Huang, Shuan Shian; Huang, Jung San

    2011-01-01

    Cell-surface retention sequence (CRS) binding protein (CRSBP-1) is a membrane glycoprotein identified by its ability to bind PDGF-BB and VEGF-A via their CRS motifs (clusters of basic amino acid residues). CRSBP-1 is identical to LYVE-1 and exhibits dual ligand (CRS-containing proteins and hyaluronic acid) binding activity, suggesting the importance of CRSBP-1 ligands in lymphatic function. Here, we show that CRSBP-1 ligands induce disruption of VE-cadherin-mediated intercellular adhesion and opening of intercellular junctions in lymphatic endothelial cell (LEC) monolayers as determined by immunofluorescence microscopy and Transwell permeability assay. This occurs by interaction with CRSBP-1 in the CRSBP-1–PDGFβR–β-catenin complex, resulting in tyrosine phosphorylation of the complex, dissociation of β-catenin and p120-catenin from VE-cadherin, and internalization of VE-cadherin. Pretreatment of LECs with a PDGFβR kinase inhibitor abolishes ligand-stimulated tyrosine phosphorylation of VE-cadherin, halts the ligand-induced disruption of VE-cadherin intercellular adhesion and blocks the ligand-induced opening of intercellular junctions. These CRSBP-1 ligands also induce opening of lymphatic intercellular junctions that respond to PDGFβR kinase inhibitor in wild-type mice (but not in Crsbp1-null mice) as evidenced by increased transit of injected FITC–dextran and induced edema fluid from the interstitial space into lymphatic vessels. These results disclose a novel mechanism involved in the opening of lymphatic intercellular junctions. PMID:21444752

  18. Comparison of Methods for Xenomonitoring in Vectors of Lymphatic Filariasis in Northeastern Tanzania.

    PubMed

    Irish, Seth R; Stevens, William M B; Derua, Yahya A; Walker, Thomas; Cameron, Mary M

    2015-11-01

    Monitoring Wuchereria bancrofti infection in mosquitoes (xenomonitoring) can play an important role in determining when lymphatic filariasis has been eliminated, or in focusing control efforts. As mosquito infection rates can be low, a method for collecting large numbers of mosquitoes is necessary. Gravid traps collected large numbers of Culex quinquefasciatus in Tanzania, and a collection method that targets mosquitoes that have already fed could result in increased sensitivity in detecting W. bancrofti-infected mosquitoes. The aim of this experiment was to test this hypothesis by comparing U.S. Centers for Disease Control and Prevention (CDC) light traps with CDC gravid traps in northeastern Tanzania, where Cx. quinquefasciatus is a vector of lymphatic filariasis. After an initial study where small numbers of mosquitoes were collected, a second study collected 16,316 Cx. quinquefasciatus in 60 gravid trap-nights and 240 light trap-nights. Mosquitoes were pooled and tested for presence of W. bancrofti DNA. Light and gravid traps collected similar numbers of mosquitoes per trap-night, but the physiological status of the mosquitoes was different. The estimated infection rate in mosquitoes collected in light traps was considerably higher than in mosquitoes collected in gravid traps, so light traps can be a useful tool for xenomonitoring work in Tanzania. PMID:26350454

  19. 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.

  20. A Case of Abnormal Lymphatic-Like Differentiation and Endothelial Progenitor Cell Activation in Neovascularization Associated with Hemi-Retinal Vein Occlusion

    PubMed Central

    Loukovaara, Sirpa; Gucciardo, Erika; Repo, Pauliina; Lohi, Jouko; Salven, Petri; Lehti, Kaisa

    2015-01-01

    Purpose Pathological vascular differentiation in retinal vein occlusion (RVO)-related neovessel formation remains poorly characterized. The role of intraocular lymphatic-like differentiation or endothelial progenitor cell activity has not been studied in this disease. Methods Vitrectomy was performed in an eye with hemi-RVO; the neovessel membrane located at the optic nerve head was removed and subjected to immunohistochemistry. Characterization of the neovascular tissue was performed using hematoxylin and eosin, α-smooth muscle actin, and the pan-endothelial cell (EC) adhesion molecule CD31. The expression of lymphatic EC markers was studied by lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), podoplanin (PDPN), and prospero-related homeobox protein 1 (Prox-1). Potential vascular stem/progenitor cells were identified by active cellular proliferation (Ki67) and expression of the stem cell marker CD117. Results The specimen contained blood vessels lined by ECs and surrounded by pericytes. Immunoreactivity for LYVE-1 and Prox-1 was detected, with Prox-1 being more widely expressed in the active Ki67-positive lumen-lining cells. PDPN expression was instead found in the cells residing in the extravascular tissue. Expression of the stem cell markers CD117 and Ki67 suggested vascular endothelial progenitor cell activity. Conclusions Intraocular lymphatic-like differentiation coupled with progenitor cell activation may be involved in the pathology of neovessel formation in ischemia-induced human hemi-RVO. PMID:26327908

  1. A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound

    PubMed Central

    Kato, Shigeki; Mori, Shiro; Kodama, Tetsuya

    2015-01-01

    Chemotherapy based on hematogenous administration of drugs to lymph nodes (LNs) located outside the surgically resected area shows limited tissue selectivity and inadequate response rates, resulting in poor prognosis. Here, we demonstrate proof of concept for a lymphatic drug delivery system using nano/microbubbles (NMBs) and ultrasound (US) to achieve sonoporation in LNs located outside the dissection area. First, we demonstrated the in vitro effectiveness of doxorubicin (Dox) delivered into three different tumor cell lines by sonoporation. Sonoporation increased the Dox autofluorescence signal and resulted in a subsequent decrease in cell viability. Next, we verified the antitumor effects of Dox in vivo using MXH10/Mo-lpr/lpr mice that exhibit systemic lymphadenopathy, with some peripheral LNs reaching 10 mm in diameter. We defined the subiliac LN (SiLN) as the upstream LN within the dissection area, and the proper axillary LN (PALN) as the downstream LN outside the dissection area. Dox and NMBs were injected into the SiLN and delivered to the PALN via lymphatic vessels; the PALN was then exposed to US when it had filled with solution. We found that sonoporation enhanced the intracellular uptake of Dox leading to high cytotoxicity. We also found that sonoporation induced extravasation of Dox from lymphatic endothelia and penetration of Dox into tumor tissues within the PALN. Furthermore, our method inhibited tumor growth and diminished blood vessels in the PALN while avoiding systemic toxic effects of Dox. Our findings indicate that a lymphatic drug delivery system with sonoporation represents a promising method for treating metastatic LNs located outside the dissection area. PMID:26640589

  2. An Experimental Investigation of the Lymphatic System of the Teeth and Jaws

    PubMed Central

    MacGregor, Alexander

    1936-01-01

    A review of the literature is given, followed by a consideration of the available methods of demonstrating the lymphatic system in the area of the teeth and jaws. A new method of demonstrating this system by the injection or application of lead acetate intra vitam, is described, and the technique is explained. The method can be employed to reveal macroscopic or microscopic lymph channels in any part of the body, and is especially of value where decalcification of the hard tissues has to be carried out in the preparation of the sections. The various types of experiments which have been performed are described, and the macroscopic and microscopic results dealt with separately. Among the macroscopic results, the lymphatic drainage of various parts the jaws is described, and the large amount of anastomosis and cross anastomosis between the vessels is shown. A comparison of the lymphatic system in this region in the guinea-pig, cat, dog, and monkey is given, and it is demonstrated that the guinea-pig and monkey possess submental and supraclavicular lymph nodes which assist in the drainage of this area in addition to the submaxillary and cervical groups of nodes possessed by the cat and the dog. Among the microscopic results, the way in which the mass makes its way from the gingival tissues through the bone, and is found in the pulp, dentine, and cementum of the tooth, even where no pressure is applied, is described. The communication of the lymphatic vessels of the pulp with those of the periodontal membrane and the path of the mass down the periodontal membrane from the gingival trough, and its entry into the alveolar bone from this situation are demonstrated, and the way in which the mass reaches the pulp, dentine, and cementum of the tooth from the gingival tissues is discussed. The significance of various concentrations of the mass in the tissues, particularly the dentine, is also discussed. Control experiments are described, the conclusions which have been reached

  3. Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab' Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity.

    PubMed

    Chan, Linda J; Ascher, David B; Yadav, Rajbharan; Bulitta, Jürgen B; Williams, Charlotte C; Porter, Christopher J H; Landersdorfer, Cornelia B; Kaminskas, Lisa M

    2016-04-01

    The lymphatic system is a major conduit by which many diseases spread and proliferate. There is therefore increasing interest in promoting better lymphatic drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, which can limit the lymphatic exposure and activity of Fabs against lymph-resident diseases. This study therefore explored ideal PEGylation strategies to maximize biological activity and lymphatic exposure using trastuzumab Fab' as a model. Specifically, the Fab' was conjugated with single linear 10 or 40 kDa PEG chains at the hinge region. PEGylation led to a 3-4-fold reduction in binding affinity to HER2, but antiproliferative activity against HER2-expressing BT474 cells was preserved. Lymphatic pharmacokinetics were then examined in thoracic lymph duct cannulated rats after intravenous and subcutaneous dosing at 2 mg/kg, and the data were evaluated via population pharmacokinetic modeling. The Fab' displayed limited lymphatic exposure, but conjugation of 10 kDa PEG improved exposure by approximately 11- and 5-fold after intravenous (15% dose collected in thoracic lymph over 30 h) and subcutaneous (9%) administration, respectively. Increasing the molecular weight of the PEG to 40 kDa, however, had no significant impact on lymphatic exposure after intravenous (14%) administration and only doubled lymphatic exposure after subcutaneous administration (18%) when compared to 10 kDa PEG-Fab'. The data therefore suggests that minimal PEGylation has the potential to enhance the exposure and activity of Fab's against lymph-resident diseases, while no significant benefit is achieved with very large PEGs. PMID:26871003

  4. A Model for Interstitial Drainage Through a Sliding Lymphatic Valve.

    PubMed

    Heppell, Charles; Roose, Tiina; Richardson, Giles

    2015-06-01

    This study investigates fluid flow and elastic deformation in tissues that are drained by the primary lymphatic system. A model is formulated based on the Rossi hypothesis that states that the primary lymphatic valves, which are formed by overlapping endothelial cells around the circumferential lining of lymphatic capillaries, open in response to swelling of the surrounding tissue. Tissue deformation and interstitial fluid flow through the tissue are treated using the Biot equations of poroelasticity and, the fluid flux (into the interstitium) across the walls of the blood capillaries, is assumed to be linearly related to the pressure difference across the walls via a constant of proportionality (the vascular permeability). The resulting model is solved in a periodic domain containing one blood capillary and one lymphatic capillary starting from a configuration in which the tissue is undeformed. On imposition of a constant pressure difference between blood and lymphatic capillaries, the solutions are found to settle to a steady state. Given that the magnitude of pressure fluctuations in the lymphatic system is much smaller than this pressure difference between blood and lymph, it is postulated that the resulting steady-state solution gives a good representation of the state of the tissue under physiological conditions. The effects of changes to the Young's modulus of the tissue, the blood-lymphatic pressure difference, vascular permeability and valve dimensions on the steady state are investigated and discussed in terms of their effects on oedema in the context of age- and pregnancy-related changes to the body. PMID:25911590

  5. In vivo dual-modality imaging of lymphatic systems using indocyanine green in rats: three-dimensional photoacoustic imaging and planar fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Kim, Chulhong; Song, Kwang Hyun; Wang, Lihong V.

    2010-02-01

    The purpose of this study is to map non-invasively sentinel lymph nodes (SLNs) and lymphatic vessels of rats in vivo using FDA-approved indocyanine green (ICG) and two non-ionizing imaging modalities: volumetric spectroscopic photoacoustic (PA) imaging, which measures optical absorption, and planar fluorescence imaging, which measures fluorescent emission. SLNs and lymphatic vessels were clearly visible after a 0.2 ml-intradermal-injection of 1 mM ICG in both imaging systems. We also imaged deeply positioned lymph nodes in vivo by layering biological tissues on top of rats. These two modalities, when used together with ICG, have the potential to map SLNs in axillary staging and to study tumor metastasis in breast cancer patients.

  6. Tailoring of chronic lymphatic leukemia therapy

    PubMed Central

    Elhefni, Ashraf M

    2013-01-01

    Chronic lymphocytic leukemia (CLL) remains an incurable disease, with all patients who require therapy destined to relapse and understanding of the pathophysiology of chronic lymphocytic leukemia has advanced significantly. It is now clear that chronic lymphocytic leukemia is a relatively proliferative disorder that requires the help of its microenvironment to be maintained and to progress. The stimulation of the chronic lymphatic leukemia cell occurs in most, if not all, patients through antigen stimulation via the B cell receptors. In addition, there is now a appreciation of the role of the p53 pathway leading to chemoresistance and the elucidation of the molecular and intracellular signaling mechanisms of disease is just beginning to facilitate the development of several targeted small molecules that promise to revolutionize the treatment of Chronic lymphocytic leukemia. PMID:23997983

  7. Distribution of prosaposin in rat lymphatic tissues.

    PubMed

    Shimokawa, Tetsuya; Nabeka, Hiroaki; Yamamiya, Kimiko; Wakisaka, Hiroyuki; Takeuchi, Takashi; Kobayashi, Naoto; Matsuda, Seiji

    2013-06-01

    Prosaposin (PSAP) is as a trophic factor and an activator protein for sphingolipid hydrolase in lysosomes. We generated a specific antibody to PSAP and examined the spatiotemporal distribution of PSAP-immunoreactive (PSAP-IR) cells in the lymphatic tissues of Wistar rats. Immunoblots of tissue homogenates separated electrophoretically showed a single band for PSAP in brain but two bands in spleen. PSAP-IR cells were distributed in both the red and white pulp of the spleen, in both the cortex and medulla of the thymus and in mesenteric lymph nodes. Many PSAP-IR cells were found in the dome portion of Peyer's patches and the number of PSAP-IR cells increased with the age of the rat. To identify the PSAP-IR cells, double- and triple-immunostainings were performed with antibodies against PSAP, CD68 and CD1d. The large number of double- and triple-positive cells suggested that antigen-presenting cells contained much PSAP in these lymphatic tissues. Intense expression of PSAP mRNA, examined by in situ hybridisation, was observed in the red pulp and corona of the spleen. In rats, the PSAP gene generates two alternative splicing forms of mRNA: Pro+9 containing a 9-base insertion and Pro+0 without the insertion. We examined the expression patterns of the alternative splicing forms of PSAP mRNA in the spleen. The presence of both types of mRNA (Pro+9 and Pro+0) indicated that the spleen contains various types of prosaposin-producing and/or secreting cells. These findings suggest diverse functions for PSAP in the immune system. PMID:23420452

  8. Conjugated Linoleic Triacylglycerols Exhibit Superior Lymphatic Absorption Than Free Conjugate Linoleic Acids and Have Antiobesity Properties.

    PubMed

    Woo, Hyunjoon; Chung, Min-Yu; Kim, Juyeon; Kong, Daecheol; Min, Jinyoung; Choi, Hee-Don; Choi, In-Wook; Kim, In-Hwan; Noh, Sang K; Kim, Byung Hee

    2016-05-01

    This study aimed to compare lymphatic absorption of conjugated linoleic acids (CLAs) in the triacylglycerol (TAG) or free fatty acid (FFA) form and to examine the antiobesity effects of different doses of CLAs in the TAG form in animals. Conjugated linoleic TAGs (containing 70.3 wt% CLAs; CLA-TAG) were prepared through lipase-catalyzed esterification of glycerol with commercial CLA mixtures (CLA-FFA). Lymphatic absorption of CLA-TAG and CLA-FFA was compared in a rat model of lymphatic cannulation. Greater amounts of cis-9,trans-11 and trans-10,cis-12 CLAs were detected in the collected lymph from a lipid emulsion containing CLA-TAG. This result suggests that CLA-TAG has greater capacity for lymphatic absorption than does CLA-FFA. The antiobesity efficacy of CLA-TAG at different doses was examined in mice with diet-induced obesity. A high-fat diet (HFD) for 12 weeks caused a significant increase in body weight and epididymal and retroperitoneal fat weights, which were significantly decreased by 2% dietary supplementation (w/w) with CLA-TAG. CLA-TAG at 2% significantly attenuated the HFD-induced upregulation of serum TAG, but led to hepatomegaly and exacerbated HFD-induced hypercholesterolemia. CLA-TAG at 1% significantly attenuated upregulation of retroperitoneal fat weight and significantly increased liver weight, which was decreased by the HFD. Nonetheless, the liver weight in group "HFD +1% CLA-TAG" was not significantly different from that of normal diet controls. CLA-TAG at 1% significantly reduced serum TAG levels and did not exacerbate HFD-induced hypercholesterolemia. Thus, 1% dietary supplementation with CLA-TAG reduces retroperitoneal fat weight without apparent hepatomegaly, a known side-effect of CLAs in mouse models of obesity. PMID:27081749

  9. ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells.

    PubMed

    Mężyk-Kopeć, Renata; Wyroba, Barbara; Stalińska, Krystyna; Próchnicki, Tomasz; Wiatrowska, Karolina; Kilarski, Witold W; Swartz, Melody A; Bereta, Joanna

    2015-01-01

    Tumor-associated lymphatic vessels actively participate in tumor progression and dissemination. ADAM17, a sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules, is believed to promote tumor development, facilitating both tumor cell proliferation and migration, as well as tumor angiogenesis. In this work we addressed the issue of whether ADAM17 may also promote tumor lymphangiogenesis. First, we found that ADAM17 is important for the migratory potential of immortalized human dermal lymphatic endothelial cells (LEC). When ADAM17 was stably silenced in LEC, their proliferation was not affected, but: (i) single-cell motility, (ii) cell migration through a 3D Matrigel/collagen type I matrix, and (iii) their ability to form sprouts in a 3D matrix were significantly diminished. The differences in the cell motility between ADAM17-proficient and ADAM17-silenced cells were eliminated by inhibitors of EGFR and HER2, indicating that ADAM17-mediated shedding of growth factors accounts for LEC migratory potential. Interestingly, ADAM17 depletion affected the integrin surface expression/functionality in LEC. ADAM17-silenced cells adhered to plastic, type I collagen, and fibronectin faster than their ADAM17-proficient counterparts. The difference in adhesion to fibronectin was abolished by a cyclic RGD peptide, emphasizing the involvement of integrins in the process. Using a soluble receptor array, we identified BIG-H3 among several candidate proteins involved in the phenotypic and behavioral changes of LEC upon ADAM17 silencing. In additional assays, we confirmed the increased expression of BIG-H3, as well as TGFβ2 in ADAM17-silenced LEC. The antilymphangiogenic effects of ADAM17 silencing in lymphatic endothelial cells suggest further relevance of ADAM17 as a potential target in cancer therapy. PMID:26176220

  10. Insights into the Pathogenesis of Disease in Human Lymphatic Filariasis

    PubMed Central

    2013-01-01

    Abstract 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. PMID:24044755

  11. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    PubMed Central

    Luo, Guopei; Liu, Chen; Wu, Chuntao; Liu, Liang; Liu, Zuqiang; Ni, Quanxing; Long, Jiang; Yu, Xianjun

    2014-01-01

    As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer. PMID:24587996

  12. Latanoprost Stimulates Ocular Lymphatic Drainage: An In Vivo Nanotracer Study

    PubMed Central

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

    2013-01-01

    Purpose Ocular lymphatics have been recently shown to contribute to aqueous humor outflow. It is not yet known whether lymphatic outflow can be stimulated by pharmacological agents. Here we determine whether latanoprost, a prostaglandin F2 alpha analog commonly used to lower IOP to treat glaucoma, increases lymphatic drainage from the eye. Methods Lymphatic drainage in mice was assessed in vivo, in 11 latanoprost-treated and 11 control animals using hyperspectral imaging at multiple times following quantum dot (QD) injection into the eye. QD signal intensity was also measured in tissue sections using hyperspectral imaging. Results In the latanoprost-treated group, lymphatic drainage rate into the submandibular lymph node was increased compared with controls (1.23 ± 1.06 hours−1 vs. 0.30 ± 0.17 hours−1, mean ± SD, P < 0.02). Total QD signal intensity in the submandibular lymph node was greater in the latanoprost-treated group compared with controls (10.55 ± 1.12 vs. 9.48 ± 1.24, log scale, P < 0.05). Conclusions This is the first evidence that latanoprost increases lymphatic drainage from the eye. The pharmacological manipulation of this newly identified lymphatic outflow pathway may be relevant to treatments aimed at lowering intraocular pressure in glaucoma. Translational Relevance This is the first evidence that a prostaglandin drug widely prescribed for glaucoma, enhances lymphatic drainage from the eye. The pharmacological stimulation of this newly identified outflow pathway may be highly relevant to treatments aimed at lowering IOP to prevent blindness from glaucoma. PMID:24049723

  13. 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

  14. Return of lymphatic function after flap transfer for acute lymphedema.

    PubMed Central

    Slavin, S A; Van den Abbeele, A D; Losken, A; Swartz, M A; Jain, R K

    1999-01-01

    OBJECTIVE: The goals of this work were to develop animal models of lymphedema and tissue flap transfer, and to observe physiologic changes in lymphatic function that occur in these models over time, both systemically with lymphoscintigraphy (LS) and locally using fluorescence microlymphangiography (FM). SUMMARY BACKGROUND DATA: Although lymphedema has been managed by a combination of medical and surgical approaches, no effective long-term cure exists. Surgical attempts aimed at reconnecting impaired lymphatic channels or bypassing obstructed areas have failed. METHODS: The tails of rats (A groups) and mice (B groups) were used because of their different features. Lymphedema was created by ligation of the lymphatics at the tail base and quantified by diameter measurements there. In the experimental group, rectus abdominis myocutaneous flap was transferred across the ligation. In addition to the ligation (A1 and B1) and ligation + flap (A2 and B2) groups, three control groups were included: sham flap with ligation (B4), sham flap alone (B5), and normal (A3 and B3) animals. Observations were made at weekly time points for lymphatic function and continuity. RESULTS: Lymphedema was successfully created in the mouse ligation groups (B1 and B4) and sustained for the entire length of observation (up to 14 weeks). Lymphatic continuity was restored in those animals with transferred flaps across the ligation site (A2 and B2), as seen both by LS and FM. Sham flaps did not visibly affect lymphatic function nor did they cause any visible swelling in the tail. CONCLUSIONS: Acute lymphedema developing after ligation of tail lymphatics in mice can be prevented by myocutaneous flap transfer. Restored lymphatic continuity and function were demonstrable using lymphoscintigraphy and fluorescence microlymphangiography. Images Figure 2. Figure 4. Figure 5. PMID:10077056

  15. Current and future lymphatic imaging modalities for tumor staging.

    PubMed

    Murtaza, Ghulam; Gao, Kuo; Liu, Tiegang; Tariq, Imran; Sajjad, Ashif; Akram, Muhammad Rouf; 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

  16. Theranostic mRNA-loaded microbubbles in the lymphatics of dogs: implications for drug delivery.

    PubMed

    Dewitte, Heleen; Vanderperren, Katrien; Haers, Hendrik; Stock, Emmelie; Duchateau, Luc; Hesta, Myriam; Saunders, Jimmy H; De Smedt, Stefaan C; Lentacker, Ine

    2015-01-01

    Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA-loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles. PMID:25553101

  17. Theranostic mRNA-loaded Microbubbles in the Lymphatics of Dogs: Implications for Drug Delivery

    PubMed Central

    Dewitte, Heleen; Vanderperren, Katrien; Haers, Hendrik; Stock, Emmelie; Duchateau, Luc; Hesta, Myriam; Saunders, Jimmy H.; De Smedt, Stefaan C.; Lentacker, Ine

    2015-01-01

    Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA-loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles. PMID:25553101

  18. 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.

  19. Lymphatic mapping of the breast: locating the sentinel lymph nodes.

    PubMed

    Uren, R F; Howman-Giles, R; Renwick, S B; Gillett, D

    2001-06-01

    When the concept of sentinel lymph node biopsy was described in patients with melanoma, researchers quickly started to use lymphatic mapping techniques in breast cancer patients in an attempt to locate the sentinel node in the axilla. We have been performing mammary lymphoscintigraphy in this role for 6 years and have now studied 159 patients. Like others, we have found that most breast cancers (93%) have lymphatic drainage that includes the axilla, and we have found an average of 1.4 axillary sentinel nodes in these patients. Surgical biopsy of the axillary sentinel nodes accurately staged the node field in 96% of patients. We have also found, however, that the pattern of lymphatic drainage from the cancer site is unpredictable; and in 49% of patients lymphatic drainage occurred across the center line of the breast to axillary or internal mammary sentinel nodes. In more than half of our patients (56%) lymphatic drainage occurred to lymph nodes outside the axilla including the internal mammary (45%), supraclavicular (13%), and interpectoral and intramammary interval nodes (12%). These nodes are also sentinel nodes, and their presence indicates that a sentinel node biopsy procedure that stages only the status of the axillary lymph nodes has the potential to understage about half the patients with breast cancer. High quality lymphoscintigraphy allows accurate mapping of peritumoral lymphatic drainage in most patients with breast cancer. It is possible that in the future accurate nodal staging in each individual will involve biopsy of all sentinel lymph nodes, regardless of their location. PMID:11376417

  20. New concept for the prevention and treatment of metastatic lymph nodes using chemotherapy administered via the lymphatic network.

    PubMed

    Kodama, Tetsuya; Matsuki, Daisuke; Tada, Asuka; Takeda, Kazu; Mori, Shiro

    2016-01-01

    Intravenous chemotherapy has poor access to metastatic lymph nodes (LNs) and is limited by short-lived drug concentrations. Here, we describe the administration of chemotherapy via the lymphatic network as a new concept for the prevention and treatment of metastatic LNs. A metastatic LN can be treated by the injection of drugs into an upstream LN, either the sentinel LN (SLN) or another upstream LN. In a mouse model, tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). Two routes were used for drug delivery to the PALN, namely from the SiLN and from the accessory axillary LN (AALN). We found that tumor masses were formed in lymphatic vessels between the SiLN and PALN. The flow of fluorescent solution injected into the SiLN towards the PALN decreased with tumor mass formation. Delivery from the AALN (free of metastatic tumor cells) to the PALN was identified as an alternative route. Intranodal injection can deliver high concentrations of drugs to secondary metastatic LNs. The study advocates a new concept for the prevention and treatment of metastatic lymph nodes whereby drugs injected into upstream lymph nodes can reach metastatic lymph nodes via the lymphatic network. PMID:27581921

  1. New concept for the prevention and treatment of metastatic lymph nodes using chemotherapy administered via the lymphatic network

    PubMed Central

    Kodama, Tetsuya; Matsuki, Daisuke; Tada, Asuka; Takeda, Kazu; Mori, Shiro

    2016-01-01

    Intravenous chemotherapy has poor access to metastatic lymph nodes (LNs) and is limited by short-lived drug concentrations. Here, we describe the administration of chemotherapy via the lymphatic network as a new concept for the prevention and treatment of metastatic LNs. A metastatic LN can be treated by the injection of drugs into an upstream LN, either the sentinel LN (SLN) or another upstream LN. In a mouse model, tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). Two routes were used for drug delivery to the PALN, namely from the SiLN and from the accessory axillary LN (AALN). We found that tumor masses were formed in lymphatic vessels between the SiLN and PALN. The flow of fluorescent solution injected into the SiLN towards the PALN decreased with tumor mass formation. Delivery from the AALN (free of metastatic tumor cells) to the PALN was identified as an alternative route. Intranodal injection can deliver high concentrations of drugs to secondary metastatic LNs. The study advocates a new concept for the prevention and treatment of metastatic lymph nodes whereby drugs injected into upstream lymph nodes can reach metastatic lymph nodes via the lymphatic network. PMID:27581921

  2. Intravital Two-Photon Imaging of Lymphocytes Crossing High Endothelial Venules and Cortical Lymphatics in the Inguinal Lymph Node.

    PubMed

    Park, Chung; Hwang, Il-Young; Kehrl, John H

    2016-01-01

    Lymphocyte recirculation through lymph nodes (LNs) requires their crossing of endothelial barriers present in blood vessels and lymphatics by means of chemoattractant-triggered cell migration. The chemoattractant-chemoattractant receptor axes that predominately govern the trafficking of lymphocytes into, and out of, LNs are CCL19/CCR7 and sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1PR1), respectively. Blood-borne lymphocytes downregulate S1PR1 and use CCR7 signaling to adhere to high endothelial venules (HEVs) for transmigration. During their LN residency, recirculating lymphocytes reacquire S1PR1 and attenuate their sensitivity to chemokines. Eventually lymphocytes exit the LN by entering the cortical or medullary lymphatics, a process that depends upon S1PR1 signaling. Upon entering into the lymph, lymphocytes lose their polarity, downregulate their sensitivity to S1P due to the high concentration of S1P, and upregulate their sensitivity to chemokines. However, many of the details of lymphocyte transmigration across endothelial barriers remain poorly understood. Intravital two-photon imaging with advanced microscope technologies not only allows the real-time observation of immune cells in intact LN of a live mouse, but also provides a means to monitor the interactions between circulating lymphocytes and stromal barriers. Here, we describe procedures to visualize lymphocytes engaging and crossing HEVs, and approaching and crossing the cortical lymphatic endothelium to enter the efferent lymph in live mice. PMID:27271904

  3. Subcutaneously Administered Ultrafine PLGA Nanoparticles Containing Doxycycline Hydrochloride Target Lymphatic Filarial Parasites.

    PubMed

    Singh, Yuvraj; Srinivas, Adepu; Gangwar, Mamta; Meher, Jaya Gopal; Misra-Bhattacharya, Shailja; Chourasia, Manish K

    2016-06-01

    Systemic chemotherapeutic targeting of filarial parasites is unfocused due to their deep seated location in lymphatic vessels. This warrants a prolonged dosing regimen in high doses for an anthelmintic like doxycycline hydrochloride (DOX). In order to provide an alternative, we have constructed ultrafine PLGA nanoparticles of DOX (DPNPs), so as to exploit the peculiarity of lymphatic vasculature underneath the subcutaneous layer of skin, which preferentially allows entry of only 10-100 nm sized particles. DPNPs were constructed using a novel solvent diffusion method aided by probe sonication, which resulted in an average size 95.43 ± 0.8 nm as per DLS, PDI 0.168 ± 0.03, zeta potential -7.38 ± 0.32, entrapment efficiency 75.58 ± 1.94%, and refrigerator stability of 7 days with respect to size in the optimized batch. TEM further substantiated the spherical shape of DPNPs along with their actual nonhydrated size as being well below 100 nm. FTIR analysis of DOX, dummy nanoparticles, and freeze-dried DPNPs revealed that the formulation step did not induce prominent changes in the chemical nature of DOX. The drug release was significantly altered (p < 0.05) with 64.6 ± 1.67% release in 48 h from DPNPs and was dictated by Fickian diffusion. Pharmacokinetic studies in Wistar rats further revealed that DPNPs caused a 16-fold prolongation in attainment of plasma Tmax and a 2-fold extension of elimination half-life (28.569 ± 1.27 h) at a dose of 5 mg/kg when compared to native drug (DOX solution) of the same strength. Contrastingly the trend was reversed in regional lymph nodes where Cmax for DPNPs (820 ± 84 ng/mg) was 4-fold greater, and lymphatic Tmax was attained in one-fourth of what was required for DOX solution. This size based preferential lymphatic targeting resulted in significantly greater in vivo antifilarial activity of DPNPs when compared to DOX solution as gauged by several parameters in Brugia malayi infected Mastomys coucha. Interestingly, the

  4. Vascular, glial, and lymphatic immune gateways of the central nervous system.

    PubMed

    Engelhardt, Britta; Carare, Roxana O; Bechmann, Ingo; Flügel, Alexander; Laman, Jon D; Weller, Roy O

    2016-09-01

    Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood-brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system. Recent developments in high-resolution imaging techniques have prompted a reassessment of the relationships between the CNS and the immune system. This review will take these developments into account in describing our present understanding of the anatomical connections of the CNS fluid drainage pathways towards regional lymph nodes and our current concept of immune cell trafficking into the CNS during immunosurveillance and neuroinflammation. Cerebrospinal fluid (CSF) and interstitial fluid are the two major components that drain from the CNS to regional lymph nodes. CSF drains via lymphatic vessels and appears to carry antigen-presenting cells. Interstitial fluid from the CNS parenchyma, on the other hand, drains to lymph nodes via narrow and restricted basement membrane pathways within the walls of cerebral capillaries and arteries that do not allow traffic of antigen-presenting cells. Lymphocytes targeting the CNS enter by a two-step process entailing receptor-mediated crossing of vascular endothelium and enzyme-mediated penetration of the glia limitans that covers the CNS. The contribution of the pathways into and out of the CNS as initiators or contributors to neurological disorders, such as multiple sclerosis and Alzheimer's disease, will be discussed. Furthermore, we propose a clear nomenclature allowing improved precision when describing the CNS-specific communication pathways with the immune system. PMID:27522506

  5. Automated analysis of investigational near-infrared fluorescence lymphatic imaging in humans

    PubMed Central

    Zhang, Jingdan; Zhou, Shaohua Kevin; Xiang, Xiaoyan; Bautista, Merrick L.; Niccum, Blake A.; Dickinson, Gabriel S.; Tan, I-Chih; Chan, Wenyaw; Sevick-Muraca, Eva M.; Rasmussen, John C.

    2012-01-01

    ALFIA (Automated Lymphatic Function Imaging Analysis), an algorithm providing quantitative analysis of investigational near-infrared fluorescence lymphatic images, is described. Images from nine human subjects were analyzed for apparent lymphatic propagation velocities and propulsion periods using manual analysis and ALFIA. While lymphatic propulsion was more easily detected using ALFIA than with manual analysis, statistical analyses indicate no significant difference in the apparent lymphatic velocities although ALFIA tended to calculate longer propulsion periods. With the base ALFIA algorithms validated, further automation can now proceed to provide a clinically relevant analytic tool for quantitatively assessing lymphatic function in humans. PMID:22808440

  6. 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.

  7. Spatio-Temporal Distribution of Dengue and Lymphatic Filariasis Vectors along an Altitudinal Transect in Central Nepal

    PubMed Central

    Dhimal, Meghnath; Gautam, Ishan; Kreß, Aljoscha; Müller, Ruth; Kuch, Ulrich

    2014-01-01

    Background Rapidly increasing temperatures in the mountain region of Nepal and recent reports of dengue fever and lymphatic filariasis cases from mountainous areas of central Nepal prompted us to study the spatio-temporal distribution of the vectors of these two diseases along an altitudinal transect in central Nepal. Methodology/Principal Findings We conducted a longitudinal study in four distinct physiographical regions of central Nepal from September 2011 to February 2012. We used BG-Sentinel and CDC light traps to capture adult mosquitoes. We found the geographical distribution of the dengue virus vectors Aedes aegypti and Aedes albopictus along our study transect to extend up to 1,310 m altitude in the Middle Mountain region (Kathmandu). The distribution of the lymphatic filariasis vector Culex quinquefasciatus extended up to at least 2,100 m in the High Mountain region (Dhunche). Statistical analysis showed a significant effect of the physiographical region and month of collection on the abundance of A. aegypti and C. quinquefasciatus only. BG-Sentinel traps captured significantly higher numbers of A. aegypti than CDC light traps. The meteorological factors temperature, rainfall and relative humidity had significant effects on the mean number of A. aegypti per BG-Sentinel trap. Temperature and relative humidity were significant predictors of the number of C. quinquefasciatus per CDC light trap. Dengue fever and lymphatic filariasis cases had previously been reported from all vector positive areas except Dhunche which was free of known lymphatic filariasis cases. Conclusions/Significance We conclude that dengue virus vectors have already established stable populations up to the Middle Mountains of Nepal, supporting previous studies, and report for the first time the distribution of lymphatic filariasis vectors up to the High Mountain region of this country. The findings of our study should contribute to a better planning and scaling-up of mosquito

  8. FOXC2 and FLT4 Gene Variants in Lymphatic Filariasis.

    PubMed

    Sheik, Yasmeen; Qureshi, Sameera Fatima; Mohhammed, Basheeruddin; Nallari, Pratibha

    2015-06-01

    Lymphatic filariasis is the leading cause of secondary lymphedema wherein lymph transport is impaired due to lymphatic damage. FLT4 signaling and transcription factors such as FOXC2 play an important role in this type of lymphangiogenesis process induced by filarial parasites. The present study aims to assess the association of FLT4 and FOXC2 genes in lymphatic development/remodeling in lymphatic filariasis. A total of 118 lymphatic filariasis patients and 100 non-endemic and 50 endemic healthy subjects were enrolled for the present study. Allele-specific PCR and PCR-RFLP were adopted for the genotyping, and screening of FLT4 and FOXC2 genes was carried out by PCR-SSCP, followed by in-silico and statistical analysis. A novel variation (G357A SNP) was identified on FOXC2 gene screening that may have an effect on codon usage frequency during translational process. In FLT4, A3123G mutation was found in 3.39% of the case subjects but the functional role of this mutation, along with subject's clinical presentations and patient's age, emphasize its pathogenic role in lymphedema development. Two of the subjects exhibit compound heterozygosity (A3123G FLT4 mutation and G357A SNP of FOXC2 gene). As these two genes share a common pathway, we hypothesise a synergistic interaction of these two SNPs in inhibiting the downstream signaling resulting in lymphedema progression. PMID:26091406

  9. Lymphatic Targeting of Nanosystems for Anticancer Drug Therapy.

    PubMed

    Abellan-Pose, Raquel; Csaba, Noemi; Alonso, Maria Jose

    2016-01-01

    The lymphatic system represents a major route of dissemination in metastatic cancer. Given the lack of selectivity of conventional chemotherapy to prevent lymphatic metastasis, in the last years there has been a growing interest in the development of nanocarriers showing lymphotropic characteristics. The goal of this lymphotargeting strategy is to facilitate the delivery of anticancer drugs to the lymph node-resident cancer cells, thereby enhancing the effectiveness of the anti-cancer therapies. This article focuses on the nanosystems described so far for the active or passive targeting of oncological drugs to the lymphatic circulation. To understand the design and performance of these nanosystems, we will discuss first the physiology of the lymphatic system and how physiopathological changes associated to tumor growth influence the biodistribution of nanocarriers. Second, we provide evidence on how the tailoring of the physicochemical characteristics of nanosystems, i.e. particle size, surface charge and hydrophilicity, allows the modulation of their access to the lymphatic circulation. Finally, we provide an overview of the relationship between the biodistribution and antimetastatic activity of the nanocarriers loaded with oncological drugs, and illustrate the most promising active targeting approaches investigated so far. PMID:26675222

  10. Lymphatic capillary pressure in patients with primary lymphedema.

    PubMed

    Zaugg-Vesti, B; Dörffler-Melly, J; Spiegel, M; Wen, S; Franzeck, U K; Bollinger, A

    1993-09-01

    Flow and pressure dynamics in minute human lymphatics are unexplored. Lymphatic capillary pressure was measured by the servo-nulling technique at the foot dorsum of 14 patients with primary lymphedema and 15 healthy controls. Glass micropipettes (7-9 microns) were inserted under microscopic control into lymphatic microvessels previously stained by fluorescence microlymphography (FITC-Dextran 150,000). Mean lymphatic capillary pressure was 7.9 +/- 3.4 mm Hg in the controls and 15.0 +/- 5.1 mm Hg in the patients. The difference was significant at the P < 0.001 level. In about half of the patients and control subjects studied pressure fluctuated by more than 3 mm Hg. The mean intralymphatic pressure of lymphedema patients was slightly below mean interstitial pressure measured by J. T. Christensen, N. J. Shaw, M. M. Hamas and H. K. Al Hassan (1985, Microcirc., Endothelium, Lymphatics 2, 267-384) (17.9 mm Hg) in lower leg lymphedema. Microlymphatic hypertension present in patients with primary lymphedema is probably an important factor for edema formation. PMID:8246814

  11. Reactor pressure vessel nozzle

    DOEpatents

    Challberg, Roy C.; Upton, Hubert A.

    1994-01-01

    A nozzle for joining a pool of water to a nuclear reactor pressure vessel includes a tubular body having a proximal end joinable to the pressure vessel and a distal end joinable in flow communication with the pool. The body includes a flow passage therethrough having in serial flow communication a first port at the distal end, a throat spaced axially from the first port, a conical channel extending axially from the throat, and a second port at the proximal end which is joinable in flow communication with the pressure vessel. The inner diameter of the flow passage decreases from the first port to the throat and then increases along the conical channel to the second port. In this way, the conical channel acts as a diverging channel or diffuser in the forward flow direction from the first port to the second port for recovering pressure due to the flow restriction provided by the throat. In the backflow direction from the second port to the first port, the conical channel is a converging channel and with the abrupt increase in flow area from the throat to the first port collectively increase resistance to flow therethrough.

  12. Reactor pressure vessel nozzle

    DOEpatents

    Challberg, R.C.; Upton, H.A.

    1994-10-04

    A nozzle for joining a pool of water to a nuclear reactor pressure vessel includes a tubular body having a proximal end joinable to the pressure vessel and a distal end joinable in flow communication with the pool. The body includes a flow passage therethrough having in serial flow communication a first port at the distal end, a throat spaced axially from the first port, a conical channel extending axially from the throat, and a second port at the proximal end which is joinable in flow communication with the pressure vessel. The inner diameter of the flow passage decreases from the first port to the throat and then increases along the conical channel to the second port. In this way, the conical channel acts as a diverging channel or diffuser in the forward flow direction from the first port to the second port for recovering pressure due to the flow restriction provided by the throat. In the backflow direction from the second port to the first port, the conical channel is a converging channel and with the abrupt increase in flow area from the throat to the first port collectively increase resistance to flow therethrough. 2 figs.

  13. Lymphangiogenesis and Lymphatic Absorption Are Related and Increased in Chronic Kidney Failure, Independent of Exposure to Dialysis Solutions.

    PubMed

    Vlahu, Carmen A; de Graaff, Marijke; Aten, Jan; Struijk, Dirk G; Krediet, Raymond T

    2015-01-01

    Increased lymphatic absorption might contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphangiogenesis develops during PD, but little is known about the relationship between its morphologic and functional parameters. The relationships between lymph vessel density, the effective lymphatic absorption rate (ELAR), and fibrosis were investigated in a rat model of chronic kidney failure (CKD) with exposure to dialysis solutions. Wistar rats (n = 44) were allocated to these groups: NKF (normal kidney function), CKD (70% nephrectomy), CKDD [CKD, with daily intraperitoneal (i.p.) Dianeal 3.86% (Baxter Healthcare BV, Utrecht, Netherlands)], CKDP [CKD, with daily i.p. Physioneal 3.86% (Baxter Healthcare BV)]. After 16 weeks, a peritoneal function test was performed, and the ELAR was calculated from the disappearance rate of i.p. dextran 70. The lymph vessel profile density (LVPD) was assessed using STEPanizer image analysis (Java application from Tschanz SA, Bern, Germany) of omental sections after anti-podoplanin immunostaining. Fibrosis was quantified by picro-sirius red staining. The LVPD was significantly increased in CKD rats compared with NKF rats, and no additional effect of dialysis solutions was present. The ELAR was increased in uremic rats compared with NKF rats. For all rats together, the LVPD correlated positively with the ELAR and with the amount of fibrosis. Chronic kidney disease itself induces lymphangiogenesis and fibrosis and increases the ELAR, independent of exposure to dialysis fluids. The ELAR is related to the LVPD in peritoneal tissue. PMID:26714383

  14. 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. PMID:26471369

  15. DNA-based diagnosis of lymphatic filariasis.

    PubMed

    Nuchprayoon, Surang

    2009-09-01

    Lymphatic filariasis (LF) is still a major public health problem. The disease is ranked by the World Health Organization (WHO) as the second leading cause of permanent and long-term disability, and has been targeted for elimination by 2020. Effective diagnosis LF is required for treatment of infected individuals, for epidemiological assessment and for monitoring of the control program. Conventional diagnosis of LF depends on detection of microfilariae (Mf) in blood specimens, which has low sensitivity and specificity. Detection of specific circulating filarial antigens is regarded by WHO as the 'gold standard' for diagnosis of LF. However, the limitations of the antigen tests are cost and inconsistent availability. Although anti-filarial IgG4 antibody levels are associated with active LF infections, however, cross-reactivity with other filarial parasites is common. Not as sensitive as antigen tests, DNA-based techniques have been developed to diagnose and differentiate filarial parasites in humans, animal reservoir hosts, and mosquito vectors. These include DNA hybridization, polymerase chain reaction (PCR) amplification using specific primers (eg Ssp I repeat, pWb12 repeat, pWb-35 repeat, and LDR repeat for Wuchereria bancrofti and Hha I repeat, glutathione peroxidase gene, mitochondrial DNA for Brugia malayi), and universal primers, multiplex-PCR, PCR-restriction fragment length polymorphism (PCR-RFLP), PCR-enzyme linked immunosorbent assay (PCR-ELISA), as well as quantitative PCR. Furthermore, because bancroftian filariasis is endemic on the Thai-Myanmar border, the potential now exists for a re-emergence of bancroftian filariasis in Thailand, and random amplified polymorphic DNA (RAPD) analysis has proved effective to differentiate Thai and Myanmar strains of W. bancrofti. PMID:19842372

  16. Neuropilin signalling in vessels, neurons and tumours.

    PubMed

    Raimondi, Claudio; Ruhrberg, Christiana

    2013-03-01

    The neuropilins NRP1 and NRP2 are transmembrane proteins that regulate many different aspects of vascular and neural development. Even though they were originally identified as adhesion molecules, they are most commonly studied as co-receptors for secreted signalling molecules of the class 3 semaphorin (SEMA) and vascular endothelial growth factor (VEGF) families. During nervous system development, both classes of ligands control soma migration, axon patterning and synaptogenesis in the central nervous system, and they additionally help to guide the neural crest cell precursors of neurons and glia in the peripheral nervous system. Both classes of neuropilin ligands also control endothelial cell behaviour, with NRP1 acting as a VEGF-A isoform receptor in blood vascular endothelium and as a semaphorin receptor in lymphatic valve endothelium, and NRP2 promoting lymphatic vessel growth induced by VEGF-C. Here we provide an overview of neuropilin function in neurons and neural crest cells, discuss current knowledge of neuropilin signalling in the vasculature and conclude with a summary of neuropilin roles in cancer. PMID:23319134

  17. Disorders of the lymphatic system of the abdomen.

    PubMed

    Patil, A R; Nandikoor, S; De Marco, J; Bhat, R; Shivakumar, S; Mallrajapatna, G

    2016-10-01

    The lymphatic system of the abdomen comprises of the cisterna chyli, its major and minor lymphatic tributaries, and lymph nodes. Disorders of the lymphatic system of the abdomen are rarely encountered and consist of primary and secondary types. Abdominal lymphangiomas constitute the majority and have characteristic imaging features. Complicated lymphangiomas may pose a diagnostic dilemma. Generalised systemic lymphangiomatosis is a rare condition and affects major organs with a poor prognosis. Retroperitoneal lymphangiectasia in the appropriate setting might predict underlying infection, such as filariasis. Other acquired conditions include iatrogenic or treatment-induced chylocoele. Chylous ascites can be secondary to multiple causes and can be confirmed by biochemical testing and lymphangiogram in appropriate settings. PMID:27450410

  18. Mechanosensitive β-catenin signaling regulates lymphatic vascular development.

    PubMed

    Cha, Boksik; Srinivasan, R Sathish

    2016-08-01

    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

  19. Lymphatic system: a vital link between metabolic syndrome and inflammation.

    PubMed

    Chakraborty, Sanjukta; Zawieja, Scott; Wang, Wei; Zawieja, David C; Muthuchamy, Mariappan

    2010-10-01

    Metabolic syndrome is defined by a cluster of different metabolic risk factors that include overall and central obesity, elevated fasting glucose levels, dyslipidemia, hypertension, and intimal atherogenesis. Metabolic syndrome leads to increased risk for the development of type 2 diabetes and cardiovascular disease (e.g., heart disease and stroke). The exacerbated progression of metabolic syndrome to cardiovascular disease has lead to intense study of the physiological ramifications of metabolic syndrome on the blood vasculature. These studies have particularly focused on the signaling and architectural alterations that manifest in hypertension and atherosclerosis. However, despite the overlap of metabolic syndrome pathology with lymphatic function, tangent effects on the lymphatic system have not been extensively documented. In this review, we discuss the current status of metabolic syndrome and provide evidence for, and the remaining challenges in studying, the connections among the lymphatic system, lipid transport, obesity, insulin resistance, and general inflammation. PMID:20961312

  20. 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...

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. Lymphatic filariasis baseline survey in two sentinel sites of Ogun state, Nigeria

    PubMed Central

    Okorie, Patricia Nkem; Davies, Emmanuel; Ogunmola, Olushola Omoniyi; Ojurongbe, Olusola; Saka, Yisa; Okoeguale, Bridget; Braide, Ekanem Ikpi

    2015-01-01

    Introduction In preparation for Mass Drug Administration by National Lymphatic Filariasis Elimination Programme, a baseline epidemiological investigation on lymphatic filariasis (LF) was conducted in two sentinel sites of Ogun State, Nigeria. The study was carried out in Ado-Odo Ota and Abeokuta South Local Government Areas (LGAs) to determine LF prevalence, microfilarial density and the abundance of Wucheraria bancrofti in the mosquito vectors. Methods Microscopic examination of thick blood smears of 299 and 288 participants from Ado-Odo Ota and Abeokuta South LGAs was conducted. Visual observations of clinical manifestations of chronic infection and questionnaire administration were also conducted. Indoor resting mosquitoes were collected using the pyrethrum spray technique and CDC light traps and mosquitoes were dissected for filarial larvae. Results Microfilaria prevalences were 4.0% and 2.4% in Ado-odo Ota and Abeokuta South LGAs. The microflarial density (mfd) was 30.6mf/ml and 23.9 mf/ml in the same areas. No clinical manifestations of the infection were found at both sites. Knowledge of LF by inhabitants was very low in the two areas. Anopheles gambiae s.l and Culex species mosquitoes were collected but none was found positive for stage L3 infective larvae. Conclusion Mass awareness campaigns on the goal of mass drug administration, cause of LF, mode of transmission, the relationship between infection and clinical signs/symptoms is advocated so as to increase acceptance and support of the control programme by the community. PMID:26185587

  6. 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. PMID:27246594

  7. An Effective Case for Chyluria by Retroperitoneoscopic Lymphatic Disconnection

    PubMed Central

    Hamasuna, Ryoichi; Fujimoto, Naohiro

    2016-01-01

    Abstract Background: Chyluria is a rare disease in Japan. Lymphatic disconnection is the most effective treatment for patients with Chyluria, and laparoscopic approach is performed as a minimally invasive technique. Case Presentation: We present a case of a 40-year-old man who referred to our hospital because of recurrence of chyluria. Chyluria had continued for 20 years, and the patient had received retrograde instillations of silver nitrate three times. The patient underwent retroperitoneoscopic nephrolympholysis, and the chyluria disappeared immediately. One year after surgery, chyluria has not recurred. Conclusion: We treated a patient with chyluria by performing retroperitoneoscopic lymphatic disconnection and this procedure is less invasive and easy to perform. PMID:27579424

  8. Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs.

    PubMed

    Wang, Weirong; Chen, Nancy; Shen, Xiaolan; Cunningham, Paul; Fauty, Scott; Michel, Kimberly; Wang, Bo; Hong, Xuening; Adreani, Christine; Nunes, Christian N; Johnson, Chris V; Yin, Kuo-Chang; Groff, Michelle; Zou, Yan; Liu, Liming; Hamuro, Lora; Prueksaritanont, Thomayant

    2012-05-01

    The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ∼70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2- to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development. PMID:22328584

  9. Effect of intestinal lymphatic circulation blockage in two-hit rats

    PubMed Central

    Niu, Chun-Yu; Li, Ji-Cheng; Zhao, Zi-Gang; Zhang, Jing; Shao, Xue-Hui

    2006-01-01

    AIM: To study the effect of blocking intestinal lymphatic circulation in two-hit rats and explore the significance of intestinal lymphatic circulation in two-hit. METHODS: Wistar rats were divided equally into three groups: mesenteric lymph duct ligation group, non-ligation group and sham group. Mesenteric lymph was diverted by ligation of mesenteric lymph duct, and the two-hit model was established by hemorrhage and lipopolysaccharide (LPS) methods. All rats were sampled for serum pre-experiment and 24 h post-experiment. The organs including kidney, liver, lung and heart were collected for pathomorphologic observation and biochemical investigation. The nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined in serum and tissue homogenate. RESULTS: Pathomorphology study showed that the structures of kidney, lung, liver and heart tissues were normal in sham group; congestion, degeneration and necrosis in non-ligation group; but only mild lesions in ligation group. After two-hits, the contents of AST, ALT, BUN, Cr and LDH-1 in the serum of non-ligation group and ligation group were obviously higher than that in pre-experiment group and sham group, but obviously lower than that in non-ligation group. The contents of NO2-/NO3-, NOS, iNOS and MDA in the serum of non-ligation group were significantly increased, compared with pre-experiment and sham group, but SOD was significantly lower. These parameters were significantly different in ligation group compared with that in sham group, but NO2-/NO3-, iNOS and MDA in ligation group were significantly lower than that in non-ligation group. CONCLUSION: Ligation of mesenteric lymph duct could improve the disturbance of organic function and morphologic damage in two-hit rats; the lymphatic mechanism in two-hit should be emphasized. PMID:17007046

  10. 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…

  11. 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.

  12. Prognostic Value of a Simplified Anatomically Based Nomenclature for Fetal Nuchal Lymphatic Anomalies

    PubMed Central

    Longstreet, Beck; Balakrishnan, Karthik; Saltzman, Babette; Perkins, Jonathan A.; Dighe, Manjiri

    2015-01-01

    Objective To propose an anatomic classification for fetal nuchal lymphatic anomalies that will be clinically useful and to evaluate the classification’s value in predicting chromosomal abnormalities, pregnancy outcomes, other associated fetal anomalies, and spontaneous resolution of these lesions. Study Design Retrospective cohort study. Setting Tertiary academic hospital and affiliated tertiary children’s hospital. Subjects and Methods Mother-baby pairs diagnosed with fetal nuchal lymphatic anomalies in a prenatal ultrasound database. Anomalies were classified as nuchal thickening, dorsal lymphatic malformation, or ventral lymphatic malformation. Pregnancy outcomes, prevalence of chromosomal and anatomic abnormalities, and rates of spontaneous lesion resolution were determined for each group. Results The study included 189 patients: 58 with nuchal thickening, 120 with dorsal lymphatic malformation, and 11 with ventral lymphatic malformation. In fetuses for whom chromosomal analysis was available, chromosomal abnormalities were strongly associated with dorsal lymphatic malformations (83%), less associated with nuchal thickening (29%), and not associated with ventral lymphatic malformations. Dorsal lymphatic malformation predicted high rates of elective (43%) and spontaneous (20%) termination of pregnancy and showed the strongest association with cardiac, renal, and skeletal anomalies. Nuchal thickening was more likely to resolve in utero than dorsal lymphatic malformations, while no ventral lymphatic malformation resolved spontaneously. Conclusions Fetal nuchal anomalies demonstrate significant and clinically important prognostic differences depending on their anatomic location. The simple classification system proposed here therefore provides useful information to clinicians involved in the pre- and postnatal management of children with these anomalies. PMID:25411310

  13. Temporal Change of Alcian Blue-Stained Primo Vascular System in Lymph Vessels of Rats.

    PubMed

    Kim, Jungdae; Kim, Dong-Hyun; Jung, Sharon Jiyoon; Soh, Kwang-Sup

    2016-01-01

    This study aims to investigate the temporal change of a vascular system now known as the primo vascular system (PVS). We used Alcian blue (AB) dye for imaging the distribution of the PVS in lymphatic vessels. The target lymph vessels were chosen as they are easily accessible from the skin, and long-term observation is possible with intact physiological conditions due to a minimal surgical procedure. AB solution was injected into the inguinal lymph node and the target lymph vessels were located along the superficial epigastric vessels. The imaging system allowed processing for extraction of images showing changes in the AB intensity of the visualized PVS components. This newly developed procedure can be used for further study on various dynamic processes of PVS in lymph vessels. PMID:27526158

  14. BIOASSAY VESSEL FAILURE ANALYSIS

    SciTech Connect

    Vormelker, P

    2008-09-22

    Two high-pressure bioassay vessels failed at the Savannah River Site during a microwave heating process for biosample testing. Improper installation of the thermal shield in the first failure caused the vessel to burst during microwave heating. The second vessel failure is attributed to overpressurization during a test run. Vessel failure appeared to initiate in the mold parting line, the thinnest cross-section of the octagonal vessel. No material flaws were found in the vessel that would impair its structural performance. Content weight should be minimized to reduce operating temperature and pressure. Outer vessel life is dependent on actual temperature exposure. Since thermal aging of the vessels can be detrimental to their performance, it was recommended that the vessels be used for a limited number of cycles to be determined by additional testing.

  15. Collecting apparatus

    DOEpatents

    Duncan, Charles P.

    1983-01-01

    An improved collecting apparatus for small aquatic or airborne organisms such as plankton, larval fish, insects, etc. The improvement constitutes an apertured removal container within which is retained a collecting bag, and which is secured at the apex of a conical collecting net. Such collectors are towed behind a vessel or vehicle with the open end of the conical net facing forward for trapping the aquatic or airborne organisms within the collecting bag, while allowing the water or air to pass through the apertures in the container. The container is readily removable from the collecting net whereby the collecting bag can be quickly removed and replaced for further sample collection. The collecting bag is provided with means for preventing the bag from being pulled into the container by the water or air flowing therethrough.

  16. Analysis of lymphatic drainage in various forms of leg edema using two compartment lymphoscintigraphy.

    PubMed

    Bräutigam, P; Földi, E; Schaiper, I; Krause, T; Vanscheidt, W; Moser, E

    1998-06-01

    The anatomical and functional status of the epifascial and subfascial lymphatic compartments was analyzed using two compartment lymphoscintigraphy in five groups of patients (total 55) with various forms of edema of the lower extremities. Digital whole body scintigraphy enabled semiquantitative estimation of radiotracer transport with comparison of lymphatic drainage between those individuals without (normal) and those with leg edema by calculating the uptake of the radiopharmaceutical transported to regional lymph nodes. A visual assessment of the lymphatic drainage pathways of the legs was also performed. In patients with cyclic idiopathic edema, an accelerated rate of lymphatic transport was detected (high lymph volume overload or dynamic insufficiency). In those with venous (phlebo) edemas, high volume lymphatic overload (dynamic insufficiency) of the epifascial compartment was scintigraphically detected by increased tracer uptake in regional nodes. In patients with deep femoral venous occlusion (post-thrombotic syndrome). subfascial lymphatic transport was uniformly markedly reduced (safety valve lymphatic insufficiency). On the other hand, in the epifascial compartment, lymph transport was accelerated. In those patients with recurrent or extensive skin ulceration, lymph transport was reduced. Patients with lipedema (obesity) scintigraphically showed no alteration in lymphatic transport. This study demonstrates that lymphatic drainage is notably affected (except in obesity termed lipedema) in various edemas of the leg. Lymphatic drainage varied depending on the specific compartment and the pathophysiologic mechanism accounting for the edema. Two compartment lymphoscintigraphy is a valuable diagnostic tool for accurate assessment of leg edema of known and unknown origin. PMID:9664268

  17. 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.

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

    PubMed

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

    2016-05-01

    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

  19. 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

  20. Tumor implantation model for rapid testing of lymphatic dye uptake from paw to node in small animals

    NASA Astrophysics Data System (ADS)

    DSouza, Alisha V.; Elliott, Jonathan T.; Gunn, Jason R.; Barth, Richard J.; Samkoe, Kimberley S.; Tichauer, Kenneth M.; Pogue, Brian W.

    2015-03-01

    Morbidity and complexity involved in lymph node staging via surgical resection and biopsy calls for staging techniques that are less invasive. While visible blue dyes are commonly used in locating sentinel lymph nodes, since they follow tumor-draining lymphatic vessels, they do not provide a metric to evaluate presence of cancer. An area of active research is to use fluorescent dyes to assess tumor burden of sentinel and secondary lymph nodes. The goal of this work was to successfully deploy and test an intra-nodal cancer-cell injection model to enable planar fluorescence imaging of a clinically relevant blue dye, specifically methylene blue - used in the sentinel lymph node procedure - in normal and tumor-bearing animals, and subsequently segregate tumor-bearing from normal lymph nodes. This direct-injection based tumor model was employed in athymic rats (6 normal, 4 controls, 6 cancer-bearing), where luciferase-expressing breast cancer cells were injected into axillary lymph nodes. Tumor presence in nodes was confirmed by bioluminescence imaging before and after fluorescence imaging. Lymphatic uptake from the injection site (intradermal on forepaw) to lymph node was imaged at approximately 2 frames/minute. Large variability was observed within each cohort.

  1. Probabilistic retinal vessel segmentation

    NASA Astrophysics Data System (ADS)

    Wu, Chang-Hua; Agam, Gady

    2007-03-01

    Optic fundus assessment is widely used for diagnosing vascular and non-vascular pathology. Inspection of the retinal vasculature may reveal hypertension, diabetes, arteriosclerosis, cardiovascular disease and stroke. Due to various imaging conditions retinal images may be degraded. Consequently, the enhancement of such images and vessels in them is an important task with direct clinical applications. We propose a novel technique for vessel enhancement in retinal images that is capable of enhancing vessel junctions in addition to linear vessel segments. This is an extension of vessel filters we have previously developed for vessel enhancement in thoracic CT scans. The proposed approach is based on probabilistic models which can discern vessels and junctions. Evaluation shows the proposed filter is better than several known techniques and is comparable to the state of the art when evaluated on a standard dataset. A ridge-based vessel tracking process is applied on the enhanced image to demonstrate the effectiveness of the enhancement filter.

  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. The role of the lymphatic system in cholesterol transport

    PubMed Central

    Huang, Li-Hao; Elvington, Andrew; Randolph, Gwendalyn J.

    2015-01-01

    Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease. PMID:26388772

  4. 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

  5. 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. PMID:26815877

  6. VESSELS IN SOME ASLEPIADCEAE

    PubMed Central

    Nag, Anita; Kshetrapal, S.

    1990-01-01

    In the present investigation vessels of 16 species of family Asclepiadaceae have been studied. Through a lot of variation exists in the size and shape of vessels, number of perforation plates and intravascular thickening of walls in the taxa, the vessels in asclepiadaceae are found highly specified. PMID:22557694

  7. Incidentally Detected Lymphatic Filariasis in a Renal Allograft Recipient

    PubMed Central

    Vanikar, A. V.; Suthar, K. S.; Kute, V. B.; Rizvi, S. J.; Trivedi, H. L.

    2013-01-01

    Post-transplntation lymphocele is a well known complication, and lymphatic filariasis (LF) has occasionally been found to present as post-transplantation lymphocele. However, incidentally detected LF during transplantation surgery has not been reported. We present an incidentally detected LF presenting as enlarged lymph node in the right iliac fossa of a recipient during transplantation of donor kidney. He was subsequently treated after transplantation and had stable graft function without any complications after 8 months of follow-up. PMID:25013664

  8. Setaria digitata in advancing our knowledge of human lymphatic filariasis.

    PubMed

    Perumal, A N I; Gunawardene, Y I N S; Dassanayake, R S

    2016-03-01

    Setaria digitata is a filarial parasite that causes fatal cerebrospinal nematodiasis in goats, sheep and horses, resulting in substantial economic losses in animal husbandry in the tropics. Due to its close resemblance to Wuchereria bancrofti, this nematode is also frequently used as a model organism to study human lymphatic filariasis. This review highlights numerous insights into the morphological, histological, biochemical, immunological and genetic aspects of S. digitata that have broadened our understanding towards the control and eradication of filarial diseases. PMID:25924635

  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. PMID:25642273

  10. 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. PMID:27366065

  11. 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

  12. 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

  13. 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.

  14. Eicosanoid generation and responsiveness of human lymphatics in hyperlipoproteinemia.

    PubMed

    Oguogho, A; Kaliman, J; Sinzinger, H

    2000-01-01

    In this work, the oxidation injury in hyperlipoproteinemia (HLP) was determined by measuring the isoprostane 8-epi-prostaglandin (PG) F2alpha in human lymphatics, lymph fluid, plasma, serum and urine. Lymphatics from 6 patients with HLP generated less PGI2 and contained more 8-epi-PGF2alpha as compared to 6 normolipemics without risk factors. Likewise, plasma (29.3 vs 19.7 pg/ml), lymph fluid (137.3 vs 65.3 pg/ml), serum (286.7 vs 204.1 pg/ml) and urinary (360.8 vs 241.0 pg/mg creatinine) values of 8-epi-PGF2alpha in HLP (as compared to normolipemics) were significantly elevated. Lymphatics from HLP showed an enhanced contractile response, less 14C-arachidonic acid conversion to PGI2 and less PGI2-formation upon various stimuli compared to normolipemics of comparable age. These findings indicate that HLP-induced oxidation injury, resulting in an altered (iso-)eicosanoid production and function, may also significantly affect (patho-) physiology of lymphathics. PMID:10765978

  15. VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes.

    PubMed

    Igarashi, Yasuyuki; Chosa, Naoyuki; Sawada, Shunsuke; Kondo, Hisatomo; Yaegashi, Takashi; Ishisaki, Akira

    2016-04-01

    The direction of mesenchymal stem cell (MSC) differentiation is regulated by stimulation with various growth factors and cytokines. We recently established MSC lines, [transforming growth factor-β (TGF-β)-responsive SG‑2 cells, bone morphogenetic protein (BMP)-responsive SG‑3 cells, and TGF-β/BMP-non-responsive SG‑5 cells], derived from the bone marrow of green fluorescent protein-transgenic mice. In this study, to compare gene expression profiles in these MSC lines, we used DNA microarray analysis to characterize the specific gene expression profiles observed in the TGF-β-responsive SG‑2 cells. Among the genes that were highly expressed in the SG‑2 cells, we focused on vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), the gene product of FMS-like tyrosine kinase 4 (Flt4). We found that VEGF-C, a specific ligand of VEGFR3, significantly induced the cell proliferative activity, migratory ability (as shown by Transwell migration assay), as well as the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the SG‑2 cells. Additionally, VEGF-C significantly increased the expression of prospero homeobox 1 (Prox1) and lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), which are lymphatic endothelial cell markers, and decreased the expression of osteogenic differentiation marker genes in these cells. By contrast, TGF-β significantly increased the expression of early-phase osteogenic differentiation marker genes in the SG‑2 cells and markedly decreased the expression of lymphatic endothelial cell markers. The findings of our study strongly suggest the following: i) that VEGF-C promotes the proliferative activity and migratory ability of MSCs; and ii) VEGF-C and TGF-β reciprocally regulate MSC commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes, respectively. Our findings provide new insight into the molecular mechanisms underlying the regenerative ability of MSCs. PMID:26934950

  16. VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes

    PubMed Central

    IGARASHI, YASUYUKI; CHOSA, NAOYUKI; SAWADA, SHUNSUKE; KONDO, HISATOMO; YAEGASHI, TAKASHI; ISHISAKI, AKIRA

    2016-01-01

    The direction of mesenchymal stem cell (MSC) differentiation is regulated by stimulation with various growth factors and cytokines. We recently established MSC lines, [transforming growth factor-β (TGF-β)-responsive SG-2 cells, bone morphogenetic protein (BMP)-responsive SG-3 cells, and TGF-β/BMP-non-responsive SG-5 cells], derived from the bone marrow of green fluorescent protein-transgenic mice. In this study, to compare gene expression profiles in these MSC lines, we used DNA microarray analysis to characterize the specific gene expression profiles observed in the TGF-β-responsive SG-2 cells. Among the genes that were highly expressed in the SG-2 cells, we focused on vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), the gene product of FMS-like tyrosine kinase 4 (Flt4). We found that VEGF-C, a specific ligand of VEGFR3, significantly induced the cell proliferative activity, migratory ability (as shown by Transwell migration assay), as well as the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the SG-2 cells. Additionally, VEGF-C significantly increased the expression of prospero homeobox 1 (Prox1) and lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), which are lymphatic endothelial cell markers, and decreased the expression of osteogenic differentiation marker genes in these cells. By contrast, TGF-β significantly increased the expression of early-phase osteogenic differentiation marker genes in the SG-2 cells and markedly decreased the expression of lymphatic endothelial cell markers. The findings of our study strongly suggest the following: i) that VEGF-C promotes the proliferative activity and migratory ability of MSCs; and ii) VEGF-C and TGF-β reciprocally regulate MSC commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes, respectively. Our findings provide new insight into the molecular mechanisms underlying the regenerative ability of MSCs. PMID:26934950

  17. Lymphatic edema of the lower limbs after orthopedic surgery: results of a randomized, open-label clinical trial with a new extended-release preparation.

    PubMed

    Lessiani, G; Iodice, P; Nicolucci, E; Gentili, M

    2015-01-01

    The lymphedema is a high interstitial protein concentration edema, caused by impaired lymphatic transport capacity. It can be primary or secondary. The secondary form may be caused by a lesion of the lymphatic vessels and/or lymph nodes during diagnostic or therapeutic procedures such as surgical interventions. Often, in clinical practice, there is lymphedema after orthopedic surgery, even in minor orthopedic surgery. Lymphedema, typically presents symptoms of swelling, pain, inflammation, and itching, and it can generate, over the years, acute disability in the affected limbs. The standard therapy is mainly represented by medical treatment, such as manual lymphatic drainage and compression with bandages and stockings. In literature it is documented that lymphedema is responsive to alpha and the gamma benzopyrones. The aim of this study was to determine the effectiveness of delayed extended-release formulation of a compound containing apha-benzo-pyrone (Coumarin), benzo-gamma-pyrone (Troxuretina) and oligomeric proanthocyanidins from Vitis vinifera (OPC), in addition to compression therapy, in the reduction of lymphatic edema after prosthetic hip and knee surgery. In the group treated, after 30 days, a reduction was observed of the edema of 4.8% in the ankle area (p less than 0.008) and 2.7% in the calf area (p less than 0.013). The control group showed no significant reduction. The treated group showed a marked reduction of all the secondary symptoms considered in the study, although variations were not significant. The results show that the compound used was effective in reducing edema after major orthopedic surgery, and consequently in alleviating some related symptoms, such as pain, itching, and burning. As an edema has extensive inflammatory components in patients with reduced mobility, the final data seems interesting, however, further investigations and a better follow-up are required. PMID:26753640

  18. 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

  19. 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

  20. Advanced drug delivery to the lymphatic system: lipid-based nanoformulations.

    PubMed

    Ali Khan, Arshad; 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

  1. Multiple cotton wool spots following bone marrow transplantation for treatment of acute lymphatic leukaemia.

    PubMed Central

    Gloor, B; Gratwohl, A; Hahn, H; Kretzschmar, S; Robert, Y; Speck, B; Daicker, B

    1985-01-01

    Three patients with acute lymphatic leukaemia developed visual impairment due to occlusion of small retinal vessels with multiple cotton wool spots after treatment which included whole body and skull irradiation followed by bone marrow transplantation and cyclosporin A. Withdrawal of cyclosporin A and treatment with corticosteroids was followed by recovery of visual acuity. This retinopathy and the retinal changes seen in the immunodeficiency syndrome are thought to be closely related. The possible role of cyclosporin A is discussed, though cotton wool spots and retinal haemorrhages have never been described in renal transplant patients during treatment with this drug. Withdrawal of cyclosporin A, which is highly effective in preventing graft-versus-host disease, can be fatal. Irradiation of the skull prior to bone marrow transplantation and intrathecal administration of methotrexate may be the most important factors causing the retinal ischaemic signs described here. The inclusion of an ophthalmologist in the team monitoring transplant patients would lead to increased documentation and a better understanding of this disease. Images PMID:3888252

  2. MOSQUITO IDENTIFICATION AND MOLECULAR XENOMONITORING OF LYMPHATIC FILARIASIS IN SELECTED ENDEMIC AREAS IN GIZA AND QUALIOUBIYA GOVERNORATES, EGYPT.

    PubMed

    Abdel-Shafi, Iman R; Shoeib, Eman Y; Attia, Samar S; Rubio, José M; Edmardash, Yusuf; El-Badry, Ayman A

    2016-04-01

    Lymphatic filariasis is a vector-borne health problem that has been focally endemic in Egypt for centuries. The chief vectors of transmission are Culicinae species. Control measures in the form of mass drug administration of DEC citrate treatment have been implemented in Nile delta for almost a decade. This study aimed to identify the prevalent mosquito species in endemic areas in Giza and Qualioubiya governorates and to monitor Wuchereria bancrofti infection by detecting the parasite DNA in collected mosquitoes. Adult mosquitoes were collected using light traps hung indoors. Microscopic examination was performed to identify and examine the morphologic characters of mosquitoes. Female Culex mosquitoes were subjected to semi-nested PCR to detect filarial DNA targeting repetitive DNA sequences (pWbl2 repetitive region) specific for W. bancrofti. The results revealed 3 species of mosquitoes Culex pipiens, Culex pusillus and Culex quinquefasciatus with the predominance of Culex pipiens (85.7%). Wuchereria bancrofti DNA was not detected in any of the collected mosquito pools. With progress of elimination programme in Nile Delta, follow up studies with larger sample size are recommended as the predominance of Culex pipiens the main lymphatic filariasis vector remains a risk of transmission in such areas. PMID:27363044

  3. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3

    PubMed Central

    2011-01-01

    Introduction Metastasis is a common event and the main cause of death in cancer patients. Lymphangiogenesis refers to the formation of new lymphatic vessels and is thought to be involved in the development of metastasis. Sunitinib is a multi-kinase inhibitor that blocks receptor tyrosine kinase activity, including that of vascular endothelial growth factor receptors (VEGFRs). Although sunitinib is a clinically available angiogenesis inhibitor, its effects on lymphangiogenesis and lymph node metastasis remain unclear. The purpose of this study was to investigate the effects of sunitinib on vascular endothelial growth factor receptor 3 (VEGFR-3) and a related event, lymphangiogenesis. Methods The effects of sunitinib on the degree of phosphorylation of VEGFR-2/3 and other signaling molecules was examined in lymphatic endothelial cells (LECs) treated with the drug; VEGF-induced LEC growth, migration, and tube formation were also examined. For the in vivo study, luciferase-expressing breast cancer cells were transplanted into mammary fat pads of mice; the microvessel and lymphatic vessel density was then measured after treatment with sunitinib and anti-VEGFR-2 antibody. Results First, in human LECs, sunitinib blocked both VEGFR-2 and VEGFR-3 phosphorylation induced by VEGF-C or VEGF-D, and abrogated the activation of the downstream molecules extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. Furthermore, sunitinib attenuated the cell-proliferation activity induced by VEGF-C/D and prevented VEGF-C-induced migration and tube formation of the LECs; however, anti-VEGFR2 treatment shows only a partial effect on the growth and functions of the LECs. We used a breast cancer cell line expressing luciferase as a metastatic cancer model. Sunitinib treatment (40 mg/kg/day) inhibited the growth of the primary tumor transplanted in the mammary fat pad of the mice and significantly reduced the number of blood and lymphatic vessels in the tumor. Furthermore, the development

  4. Pressure vessel bottle mount

    NASA Technical Reports Server (NTRS)

    Wingett, Paul (Inventor)

    2001-01-01

    A mounting assembly for mounting a composite pressure vessel to a vehicle includes a saddle having a curved surface extending between two pillars for receiving the vessel. The saddle also has flanged portions which can be bolted to the vehicle. Each of the pillars has hole in which is mounted the shaft portion of an attachment member. A resilient member is disposed between each of the shaft portions and the holes and loaded by a tightening nut. External to the holes, each of the attachment members has a head portion to which a steel band is attached. The steel band circumscribes the vessel and translates the load on the springs into a clamping force on the vessel. As the vessel expands and contracts, the resilient members expand and contract so that the clamping force applied by the band to the vessel remains constant.

  5. Tumor Blood Vessel Dynamics

    NASA Astrophysics Data System (ADS)

    Munn, Lance

    2009-11-01

    ``Normalization'' of tumor blood vessels has shown promise to improve the efficacy of chemotherapeutics. In theory, anti-angiogenic drugs targeting endothelial VEGF signaling can improve vessel network structure and function, enhancing the transport of subsequent cytotoxic drugs to cancer cells. In practice, the effects are unpredictable, with varying levels of success. The predominant effects of anti-VEGF therapies are decreased vessel leakiness (hydraulic conductivity), decreased vessel diameters and pruning of the immature vessel network. It is thought that each of these can influence perfusion of the vessel network, inducing flow in regions that were previously sluggish or stagnant. Unfortunately, when anti-VEGF therapies affect vessel structure and function, the changes are dynamic and overlapping in time, and it has been difficult to identify a consistent and predictable normalization ``window'' during which perfusion and subsequent drug delivery is optimal. This is largely due to the non-linearity in the system, and the inability to distinguish the effects of decreased vessel leakiness from those due to network structural changes in clinical trials or animal studies. We have developed a mathematical model to calculate blood flow in complex tumor networks imaged by two-photon microscopy. The model incorporates the necessary and sufficient components for addressing the problem of normalization of tumor vasculature: i) lattice-Boltzmann calculations of the full flow field within the vasculature and within the tissue, ii) diffusion and convection of soluble species such as oxygen or drugs within vessels and the tissue domain, iii) distinct and spatially-resolved vessel hydraulic conductivities and permeabilities for each species, iv) erythrocyte particles advecting in the flow and delivering oxygen with real oxygen release kinetics, v) shear stress-mediated vascular remodeling. This model, guided by multi-parameter intravital imaging of tumor vessel structure

  6. Macrofilaricidal activity and amelioration of lymphatic pathology in bancroftian filariasis after 3 weeks of doxycycline followed by single-dose diethylcarbamazine.

    PubMed

    Mand, Sabine; Pfarr, Kenneth; Sahoo, Prakash K; Satapathy, Ashok K; Specht, Sabine; Klarmann, Ute; Debrah, Alexander Y; Ravindran, Balachandran; Hoerauf, Achim

    2009-10-01

    In a placebo controlled trial, the effects of 21- and 10-day doxycycline treatments (200 mg/day) followed by single dose diethylcarbamazine (administered 4 months post treatment) on depletion of Wolbachia endobacteria from Wuchereria bancrofti, filaricidal activity, and amerlioration of scrotal lymph vessel dilation were studied in 57 men from Orissa, India. The 21-day doxycycline course reduced Wolbachia in W. bancrofti by 94% before diethylcarbamazine administration. After 12 months, all patients with this treatment were amicrofilaremic and different from the 10-day doxycycline (42.9%) and placebo (37.5%) groups, and significantly fewer were positive for scrotal worm nests (6.7%) compared with 10-day doxycycline (60%) and placebo (66.7%). Average scrotal lymph vessel diameters were reduced from 0.7 cm pre-treatment to 0.02 cm in patients after 21 days of treatment, while no significant changes were seen in the other groups. This latter feature confirms the beneficial effects of doxycycline on lymphatic dilation and thus adds to the existing evidence that doxycycline, in addition to being macrofilaricidal, may be used to prevent or reverse lymphatic pathology. PMID:19815891

  7. NCSX Vacuum Vessel Fabrication

    SciTech Connect

    Viola, M. E.; Brown, T.; Heitzenroeder, P.; Malinowski, F.; Reiersen, W.; Sutton, L.; Goranson, P.; Nelson, B.; Cole, M.; Manuel, M.; McCorkle, D.

    2005-10-07

    The National Compact Stellarator Experiment (NCSX) is being constructed at the Princeton Plasma Physics Laboratory (PPPL) in conjunction with the Oak Ridge National Laboratory (ORNL). The goal of this experiment is to develop a device which has the steady state properties of a traditional stellarator along with the high performance characteristics of a tokamak. A key element of this device is its highly shaped Inconel 625 vacuum vessel. This paper describes the manufacturing of the vessel. The vessel is being fabricated by Major Tool and Machine, Inc. (MTM) in three identical 120º vessel segments, corresponding to the three NCSX field periods, in order to accommodate assembly of the device. The port extensions are welded on, leak checked, cut off within 1" of the vessel surface at MTM and then reattached at PPPL, to accommodate assembly of the close-fitting modular coils that surround the vessel. The 120º vessel segments are formed by welding two 60º segments together. Each 60º segment is fabricated by welding ten press-formed panels together over a collapsible welding fixture which is needed to precisely position the panels. The vessel is joined at assembly by welding via custom machined 8" (20.3 cm) wide spacer "spool pieces." The vessel must have a total leak rate less than 5 X 10-6 t-l/s, magnetic permeability less than 1.02μ, and its contours must be within 0.188" (4.76 mm). It is scheduled for completion in January 2006.

  8. An ELISA kit with two detection modes for the diagnosis of lymphatic filariasis.

    PubMed

    Wongkamchai, S; Satimai, W; Loymek, S; Nochot, H; Boitano, J J

    2015-09-01

    The aim of this study was to develop a low-cost antifilarial immunoglobulin (Ig) G4 detection kit for the diagnosis of lymphatic filariasis. The kit was designed to be used by minimally trained personnel without the constraints of expensive laboratory equipment. We provide a description of the development and validation of a single-serum-dilution based enzyme-linked immunosorbent assay (ELISA) kit with ready-to-use reagents for measuring antifilarial IgG4 antibodies. The kit was tested on residents in Brugia malayi-endemic areas in southern Thailand. Detection was performed by naked-eye observation of the resultant colour of the immunological reactivity. The coefficient of variation (CV) was used to assess the reproducibility of the results. Long-term stability was measured over a 6-month period. Sensitivity of the test kit was 97% when compared with microfilariae detection in thick blood smears. Specificity was 98.7% based on the sera of 57 patients living outside the endemic areas who were infected with other parasites and 100 parasite-free subjects. All positive CVs were < 10%. The test kit was remarkably stable over 6 months. Field validation was performed by the detection of antifilarial IgG4 in 4365 serum samples collected from residents of brugian filariasis-endemic areas and compared with outcome colours of the test samples by the naked eye. Subsequent ELISA evaluation of these results using an ELISA reader indicated high agreement by the kappa statistic. These results demonstrate that the test kit is efficient and useful for public health laboratories as an alternative tool for the diagnosis of lymphatic filarial infection. PMID:24916386

  9. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique.

    PubMed

    Goldstein, M; Gilbert, B R; Dicker, A P; Dwosh, J; Gnecco, C

    1992-12-01

    Conventional techniques of varicocele repair are associated with substantial risks of hydrocele formation, ligation of the testicular artery, and varicocele recurrence. We describe a microsurgical technique of varicocelectomy that significantly lowers the incidence of these complications. The testicle is delivered through a 2 to 3 cm. inguinal incision, and all external spermatic and gubernacular veins are ligated. The testis is returned to the scrotum and the spermatic cord is dissected under the operating microscope. The testicular artery and lymphatics are identified and preserved. All internal spermatic veins are doubly ligated with small hemoclips or 4-zero silk and divided. The vas deferens and its vessels are preserved. Initially, we performed 33 conventional inguinal varicocelectomies in 24 men without delivery of the testis or use of a microscope. Postoperatively, 3 unilateral hydroceles (9%) and 3 unilateral recurrences (9%) were detected. For the next 12 cases 2.5x loupes were used resulting in no hydroceles but another recurrence (8%). We then performed 640 varicocelectomies in 429 men using the microsurgical technique with delivery of the testis. Among 382 men available for followup examination from 6 months to 7 years postoperatively no hydroceles and no cases of testicular atrophy were found. A total of 4 unilateral recurrent varicoceles (0.6%) was identified. The differences between the techniques in the incidence of hydrocele formation and varicocele recurrence are highly significant (p < 0.001). No wound infections occurred in any men. Four scrotal hematomas (0.6%), 1 of which required surgical drainage, occurred in the group with microsurgical ligation and delivery of the testis compared to none with the conventional technique. Preoperative and postoperative semen analyses (mean 3.57 analyses per patient) were obtained on 271 men. The changes in sperm count x 10(6) cc (36.9 to 46.8, p < 0.001), per cent motility (39.6 to 45.7%, p < 0.001) and per

  10. Lymphatic filariasis in Brazil: epidemiological situation and outlook for elimination.

    PubMed

    Fontes, Gilberto; Leite, Anderson Brandão; de Lima, Ana Rachel Vasconcelos; Freitas, Helen; Ehrenberg, John Patrick; da Rocha, Eliana Maria Mauricio

    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

  11. 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

  12. Manual lymphatic drainage for lymphedema following breast cancer treatment

    PubMed Central

    Ezzo, Jeanette; Manheimer, Eric; McNeely, Margaret L; Howell, Doris M; Weiss, Robert; Johansson, Karin I; Bao, Ting; Bily, Linda; Tuppo, Catherine M; Williams, Anne F; Karadibak, Didem

    2016-01-01

    Background More than one in five patients who undergo treatment for breast cancer will develop breast cancer-related lymphedema (BCRL). BCRL can occur as a result of breast cancer surgery and/or radiation therapy. BCRL can negatively impact comfort, function, and quality of life (QoL). Manual lymphatic drainage (MLD), a type of hands-on therapy, is frequently used for BCRL and often as part of complex decongestive therapy (CDT). CDT is a fourfold conservative treatment which includes MLD, compression therapy (consisting of compression bandages, compression sleeves, or other types of compression garments), skin care, and lymph-reducing exercises (LREs). Phase 1 of CDT is to reduce swelling; Phase 2 is to maintain the reduced swelling. Objectives To assess the efficacy and safety of MLD in treating BCRL. Search methods We searched Medline, EMBASE, CENTRAL, WHO ICTRP (World Health Organization’s International Clinical Trial Registry Platform), and Cochrane Breast Cancer Group’s Specialised Register from root to 24 May 2013. No language restrictions were applied. Selection criteria We included randomized controlled trials (RCTs) or quasi-RCTs of women with BCRL. The intervention was MLD. The primary outcomes were (1) volumetric changes, (2) adverse events. Secondary outcomes were (1) function, (2) subjective sensations, (3) QoL, (4) cost of care. Data collection and analysis We collected data on three volumetric outcomes. (1) LE (lymphedema) volume was defined as the amount of excess fluid left in the arm after treatment, calculated as volume in mL of affected arm post-treatment minus unaffected arm post-treatment. (2) Volume reduction was defined as the amount of fluid reduction in mL from before to after treatment calculated as the pretreatment LE volume of the affected arm minus the post-treatment LE volume of the affected arm. (3) Per cent reduction was defined as the proportion of fluid reduced relative to the baseline excess volume, calculated as volume

  13. A microarray analysis of two distinct lymphatic endothelial cell populations

    PubMed Central

    Schweighofer, Bernhard; Rohringer, Sabrina; Pröll, Johannes; Holnthoner, Wolfgang

    2015-01-01

    We have recently identified lymphatic endothelial cells (LECs) to form two morphologically different populations, exhibiting significantly different surface protein expression levels of podoplanin, a major surface marker for this cell type. In vitro shockwave treatment (IVSWT) of LECs resulted in enrichment of the podoplaninhigh cell population and was accompanied by markedly increased cell proliferation, as well as 2D and 3D migration. Gene expression profiles of these distinct populations were established using Affymetrix microarray analyses. Here we provide additional details about our dataset (NCBI GEO accession number GSE62510) and describe how we analyzed the data to identify differently expressed genes in these two LEC populations. PMID:26484194

  14. 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. PMID:16971182

  15. 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

  16. Effective isolation of primo vessels in lymph using sound- and ultrasonic-wave stimulation.

    PubMed

    Park, Do-Young; Lee, Hye-Rie; Rho, Min-Suk; Lee, Sang-Suk

    2014-12-01

    The effects of stimulation with sound and ultrasonic waves of a specific bandwidth on the microdissection of primo vessels in lymphatic vessels of rabbit were investigated. The primo vessels stained with alcian-blue dye injected in the lymph nodes were definitely visualized and more easily isolated by sound-wave vibration and ultrasonic stimulation applied to rabbits at various frequencies and intensities. With sound wave at 7 Hz and ultrasonic waves at 2 MHz, the probability of detecting the primo vessels was improved to 90%; however, without wave stimulation the probability of discovering primo vessels was about 50% only. Sound and ultrasonic waves at specific frequency bands should be effective for microdissection of the primo vessels in the abdominal lymph of rabbit. We suggest that oscillation of the primo vessels by sound and ultrasonic waves may be useful to visualize specific primo structure, and wave vibration can be a very supportive process for observation and isolation of the primo vessels of rabbits. PMID:25499563

  17. 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

  18. Imprinted Clay Coil Vessels

    ERIC Educational Resources Information Center

    Lohr, Tresa Rae

    2006-01-01

    The author teaches clay vessel construction in the fifth grade, and it is amazing what can be accomplished in one forty-five minute period when the expectations are clarified in the initial lesson. The author introduces clay coil vessels with a discussion of the sources of clay and how clay relates to fifth-grade science curriculum concepts such…

  19. REUSABLE REACTION VESSEL

    DOEpatents

    Soine, T.S.

    1963-02-26

    This patent shows a reusable reaction vessel for such high temperature reactions as the reduction of actinide metal chlorides by calcium metal. The vessel consists of an outer metal shell, an inner container of refractory material such as sintered magnesia, and between these, a bed of loose refractory material impregnated with thermally conductive inorganic salts. (AEC)

  20. VESSELS IN SOME APOCYNACEAE

    PubMed Central

    Nag, Anita; Kshetrapal, Shashikala

    1988-01-01

    In the present investigation vessels of 24 species of the family Apocynaceae have been studied. Lot of variation exist in the size and shape of vessels, number of perforation plates and intervascular thickening of walls in the taxa of Apocynaceae. PMID:22557619

  1. 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

  2. Effect of postural changes on human lymphatic capillary pressure of the skin.

    PubMed Central

    Franzeck, U K; Fischer, M; Costanzo, U; Herrig, I; Bollinger, A

    1996-01-01

    1. The influence of postural changes on cutaneous lymphatic capillary pressure and venous pressure was measured at the dorsum of the foot in twelve healthy volunteers. Measurements were performed in the supine and sitting positions. 2. Lymphatic skin capillaries were visualized by fluorescence microlymphography with fluorescein isothiocyanate (FITC)-Dextran 150000. Subsequently a lymphatic capillary was punctured with a glass micropipette and pressure was measured using the servo-nulling technique. Lymphatic capillary pressure, venous pressure, heart and respiration rates were recorded simultaneously. 3. Mean lymphatic capillary pressure was significantly higher (P = 0.0096) in the sitting (9.9 +/- 3.0 mmHg) than in the supine (3.9 +/- 4.2 mmHg) position. There was no significant difference (P = 0.09) between lymphatic capillary pressure and venous pressure (6.8 +/- 3.4 mmHg) in the supine position. During sitting mean lymphatic capillary pressure was significantly lower (P = 0.0022) than mean venous pressure (53.3 +/- 4.1 mmHg). The smaller increase in lymphatic capillary pressure may be caused by the discontinuous fluid column in the lymphatic system and enhanced orthostatic contractile activity of lymphatic collectors and precollectors. Spontaneous low frequency pressure fluctuations occurred in 89% of recordings during sitting, which was significantly (P = 0.02) higher than in the supine position (54%). 4. The present results support the suggestion of enhanced intrinsic contractile activity of lymph precollectors and collectors in the dependent position. This mechanism is primarily responsible for the propulsion of lymph from the periphery to the thoracic duct during quiet sitting, when extrinsic pumping by the calf muscles is not active. PMID:8842016

  3. Dual shell pressure balanced vessel

    DOEpatents

    Fassbender, Alexander G.

    1992-01-01

    A dual-wall pressure balanced vessel for processing high viscosity slurries at high temperatures and pressures having an outer pressure vessel and an inner vessel with an annular space between the vessels pressurized at a pressure slightly less than or equivalent to the pressure within the inner vessel.

  4. The geographical distribution of lymphatic filariasis infection in Malawi.

    PubMed

    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

  5. Dissolver vessel bottom assembly

    DOEpatents

    Kilian, Douglas C.

    1976-01-01

    An improved bottom assembly is provided for a nuclear reactor fuel reprocessing dissolver vessel wherein fuel elements are dissolved as the initial step in recovering fissile material from spent fuel rods. A shock-absorbing crash plate with a convex upper surface is disposed at the bottom of the dissolver vessel so as to provide an annular space between the crash plate and the dissolver vessel wall. A sparging ring is disposed within the annular space to enable a fluid discharged from the sparging ring to agitate the solids which deposit on the bottom of the dissolver vessel and accumulate in the annular space. An inlet tangential to the annular space permits a fluid pumped into the annular space through the inlet to flush these solids from the dissolver vessel through tangential outlets oppositely facing the inlet. The sparging ring is protected against damage from the impact of fuel elements being charged to the dissolver vessel by making the crash plate of such a diameter that the width of the annular space between the crash plate and the vessel wall is less than the diameter of the fuel elements.

  6. Pressure vessel flex joint

    NASA Technical Reports Server (NTRS)

    Kahn, Jon B. (Inventor)

    1992-01-01

    An airtight, flexible joint is disclosed for the interfacing of two pressure vessels such as between the Space Station docking tunnel and the Space Shuttle Orbiter bulkhead adapter. The joint provides for flexibility while still retaining a structural link between the two vessels required due to the loading created by the internal/external pressure differential. The joint design provides for limiting the axial load carried across the joint to a specific value, a function returned in the Orbiter/Station tunnel interface. The flex joint comprises a floating structural segment which is permanently attached to one of the pressure vessels through the use of an inflatable seal. The geometric configuration of the joint causes the tension between the vessels created by the internal gas pressure to compress the inflatable seal. The inflation pressure of the seal is kept at a value above the internal/external pressure differential of the vessels in order to maintain a controlled distance between the floating segment and pressure vessel. The inflatable seal consists of either a hollow torus-shaped flexible bladder or two rolling convoluted diaphragm seals which may be reinforced by a system of straps or fabric anchored to the hard structures. The joint acts as a flexible link to allow both angular motion and lateral displacement while it still contains the internal pressure and holds the axial tension between the vessels.

  7. Modulation of the spontaneous contractions of the initial lymphatics of the bat's wing by arterial and venous occlusion.

    PubMed

    Unthank, J L; Hogan, R D

    1988-01-01

    The spontaneous contractions of the initial lymphatics of the bat's wing were observed to be modulated by changes in local blood flow. Lymphatic pressure and frequency of contraction were measured with the servo-null technique during the occlusion of the ulnar artery or vein. Lymphatic contractile activity was decreased during arterial occlusion but was increased during venous occlusion and postocclusion hyperemia. These changes in lymphatic activity are not consistent with the hypothesis that flow-associated changes in lymphatic contractile activity is mediated primarily by metabolic factors. PMID:3359051

  8. Transposition of the great vessels

    MedlinePlus

    Transposition of the great vessels is a heart defect that occurs from birth (congenital). The two major vessels that carry blood ... nutrition) Rubella or other viral illness during pregnancy ... the great vessels is a cyanotic heart defect. This means there ...

  9. Reactor vessel support system

    DOEpatents

    Golden, Martin P.; Holley, John C.

    1982-01-01

    A reactor vessel support system includes a support ring at the reactor top supported through a box ring on a ledge of the reactor containment. The box ring includes an annular space in the center of its cross-section to reduce heat flow and is keyed to the support ledge to transmit seismic forces from the reactor vessel to the containment structure. A coolant channel is provided at the outside circumference of the support ring to supply coolant gas through the keyways to channels between the reactor vessel and support ledge into the containment space.

  10. Confinement Vessel Dynamic Analysis

    SciTech Connect

    R. Robert Stevens; Stephen P. Rojas

    1999-08-01

    A series of hydrodynamic and structural analyses of a spherical confinement vessel has been performed. The analyses used a hydrodynamic code to estimate the dynamic blast pressures at the vessel's internal surfaces caused by the detonation of a mass of high explosive, then used those blast pressures as applied loads in an explicit finite element model to simulate the vessel's structural response. Numerous load cases were considered. Particular attention was paid to the bolted port connections and the O-ring pressure seals. The analysis methods and results are discussed, and comparisons to experimental results are made.

  11. Photothermolysis of lymphatic endothelial cells by gold nanoshell-mediated hyperthermia.

    PubMed

    Chen, Kui; Soto, Israel; Monroe, W Todd; Alexander, J Steven

    2014-07-01

    Tumor-associated lymphatics and lymphangiogenesis have been shown to play important roles in promoting tumor growth and metastasis. However, the lymphatic system has received much less attention as a target of intervention in cancer treatment compared to the blood vascular system. In this study, we explored the feasibility of photothermal therapy targeting the lymphatic system as a strategy for inhibiting lymphatics-mediated tumor metastasis. Specifically, photothermolysis of lymphatic endothelial cells (LECs) via gold nanoshell-mediated hyperthermia was investigated. Near-Infrared-absorbing Au nanoshells (AuNSs) were synthesized and used as the photothermal coupling agent. After 24-hr incubation, significant amount of the AuNSs were taken up by murine simian virus lymphatic endothelial cells with minimal cytotoxicity. Thermally-induced injury to LECs was found to occur above a threshold temperature of 46 degrees C. Preliminary data also suggested apoptosis as the mechanism of thermally-induced cell death in this temperature range. In a proof-of-concept experiment, AuNS-mediated photothermal heating was found to induce cell death in statistically higher percent of LECs incubated with AuNSs after 15-min laser irradiation compared to the controls. We believed that the findings in this study represent the first step in developing AuNS-mediated photothermal therapy as a potential strategy to disrupt tumor-associated lymphatics. PMID:24758030

  12. Eicosanoid production and lymphatic responsiveness in human cigarette smokers compared with non-smokers.

    PubMed

    Sinzinger, H; Kaliman, J; Oguogho, A

    2000-03-01

    Leg lymphatic segments were isolated from 10 patients (4 cigarette smokers and 6 non-smokers) undergoing conventional lymphography. Prostaglandin (PG) levels and PG synthesis in the lymphatics and in a variety of body fluids and the effects of eicosanoids on lymphatic contractility were determined. Leg lymphatics from 4 smokers generated less PGI2 and contained more 8-epi-PGF2 alpha when compared with leg lymphatics in 6 non-smokers. Similarly, levels of 8-epi-PGF2 alpha in smokers compared with non-smokers were higher in plasma (28.6 cf 19.7 pg/ml), leg lymph (146.7 cf 65.3 pg/ml), serum (299.0 cf 204.1 pg/ml), and urine (473.4 cf 241.0 pg/mg creatinine). Lymphatics from smokers also showed a higher contractile response, less 14C-arachidonic acid conversion to PGI2 and less PGI2-formation with various stimuli compared with non-smokers. Together these findings suggest that smoking induces oxidation injury, promotes altered (iso-)eicosanoid production and impacts on the function and dysfunction of peripheral lymphatics under normal circumstances and in a variety of clinical disorders. PMID:10769813

  13. PEGylation of interferon α2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases

    PubMed Central

    Kaminskas, Lisa M; Ascher, David B; McLeod, Victoria M; Herold, Marco J; Le, Caroline P; Sloan, Erica K; Porter, Christopher JH

    2014-01-01

    The efficacy of protein-based therapeutics with indications in the treatment of lymphatic diseases is expected to be improved by enhancing lymphatic disposition. This study was therefore aimed at examining whether PEGylation can usefully be applied to improve the lymphatic uptake of interferon α2 and whether this ultimately translates into improved therapeutic efficacy against lymph-resident cancer. The lymphatic pharmacokinetics of interferon α2b (IFN, 19 kDa) and PEGylated interferon α2b (IFN-PEG12, 31 kDa) or α2a (IFN-PEG40, 60 kDa) was examined in thoracic lymph duct cannulated rats. IFN was poorly absorbed from the SC injection site (Fabs 36%) and showed little uptake into lymph after SC or IV administration (≤1%). In contrast, IFN-PEG12 was efficiently absorbed from the SC injection site (Fabs 82%) and approximately 20% and 8% of the injected dose was recovered in thoracic lymph over 30 hours after SC or IV administration respectively. IFN-PEG40, however, was incompletely absorbed from the SC injection site (Fabs 23%) and showed similar lymphatic access after SC administration to IFN-PEG12 (21%). The recovery of IFN-PEG40 in thoracic lymph after IV administration, however, was significantly greater (29%) when compared to IV IFN-PEG12. The anti-tumour efficacy of interferon against axillary metastases of a highly lymph-metastatic variant of human breast MDA-MB-231 carcinoma was significantly increased by SC administration of lymph-targeted IFN-PEG12 when compared to the administration of IFN on the ipsilateral side to the axillary metastasis. Optimal PEGylation may therefore represent a viable approach to improving the lymphatic disposition and efficacy of therapeutic proteins against lymphatic diseases. PMID:23499718

  14. Pressurized Vessel Slurry Pumping

    SciTech Connect

    Pound, C.R.

    2001-09-17

    This report summarizes testing of an alternate ''pressurized vessel slurry pumping'' apparatus. The principle is similar to rural domestic water systems and ''acid eggs'' used in chemical laboratories in that material is extruded by displacement with compressed air.

  15. Nitric Oxide Regulates The Lymphatic Reactivity Following Hemorrhagic Shock Through Atp-Sensitive Potassium Channel.

    PubMed

    Zhang, Li-Min; Qin, Li-Peng; Zhang, Yu-Ping; Zhao, Zi-Gang; Niu, Chun-Yu

    2016-06-01

    Lymphatic reactivity has been shown to exhibit a biphasic change following hemorrhagic shock, and nitric oxide (NO) is involved in this process. However, the precise mechanism responsible for NO regulation of the lymphatic reactivity along with the progression of hemorrhagic shock is unclear. Therefore, the present study was to investigate how NO participates in regulating the shock-induced biphasic changes in lymphatic reactivity and its underlying mechanisms. First, the expressions or contents of inducible NO synthase, nitrite plus nitrate, and elements of cAMP-PKA-KATP and cGMP-PKG-KATP pathway in thoracic ducts tissue were assessed. The results revealed that levels of nitrite plus nitrate, cAMP, cyclic guanosine monophosphate (cGMP), p-PKA, and p-PKG were increased gradually along with the process of shock. Second, the roles of cAMP-PKA-KATP and cGMP-PKG-KATP in NO regulating lymphatic response to gradient substance P were evaluated with an isolated lymphatic perfusion system. The results showed that the NOS substrate (L-Arg), PKA donor (8-Br-cAMP) decreased the reactivity of shock 0.5 h-lymphatics, and that the PKA inhibitor (H-89) and KATP inhibitor (glibenclamide) restrained the effects of L-Arg while glibenclamide abolished the effects of 8-Br-cAMP. Meanwhile, NOS antagonist (L-NAME), protein kinase G (PKG) inhibitor (KT-5823), and soluble guanylate cyclase inhibitor (ODQ) increased the reactivity of shock 2 h-lymphatics, whereas KATP opener (pinacidil) inhibited these elevated effects induced by either L-NAME, ODQ, or KT-5823. Taken together, these results indicate that NO regulation of lymphatic reactivity during shock involves both cAMP-PKA-KATP and cGMP-PKG-KATP pathways. These findings have potential significance for the treatment of hemorrhagic shock through regulating lymphatic reactivity. PMID:26796572

  16. Blood Vessel Tension Tester

    NASA Technical Reports Server (NTRS)

    1978-01-01

    In the photo, a medical researcher is using a specially designed laboratory apparatus for measuring blood vessel tension. It was designed by Langley Research Center as a service to researchers of Norfolk General Hospital and Eastern Virginia Medical School, Norfolk, Virginia. The investigators are studying how vascular smooth muscle-muscle in the walls of blood vessels-reacts to various stimulants, such as coffee, tea, alcohol or drugs. They sought help from Langley Research Center in devising a method of measuring the tension in blood vessel segments subjected to various stimuli. The task was complicated by the extremely small size of the specimens to be tested, blood vessel "loops" resembling small rubber bands, some only half a millimeter in diameter. Langley's Instrumentation Development Section responded with a miniaturized system whose key components are a "micropositioner" for stretching a length of blood vessel and a strain gage for measuring the smooth muscle tension developed. The micropositioner is a two-pronged holder. The loop of Mood vessel is hooked over the prongs and it is stretched by increasing the distance between the prongs in minute increments, fractions of a millimeter. At each increase, the tension developed is carefully measured. In some experiments, the holder and specimen are lowered into the test tubes shown, which contain a saline solution simulating body fluid; the effect of the compound on developed tension is then measured. The device has functioned well and the investigators say it has saved several months research time.

  17. LANL Robotic Vessel Scanning

    SciTech Connect

    Webber, Nels W.

    2015-11-25

    Los Alamos National Laboratory in J-1 DARHT Operations Group uses 6ft spherical vessels to contain hazardous materials produced in a hydrodynamic experiment. These contaminated vessels must be analyzed by means of a worker entering the vessel to locate, measure, and document every penetration mark on the vessel. If the worker can be replaced by a highly automated robotic system with a high precision scanner, it will eliminate the risks to the worker and provide management with an accurate 3D model of the vessel presenting the existing damage with the flexibility to manipulate the model for better and more in-depth assessment.The project was successful in meeting the primary goal of installing an automated system which scanned a 6ft vessel with an elapsed time of 45 minutes. This robotic system reduces the total time for the original scope of work by 75 minutes and results in excellent data accumulation and transmission to the 3D model imaging program.

  18. Response of lymphatics of canine hind limb to sympathetic nerve stimulation

    PubMed Central

    Browse, N. L.

    1968-01-01

    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. ImagesFig. 1Fig. 2Fig. 4Fig. 5Fig. 6Fig. 7 PMID:5675052

  19. Temporal Space Lymphatic Malformation in a 15-Year-Old Adolescent: An Extraordinary Case.

    PubMed

    Igoumenakis, Dimosthenis; Logothetis, Ioannis; Barmpagadaki, Alina; Ieromonachou, Panayotis; Mastorakis, George

    2016-07-01

    Lymphatic malformations-previously called lymphangiomas or cystic hygromas-are regarded as non-malignant primary disorders of the lymphatic system. They appear predominantly in infants and children, with 90 % of cases being diagnosed by the age of 2 years. Also, they constitute an infrequent entity, accounting for 5 % of all benign tumors in infants and children. In adults they are extremely rare. In the present article we present an extraordinary case of a lymphatic malformation that ensued in the temporal area of a 15-year old adolescent. PMID:27408452

  20. 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. PMID:2671977

  1. Intestinal absorption and lymphatic transport of a high gamma-linolenic acid canola oil in lymph fistula Sprague-Dawley rats.

    PubMed

    Tso, Patrick; Ding, Kexi; DeMichele, Stephen; Huang, Yung-Sheng

    2002-02-01

    A new canola strain capable of producing >30% gamma-linolenic acid [GLA, 18:3(n-6)] in the seed oil has been developed in our laboratories. This study compares the intestinal absorption and lymphatic transport of this newly developed high GLA content canola oil (HGCO) with traditional GLA-rich borage oil (BO) using a lymph fistula rat model. To assess the extent that 1 mL of GLA in the supplemented oil was absorbed and transported, the fatty acid compositions of triglycerides in mesenteric lymph were compared over a 24-h collection period. The digestion, uptake and lymphatic transport of HGCO and the normal physiologic changes associated with fat absorption (e.g., lymph flow and an increase in lymphatic endogenous lipids outputs, triglycerides, cholesterol and phospholipids) were similar in the HGCO-and the BO-fed rats. The original differences in gamma-linolenic acid content in HGCO and BO were preserved in the fatty acid composition of the rats' lymph lipid. We conclude that the HGCO derived from the genetically modified canola plant is absorbed and transported into lymph similarly to BO. PMID:11823581

  2. Successful control of lymphatic filariasis in the Republic of Korea.

    PubMed

    Cheun, Hyeng-Il; Kong, Yoon; Cho, Shin-Hyeong; Lee, Jong-Soo; Chai, Jong-Yil; Lee, Joo-Shil; Lee, Jong-Koo; Kim, Tong-Soo

    2009-12-01

    A successful experience of lymphatic filariasis control in the Republic of Korea is briefly reviewed. Filariasis in the Republic of Korea was exclusively caused by infection with Brugia malayi. Over the past several decades from the 1950s to 2006, many investigators exerted their efforts to detection, treatment, and follow-up of filariasis patients in endemic areas, and to control filariasis. Mass, combined with selective, treatments with diethylcarbamazine to microfilaria positive persons had been made them free from microfilaremia and contributed to significant decrease of the microfilarial density in previously endemic areas. Significant decrease of microfilaria positive cases in an area influenced eventually to the endemicity of filariasis in the relevant locality. Together with remarkable economic growth followed by improvement of environmental and personal hygiene and living standards, the factors stated above have contributed to blocking the transmission cycle of B. malayi and led to disappearance of this mosquito-borne ancient disease in the Republic of Korea. PMID:19967079

  3. Total lymphatic irradiation and bone marrow in human heart transplantation

    SciTech Connect

    Kahn, D.R.; Hong, R.; Greenberg, A.J.; Gilbert, E.F.; Dacumos, G.C.; Dufek, J.H.

    1984-08-01

    Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and dono