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Nematode infection in Alymphoplasia (aly) mice: worm species-dependent differential effect of defects of the gut-associated lymphatic tissue system.

Mice homologous for the alymphoplasia mutation (aly) show the systemic absence of secondary lymphoid tissues, with disorganized splenic architecture, including the absence of the germinal centre and follicular dendritic cells. In this study, we examined the influence of defects of gut-associated lymphoid tissue (GALT), such as Peyer's patches and the mesenteric lymph nodes, on the host response to helminth infection in aly/aly mice. The present study showed that most of the worms were expelled by day 7 after Nippostrongylus brasiliensis infection in both control aly/+ and aly/aly mice. In aly/aly mice, the number of peripheral blood eosinophils, intestinal goblet cells and mucosal mast cells were increased by N. brasiliensis infection in aly/aly mice to the same level as in the controls. Conversely, aly/aly mice developed more severe Heligmosomoides polygyrus infections than control aly/+ mice, as demonstrated by increased faecal egg counts, with reduced immune responses such as the numbers of intestinal goblet cells and mucosal mast cells. These results suggested that the dependency of GALT in activation of Th2 responses against gastrointestinal nematodes was different depending on the species of nematode.

Animals↗

[Morphology and histochemistry of lymphatic vessels of the upper aerodigestive tract: a clinically oriented study].

BACKGROUND: Exact knowledge of lymphatic morphology and histochemistry is required to understand the clinical importance of the lymphatic system of the upper aerodigestive tract. Publications in this field are rare. METHODS: Light and electronmicroscopic examinations were carried out on lymphatics of the upper aerodigestive tract. Enzyme, immune and histochemical investigations were also performed on 764 tissue specimens from this region. RESULTS: The discontinuous basement membrane surrounding the initial lymphatic contains laminin, type IV collagen, and fibronectin and is usually continued by a fibrillar elastic apparatus that is less developed than dermal lymphatics. 5'-nucleotidase, adenylatcyclase, and guanylatcyclase activity in lymphatics is not as high as it is in blood capillaries. The endothelium of collecting lymphatics contains high concentrations of factor VIII associated antigen, while it is found in the endothelium of initial lymphatics only in small amounts or not at all. Histochemical studies of the endothelium of lymphatics show a positive lectine binding reaction for UEA I, PNA, DBA, GS I, MPA, and RCA I. CONCLUSIONS: The histochemical results obtained allow easy differentiation of lymphatics and blood capillaries. The vessel type differentiation is relevant for the examination of organ-related lymphatic systems, to determine whether tumor cell nests are located in lymphatics, blood capillaries, or artificial tissue gaps.

5'-Nucleotidase↗

Mortality from malignancies of the hematopoietic and lymphatic tissues among personnel of the first nuclear plant in the USSR.

This paper reports results from the study of mortality from malignancies of the hematopoietic and lymphatic system among personnel of the first nuclear reactor and processing plant in the USSR. Two registers have been set up. They include all personnel of the atomic reactor (register A) and of the radiochemical processing plant (register B). The operation of these installations started in 1948, and two cohorts were formed; cohort I includes those who started employment between 1948 and 1953, cohort II those who started employment from 1954 to 1958. The predominant contribution to the occupational exposure was from external gamma-radiation. Adverse radiation situations prevailed during the first years at both facilities, and this resulted in substantial exposures of the personnel. Significant increases of the total cancer mortality rates and the proportion of malignancies of the haematopoietic and the lymphatic system were seen in the internal comparison only in cohort I of male workers from facility B. In the same cohort there was a statistically significant excess of the standardized mortality rates from malignancies of the haematopoietic and the lymphatic system over the population rates in the Soviet Union. Our estimate for the excess relative leukemia risk is 1.45/Gy, which is 2.7 times less than the relative excess risk of 3.92/Gy that was observed for the A-bomb survivors over age 20 ATB (Shimizu et al. 1987).

Cohort Studies↗

Topography and ultrastructure of the uterine lymphatics in the rat.

An integrated light and electron microscopic study of the rat uterine lymphatic microcirculation reveals that the functional layer of the endometrium lacks an intrinsic lymphatic system. Only some scanty lymphatic capillaries may be observed in the basal endometrium near the endo-myometrial junction; these are in fact initial lymphatic capillaries belonging to the well-developed plexus of myometrial lymphatic capillaries which rarely permeate the entire myometrial internal muscle layer, ending blindly in the basal endometrium. The ultrastructure of these initial 'endometrial' lymphatic capillaries is detailed. The myometrium, in contrast, has a rich supply of lymphatic capillaries as well as lymphatic vessels, the latter provided with many valves. Both the topography and the fine structure of myometrial lymphatic capillaries and lymph collecting vessels-including their valves-are described and discussed.

Animals↗

Autopsy case of congenital pulmonary lymphangiectasis.

Congenital pulmonary lymphangiectasis (CPL) is a rare anomaly. We report a female infant born at 39 weeks of gestation who was found to have CPL. Cyanosis and tachypnea were noted immediately after birth, and, at room air, PaO2 was 30.7 mmHg, PaCO2 was 82.5 mmHg and pH was 7.12. The infant's symptoms did not improve even with the initiation of artificial ventilation. Chest X-ray film showed cotton-like infiltrates in both lungs and an air-leak surrounding the cardiac shadow. Echocardiography study showed no abnormality. The neonate died 3 days after birth due to hypoxemic cardiac failure. At autopsy, the pleural surface contained numerous dilated vessels that had the appearance of lymphatics. Microscopic features of the lungs were marked lymphatic dilatation of the perivascular, subpleural and interlobular areas. Lymphangiectasis was found in the liver, kidney, pancreas, thyroid and alimentary canals, such as the esophagus, stomach and rectum. Patients with lymphatic dilatations in extrapulmonary organs have mild pulmonary involvement and symptoms and a better prognosis. However, a few cases of CPL with lymphatic dilatations in extrapulmonary organs and an aggressive course, such as the present case, have been reported. The clinical behavior and prognosis of CPL depend on the extent of pulmonary involvement of the lymphatic dilatations regardless of systemic lymphatic dilations.

Fatal Outcome↗

Novel platelet and vascular roles for immunoreceptor signaling.

The immunoreceptor signaling pathway has classically been defined by its role in mediating intracellular signals downstream of immune receptors on circulating cells, but recent studies have revealed new and unexpected roles for this pathway in vascular biology. In platelets the immunoreceptor signaling pathway is coupled to 2 structurally distinct platelet collagen receptors, glycoprotein VI and integrin alpha2beta1, and is required for the activation of platelets after exposure to vessel wall collagen during plaque rupture. During vascular development immunoreceptor signaling is required for proper formation of the lymphatic system, a role that has revealed the contribution of hematopoietic endothelial progenitors to that process. In conjunction with the identification of new biological roles in vascular cell types, new molecular mechanisms of activating this signaling pathway have been discovered, including activation by integrins and immunoreceptor tyrosine activation motifs (ITAMs) on receptors that do not function as part of the immune response. Here we discuss some of these recent findings and their implications for vascular biology and the treatment of human vascular diseases.

Animals↗

Lymphatic function in the liver after hepatic venous pressure elevation.

The liver lymphatic system plays an important role in removing excess fluid from the hepatic tissue. A complete analysis of the liver lymphatic system would be difficult. However, we used a simple circuit-analysis technique to represent the intrahepatic portion of the lymph system as a single pressure source (PL) pushing lymph through a single resistance (RL). Liver lymphatic vessels were cannulated in nine halothane-anesthetized dogs. The lymphatic vessel outflow pressure (PO) was varied by raising the outflow end of the cannula. Lymph flow from the cannula (QL) decreased linearly with PO, and we calculated RL as -delta PO/delta QL and PL as the extrapolated PO at which QL = 0. At base line, PL = 8.5 +/- 2.9 cmH2O, and RL = 0.05 +/- 0.03 cmH2O.min/microliter. After we increased inferior vena caval pressure from 5.8 +/- 2.7 to 15.2 +/- 2.5 cmH2O, PL increased significantly to 13.7 +/- 3.4 cmH2O, and RL decreased to 0.02 +/- 0.02 cmH2O.min/microliter (P less than 0.05). The results indicate that increases in QL occur because the effective pressure pushing lymph from the liver (PL) increases, and the effective resistance of the intrahepatic lymph vessels (RL) decreases.

Algorithms↗

In vitro and in vivo infectivity and pathogenicity of the lymphoid cell-derived woodchuck hepatitis virus.

Woodchuck hepatitis virus (WHV) and human hepatitis B virus are closely related, highly hepatotropic mammalian DNA viruses that also replicate in the lymphatic system. The infectivity and pathogenicity of hepadnaviruses propagating in lymphoid cells are under debate. In this study, hepato- and lymphotropism of WHV produced by naturally infected lymphoid cells was examined in specifically established woodchuck hepatocyte and lymphoid cell cultures and coculture systems, and virus pathogenicity was tested in susceptible animals. Applying PCR-based assays discriminating between the total pool of WHV genomes and covalently closed circular DNA (cccDNA), combined with enzymatic elimination of extracellular viral sequences potentially associated with the cell surface, our study documents that virus replicating in woodchuck lymphoid cells is infectious to homologous hepatocytes and lymphoid cells in vitro. The productive replication of WHV from lymphoid cells in cultured hepatocytes was evidenced by the appearance of virus-specific DNA, cccDNA, and antigens, transmissibility of the virus through multiple passages in hepatocyte cultures, and the ability of the passaged virus to infect virus-naive animals. The data also revealed that WHV from lymphoid cells can initiate classical acute viral hepatitis in susceptible animals, albeit small quantities (approximately 10(3) virions) caused immunovirologically undetectable (occult) WHV infection that engaged the lymphatic system but not the liver. Our results provide direct in vitro and in vivo evidence that lymphoid cells in the infected host support propagation of infectious hepadnavirus that has the potential to induce hepatitis. They also emphasize a principal role of the lymphatic system in the maintenance and dissemination of hepadnavirus infection, particularly when infection is induced by low virus doses.

Animals↗

Lymphatic regeneration following microvascular limb replantation: a qualitative and quantitative animal study.

Lymphatic regeneration following unilateral hindlimb autotransplantation was studied in 14 Lewis rats using Technetium-99 radiolabeled sulfur colloid (TC-99) lymphoscintigraphy and compared to the lymphatic pattern exhibited in four unoperated control rats. Control animals demonstrate a reproducible flow of lymph along the deep lymphatic system from the foot, draining into the ipsilateral inguinal nodes, and then up to the para-aortic nodes. Following replantation, lymphatic outflow from the replanted limb begins to occur within 3 to 6 days, reaching normal lymphatic clearance within 12 days. However, the pattern of lymphatic flow is ill-defined, relying on multiple small channels of the superficial lymphatic system. In contrast to controls, at 3 hr post TC-99 injection, lymphatic drainage in replanted rats is via the inguinal and axillary nodal regions bilaterally. This abnormal pattern persisted in the replanted animals for the duration of this study, 160 days. It is evident that lymphatic regeneration in this animal model is associated with a rapid return to normal levels of lymphatic clearance via collateral channels within the subcutaneous tissue. The rapidity with which lymphatic drainage is restored, and its localization within the subcutaneous tissue, can explain why replanted tissues and microvascular free flaps seldom develop lymphedema. In addition, the rat hindlimb replantation model may prove useful for studies of the general mechanisms and specific factors responsible for lymphangiogenesis.

Animals↗

Molecular mechanisms in lymphangiogenesis: model systems and implications in human disease.

The basic science and development of therapies targeting the blood vascular system has enjoyed much focus due to the knowledge of the molecular mechanisms behind its development and roles in disease. However, the closely associated lymphatic system, while also being responsible for a number of serious and debilitating diseases, has not garnered as much attention due to the lack of specific molecular markers, thereby limiting this field to no more than descriptive analysis. Within the past decade, great strides have been taken to identify a number of molecular signatures unique to the lymphatic system. To this end, the timeline for lymphatic development has now been redefined at the molecular level, and diseases associated with lymphatics now have a molecular basis. With this knowledge, the current modes of treatment for disease such as lymphedema, lymphangiomas, and metastatic progression can now be augmented with potential molecular therapies that have currently been tested in a number of animal models. Much like the therapeutics that have been associated with vasculogenesis and angiogenesis, manipulation of the molecular pathways that define lymphatic development may lead to better clinical outcomes associated with developmental defects and disease.

Angiopoietin-2↗

Lymphoscintigraphy to evaluate the effect of high versus low intensity upper body dynamic exercise on lymphatic function in healthy females.

BACKGROUND: Little is known about the acute effects of exercise on the lymphatic system. Thus, the purpose was to determine the effect of low versus high intensity upper body exercise on lymphatic function in healthy females. METHODS AND RESULTS: On separate days, eight females performed either HI: 12 repeated sets of arm cranking for 2.5 min at 0.6 W.kg-1, followed by 2.5 min of rest; or LO: 12 repeated sets of arm cranking for 2.5 min at 0.3 W.kg-1, followed by 2.5 min of rest. One min spot views were taken with a gamma-radiation camera immediately after injection of 99mTc-antimony colloid and every 10 min thereafter to measure the clearance rate (CR) from the first and fourth finger-web of each hand. Radiopharmaceutical uptake in the axillary regions (AX) at 65 min postinjection was also measured. Clearance from the injection sites was linear and expressed as a slope (% administered activity.min-1). HI resulted in significantly greater CR (-0.24%.min-1+/-0.06) than LO (-0.19%.min-1+/-0.05; p=0.003). A similar trend was seen in AX (HI: 6.3%+/-1.6, LO: 4.8%+/-1.1, p=0.004). CONCLUSIONS: The results indicate that an arm cranking protocol of higher intensity is more effective in promoting lymphatic clearance from the hand. Further, the high intensity protocol may be useful in the functional evaluation of the lymphatic system in breast cancer survivors and warrants further investigation.

Adolescent↗

Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium.

Although approximately 50% of cancers give rise to metastases via the lymphatic system, the mechanisms mediating this process have remained unknown. In this study, we have investigated the role of two lymphatic endothelial molecules, the mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 in adhesion of malignant cells to the lymphatic endothelium, and analyzed their expression in two clinical series consisting of squamous cell cancers of the head and neck (n = 17) and breast cancers (n = 72). Affinity of the tested head and neck cancer cell lines to the lymphatic endothelium varied greatly, but adhesion of all cell lines was dependent on both the MR and CLEVER-1. Almost all cancer specimens contained peritumoral vessels that expressed CLEVER-1 and MR, and also the intratumoral lymph vessels often expressed them in both tumor types. However, only intratumoral expression of these molecules seems to be essential for metastatic spread to the regional lymph nodes. Only 8 (22%) of the 36 axillary node-negative breast carcinomas expressed the MR on the intratumoral lymph vessels as compared with 16 (50%) of the 32 node-positive carcinomas (P = 0.017), and all eight head and neck carcinoma patients with regional lymph node metastases at diagnosis had tumors that expressed CLEVER-1 on the intratumoral lymph vessels. These data suggest a role for both the MR and CLEVER-1 in directing the traffic of cancer cells within the lymphatic system.

Antibodies↗

Lymphangiogenesis and tumour metastasis.

The lymphatic system serves to collect and transport interstitial fluid (lymph) within tissues, and plays an important role in the immune response. The lymphatic system also constitutes one of most important pathways of tumour dissemination. In several human cancers, increased expression in primary tumours of a new member of the vascular endothelial growth factor (VEGF) family, namely VEGF-C, is correlated with regional lymph node metastasis. Experimental studies using transgenic mice overexpressing VEGF-C or xenotransplantation of VEGF-C-expressing tumour cells into immunodeficient mice have demonstrated a role for VEGF-C in tumour lymphangiogenesis and the subsequent formation of lymph node metastasis. However, there is at present very little evidence for lymphangiogenesis in human tumours, which is at variance with the data obtained in animal models. Nonetheless, the striking correlation between levels of VEGF-C in primary tumours and lymph node metastases exists. This suggests that VEGF-C may activate pre-existing lymphatics which then become actively involved in tumour cell chemotaxis, intralymphatic intravasation and distal dissemination. The role of VEGF-C in human tumour metastasis is therefore likely to involve lymphangiogenesis as well as its capacity to induce activation of pre-existing lymphatic endothelium.

Animals↗

Metastasis to infraclavicular lymph nodes in head and neck cancer: a report of three cases.

Metastasis predominantly occurs via the lymphatic system in head and neck tumors. The disturbance of the lymphatic system in the cervical region resulting from neck dissection or radiotherapy may result in unusual patterns of metastasis in patients with recurrent tumors. This is more frequent when the recurrent tumor invades the myocutaneous flap used for the primary reconstruction. We encountered three patients (2 men, 1 woman) with infraclavicular lymph node metastasis. All were previously treated by surgery, postoperative radiation therapy, and reconstruction with the use of the pectoralis major myocutaneous flap.

Carcinoma, Squamous Cell↗

Lymphangiographic findings in Behçet's disease with lymphangiectasia of the small intestine.

Bipedal lymphography was performed in 5 cases of Behçet's disease. In 4 of 5 cases, histologic examination of intestinal biopsy specimens showed lymphatic dilatation of the small intestine which were considered to be a characteristic finding of intestinal lymphangiectasia, a protein-losing enteropathy, but no patient with Behçet's disease showed reduced concentration of serum total protein as well as abnormal value of 131I-PVP test. Lymphograms showed an increase in number of iliopelvic and lumbar lymphatic vessels as a major finding, but they failed to demonstrate a hypoplasia or aplasia of lymphatic system or obstruction of thoracic duct. It is conceivable that the lymphatic dilatation of the small intestine in Behçet's disease may be related to increased flow of lymph due to excessive vascular hyperpermeability and may not be related to a block of lymphatic system which has been considered to be a cause of enteric protein loss in intestinal lymphangiectasia. The authors wish to emphasize that the dilatation of lymphatic vessel of the small intestine is not a sufficient finding to indicate the presence of protein-losing enteropathy.

Adult↗

Studies on the ultrastructure and histochemistry of the lymph system of Gastrodiscoides hominis (Paramphistoma: Digenea).

The lymphatic system of the paramphistome, Gastrodiscoides hominis consists of numerous fluid-filled branches embedded in parenchyma and surrounded by extracellular material and is closely associated with the major organ systems of the fluke. The lymph matrix consists of a cytoplasmic syncytium within which nuclei, mitochondria and various sized granules and membranous structures occur. The granules found throughout the lymph system morphologically resemble autophagosomes and lysosomes. The lymph system provides a storage site for proteins which can be broken down to amino acids via autophagy, for subsequent mobilization and transport to tissues undergoing active protein synthesis. Many branches of the lymph system are surrounded by specialized parenchymal cells referred to as juxta-lymphatic cells. These cells are apparently associated with autophagic degradation of sequestered lymph cytoplasm, which may serve as an additional mechanism for the mobilization and transport of precursor molecules throughout the fluke via the parenchymal network.

Animals↗

Effect of increased systemic venous pressure on thoracic duct and peripheral lymph flow in dogs.

In congestive heart failure, lymph flow from the cannulated thoracic duct is greatly increased. However, there has been scant data on lymph flow in the intact lymphatic system with systemic circulatory congestion. In the present study, thoracic duct and peripheral lymph flow were qualitatively determined using heated cross-thermocouples in seven mongrel dogs. Central venous pressure was raised artificially by infusing large volumes of crystalloid solution equivalent to a maximum of 30% of body weight. Although both thoracic duct and peripheral lymph flow increased with an intact (closed) lymphatic system, the increase was notably less than with a transected (opened) cervical thoracic duct. With systemic circulatory congestion, cannulated thoracic duct lymph flow circumvents a major lymph impediment to lymph flow (i.e. high central venous pressure) and therefore considerably overestimates in vivo central lymph flow in this condition.

Animals↗

Lymphatic malformation in human fetuses. A study of fetuses with Turner's syndrome or status Bonnevie-Ullrich.

In 7 spontaneously aborted fetuses characterized by a large cystic hygroma in the nuchal region and a prominent and generalized edema, the structure and extension of the lymphatic system was studied. In all fetuses marked malformations of this system were found. Although the morphologic appearance seemed to vary greatly it is suggested that the disorder is essentially a generalized hypoplasia and partial agenesis of the lymphatic system, which ceases to extend peripherally at an early embryonic stage. A suggestion as to the mechanism of this growth inhibition is made.

Female↗