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Immunity Dec 2021Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their...
Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNF mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.
Topics: Animals; Cell Movement; Cells, Cultured; Crohn Disease; Disease Models, Animal; Endothelial Cells; Humans; Ileitis; Ileum; Lymph; Lymphangitis; Lymphatic Vessels; Mesentery; Mice; Mice, Knockout; Stress, Mechanical; Tertiary Lymphoid Structures; Tumor Necrosis Factor-alpha
PubMed: 34788601
DOI: 10.1016/j.immuni.2021.10.003 -
Circulation Research Aug 2023Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell...
BACKGROUND
Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood.
METHODS
We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries.
RESULTS
By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction.
CONCLUSIONS
Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.
Topics: Mice; Animals; Vascular Endothelial Growth Factor A; Endothelial Cells; Phosphatidylinositol 3-Kinases; Chylomicrons; Lymphatic Vessels; Monomeric GTP-Binding Proteins; Capillary Permeability
PubMed: 37462027
DOI: 10.1161/CIRCRESAHA.123.322607 -
The Korean Journal of Thoracic and... Aug 2020Surgeons recommend dissecting lymph nodes in the thorax, abdomen, and neck during surgery for esophageal cancer because of the possibility of metastasis to the lymph...
Surgeons recommend dissecting lymph nodes in the thorax, abdomen, and neck during surgery for esophageal cancer because of the possibility of metastasis to the lymph nodes in those areas through the lymphatic plexus of the esophageal submucosal layer. Extensive lymph node dissection is essential for accurate staging and is thought to improve survival. However, it can result in several complications, including chyle leakage, which refers to continuous lymphatic fluid leakage and can occur in the thorax, abdomen, and neck. Malnutrition, fluid imbalance, and immune compromise may result from chyle leakage, which can be potentially life-threatening if it persists. Therefore, various treatment methods, including conservative treatment, pharmacological treatment such as octreotide infusion, and interventions such as thoracic duct embolization and surgical thoracic duct ligation, have been applied. In this article, the risk factors, diagnosis, and treatment methods of chyle leakage after esophagectomy are reviewed.
PubMed: 32793451
DOI: 10.5090/kjtcs.2020.53.4.191 -
Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells.Nature Communications Jun 2021Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain...
Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36 mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.
Topics: Animals; Antigens, CD; CD36 Antigens; Cadherins; Diabetes Mellitus, Type 2; Endothelial Cells; Female; Glucose; Inflammation; Insulin Resistance; Lymphatic Vessels; Male; Mice; Mice, Knockout; Obesity, Abdominal; Phosphorylation; Transcriptome; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-2
PubMed: 34099721
DOI: 10.1038/s41467-021-23808-3 -
Annals of Vascular Surgery Oct 2022Microsurgery is a new technique for lymphedema treatment. Its advantages and disadvantages remain controversial. This study is sought to collect clinical data from... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Microsurgery is a new technique for lymphedema treatment. Its advantages and disadvantages remain controversial. This study is sought to collect clinical data from patients who underwent lymphovenous bypass and vascularized lymph node transplantation to explore whether surgical procedures can effectively treat lymphedema.
METHODS
We performed a meta-analysis of the effectiveness of lymphatic microsurgery. We searched the databases of literature for articles in Chinese and English. These articles were graded for quality. Report details and outcomes were recorded. Data extraction, systematic review, and meta-analysis were performed.
RESULTS
Thirty-seven studies were included. Patients who underwent microsurgery had a significantly better chance of achieving an excellent result than patients who received conservative treatment (odds ratio = 7.07). The affected limb circumference was reduced by approximately, 44.68% after the microsurgery. After the microsurgery, 63% of the patients did not need physiotherapy, and 96% were free from painful skin infections. Lymphography showed that lymphatic transport capacity was enhanced. Moreover, 12% of the patients reported that edema reappeared in the long-term, 26% required reoperation for unsatisfactory results, and 32% experienced lymphatic leakage.
CONCLUSIONS
A vast majority of patients derive more benefit from lymphatic microsurgery than from conventional treatment. The advantages of lymphatic microsurgery outweigh the disadvantages for patients in the early and middle stages of chronic secondary lymphedema and patients in whom conventional treatment failed.
Topics: Humans; Anastomosis, Surgical; Treatment Outcome; Lymphedema; Lymphography; Lymphatic Vessels
PubMed: 35589027
DOI: 10.1016/j.avsg.2022.04.038 -
Frontiers in Immunology 2022Lymphatic vasculature is a network of capillaries and vessels capable of draining extracellular fluid back to blood circulation and to facilitate immune cell migration....
Lymphatic vasculature is a network of capillaries and vessels capable of draining extracellular fluid back to blood circulation and to facilitate immune cell migration. Although the role of the lymphatic vasculature as coordinator of fluid homeostasis has been extensively studied, the consequences of abnormal lymphatic vasculature function and impaired lymph drainage have been mostly unexplored. Here, by using the mice with defective lymphatic vasculature and lymphatic leakage, we provide evidence showing that lymph leakage induces an immunosuppressive environment by promoting anti-inflammatory M2 macrophage polarization in different inflammatory conditions. In fact, by using a mouse model of tail lymphedema where lymphatic vessels are thermal ablated leading to lymph accumulation, an increasing number of anti-inflammatory M2 macrophages are found in the lymphedematous tissue. Moreover, RNA-seq analysis from different human tumors shows that reduced lymphatic signature, a hallmark of lymphatic dysfunction, is associated with increased M2 and reduced M1 macrophage signatures, impacting the survival of the patients. In summary, we show that lymphatic vascular leakage promotes an immunosuppressive environment by enhancing anti-inflammatory macrophage differentiation, with relevance in clinical conditions such as inflammatory bowel diseases or cancer.
Topics: Anti-Inflammatory Agents; Humans; Immunosuppression Therapy; Lymphatic Vessels; Lymphedema; Macrophages
PubMed: 35663931
DOI: 10.3389/fimmu.2022.841641 -
Frontiers in Endocrinology 2023To evaluate whether no drainage has an advantage over routine drainage in patients with thyroid carcinoma after unilateral thyroid lobectomy and central neck dissection. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate whether no drainage has an advantage over routine drainage in patients with thyroid carcinoma after unilateral thyroid lobectomy and central neck dissection.
METHODS
A total of 104 patients with thyroid cancer who underwent unilateral thyroid lobectomy and central lymph node dissection were randomly assigned into no drainage tube (n=52) and routine drainage tube (n=52) placement groups. General information of each patient was recorded, including the postoperative drainage volume/residual cavity fluid volume, postoperative complications, incision area comfort, and other data, and the thyroid cancer-specific quality of life questionnaire (THYCA-QoL) and patient and observer scar assessment scale (POSAS) were evaluated after surgery. At the 3-6 month follow-up exam, the differences between the two groups were compared based on univariate analysis.
RESULTS
Significant differences were not observed in the general and pathological information (including sex, age, body weight, body mass index (BMI), incision length, specimen volume, Hashimoto's thyroiditis, and number of lymph nodes dissected), operation time, and postoperative complications (postoperative bleeding, incision infection, lymphatic leakage, and temporary hypoparathyroidism) between the two groups. The patients in the non-drainage group had a shorter hospital stay (2.11 ± 0.33 d) than the patients in the drainage group (3.38 ± 0.90 d) (P<0.001). The amount of cervical effusion in patients in the non-drainage group (postoperative 24h: 2.20 ± 1.24 ml/48 h: 1.53 ± 1.07 ml) was significantly less than that in the drainage group (postoperative 24 hours: 22.58 ± 5.81 ml/48 h: 36.15 ± 7.61 ml) (all P<0.001). The proportion of incision exudation and incision numbness in the non-drainage group was lower than that in the drainage group (all P<0.05), and the pain score (VAS) and neck foreign body sensation score (FBST) decreased significantly (P<0.05). During the 3- and 6-month follow-up exams, significant differences were not observed between the THYCA-QoL and drainage groups and the non-drainage group, although the scarring and POSAS values were lower than those in the drainage group. In addition, the length of stay and cost of hospitalization in the non-drainage group were lower than those in the drainage group (P<0.05).
CONCLUSION
Routine drainage tube insertion is not needed in patients with unilateral thyroid lobectomy and central neck dissection.
Topics: Humans; Quality of Life; Thyroid Neoplasms; Thyroidectomy; Postoperative Complications
PubMed: 37152955
DOI: 10.3389/fendo.2023.1148832 -
Interventional Radiology... Nov 2021Intranodal embolization using n-butyl cyanoacrylate glue is an emerging treatment option for persistent lymphatic leakage. This report describes the procedure details of...
PURPOSE
Intranodal embolization using n-butyl cyanoacrylate glue is an emerging treatment option for persistent lymphatic leakage. This report describes the procedure details of intranodal embolization for groin lymphocele and evaluates the efficacy of intranodal embolization at our institution via retrospective chart review.
MATERIAL AND METHODS
Nine consecutive patients (six men and three women; median age, 77.4 years; range, 43-95 years) who underwent intranodal embolization for groin lymphocele between January 2017 and December 2019 were included as study subjects. Intranodal lymphangiography with iodinated contrast was performed to confirm lymphatic leakage, followed by intranodal embolization using n-butyl cyanoacrylate glue mixed with iodized oil for all nine patients. The etiologies of lymphocele, technical and clinical success rates of intranodal embolization, duration of treatment, follow-up period, and acute and chronic complications were retrospectively investigated.
RESULTS
The etiologies of groin lymphoceles were the cutdown access of inguinal vessels (n = 7), lymph node biopsy (n = 1), and trauma (n = 1). The technical and clinical success rates of both lymphangiography and subsequent intranodal embolization were 100%. For intranodal embolization, 16.7%-33.3% n-butyl cyanoacrylate glue was used. The median duration of treatment was 2 days (range, 1-13 days). The follow-up period lasted 0-895 days (median, 9 days). No acute or chronic complications were observed.
CONCLUSIONS
In this study, intranodal embolization showed promising results for groin lymphocele with a short duration of treatment with a median of 2 days. Intranodal embolization using n-butyl cyanoacrylate glue could be a treatment option for persistent groin lymphocele. However, further research is warranted to further evaluate the efficacy of intranodal embolization.
PubMed: 35912276
DOI: 10.22575/interventionalradiology.2020-0034 -
Frontiers in Cell and Developmental... 2020The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance.... (Review)
Review
The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.
PubMed: 33521001
DOI: 10.3389/fcell.2020.627647 -
Frontiers in Physiology 2020Lymphatic endothelial cells (LECs) lining lymphatic vessels develop specialized cell-cell junctions that are crucial for the maintenance of vessel integrity and proper... (Review)
Review
Lymphatic endothelial cells (LECs) lining lymphatic vessels develop specialized cell-cell junctions that are crucial for the maintenance of vessel integrity and proper lymphatic vascular functions. Successful lymphatic drainage requires a division of labor between lymphatic capillaries that take up lymph via open "button-like" junctions, and collectors that transport lymph to veins, which have tight "zipper-like" junctions that prevent lymph leakage. In recent years, progress has been made in the understanding of these specialized junctions, as a result of the application of state-of-the-art imaging tools and novel transgenic animal models. In this review, we discuss lymphatic development and mechanisms governing junction remodeling between button and zipper-like states in LECs. Understanding lymphatic junction remodeling is important in order to unravel lymphatic drainage regulation in obesity and inflammatory diseases and may pave the way towards future novel therapeutic interventions.
PubMed: 32547411
DOI: 10.3389/fphys.2020.00509