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1.
Proc Natl Acad Sci U S A ; 119(32): e2111726119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914162

RESUMO

A large number of neutrophils infiltrate the lymph node (LN) within 4 h after Staphylococcus aureus skin infection (4 h postinfection [hpi]) and prevent systemic S. aureus dissemination. It is not clear how infection in the skin can remotely and effectively recruit neutrophils to the LN. Here, we found that lymphatic vessel occlusion substantially reduced neutrophil recruitment to the LN. Lymphatic vessels effectively transported bacteria and proinflammatory chemokines (i.e., Chemokine [C-X-C motif] motif 1 [CXCL1] and CXCL2) to the LN. However, in the absence of lymph flow, S. aureus alone in the LN was insufficient to recruit neutrophils to the LN at 4 hpi. Instead, lymph flow facilitated the earliest neutrophil recruitment to the LN by delivering chemokines (i.e., CXCL1, CXCL2) from the site of infection. Lymphatic dysfunction is often found during inflammation. During oxazolone (OX)-induced skin inflammation, CXCL1/2 in the LN was reduced after infection. The interrupted LN conduits further disrupted the flow of lymph and impeded its communication with high endothelial venules (HEVs), resulting in impaired neutrophil migration. The impaired neutrophil interaction with bacteria contributed to persistent infection in the LN. Our studies showed that both the flow of lymph from lymphatic vessels to the LN and the distribution of lymph in the LN are critical to ensure optimal neutrophil migration and timely innate immune protection in S. aureus infection.


Assuntos
Quimiocinas , Infiltração de Neutrófilos , Dermatopatias Bacterianas , Infecções Estafilocócicas , Animais , Quimiocinas/imunologia , Imunidade Inata , Inflamação/patologia , Linfa/imunologia , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Dermatopatias Bacterianas/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus
2.
Lymphat Res Biol ; 20(3): 247, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35687829

Assuntos
Linfa , Mesentério , Humanos
3.
Physiol Rep ; 10(10): e15289, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35586957

RESUMO

The lymphatic system is compromised in different groups of patients. To recognize pathology, we must know what is healthy. We use Near-Infrared Fluorescence (NIRF) to assess peripheral lymphatic function in humans. We have shown that external factors such as exercise, hyperthermia, and pharmacological mediators influence the function of peripheral lymphatic vessels. In this study, we explored the impact on lymphatic vessels by the ever-present external factor-gravity. We used NIRF imaging to investigate the lymphatic changes to gravity. Gravity was assessed by changing body position from supine to standing. We extracted following lymphatic functional parameters: lymphatic packet propulsion frequency (contractions/min), velocity (cm/s), and pressure (mmHg). Raw data analysis was performed using a custom-written Labview program. All sequences were analyzed by two observers and interclass correlation scores were calculated. All statistical analysis was performed using RStudio Team (2021). RStudio: Integrated Development Environment for R. RStudio, PBC. Healthy participants (n = 17, 11 males, age 28.1 ± 2.6 years) were included. The lymphatic packet propulsion frequency at baseline was 0.5 ± 0.2 contractions/min and rose within 3 min significantly to a maximum of 1.2 ± 0.5 contractions/min during upright posture and remained significantly higher than the baseline lymphatic packet propulsion frequency after lying down again for up to 6 min. The lymph velocity was 1.5 ± 0.4 cm/s at baseline and changed in both directions and without a specific pattern at different points in time during standing. Lymph pressure was significantly higher while standing (mean increase 9 mmHg, CI: 2-15 mmHg). The ICC scores were 89.8% (85.9%-92.7%), 59.3% (46.6%-69.6%) and 89.4% (79.0%-94.8%) in lymphatic packet propulsion frequency (130 observations), velocity (125 observations), and pressure (30 observations), respectively. The lymphatic system responds within few minutes to gravitational changes by increasing lymphatic packet propulsion frequency and pressure.


Assuntos
Vasos Linfáticos , Adulto , Gravitação , Humanos , Linfa , Masculino , Imagem Óptica , Postura
4.
Physiol Rep ; 10(10): e15258, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35581742

RESUMO

The thoracic duct is responsible for the circulatory return of most lymphatic fluid. The return is a well-timed synergy between the pressure in the thoracic duct, venous pressure at the thoracic duct outlet, and intrathoracic pressures during respiration. However, little is known about the forces determining thoracic duct pressure and how these respond to mechanical ventilation. We aimed to assess human thoracic duct pressure and identify elements affecting it during positive pressure ventilation and a brief ventilatory pause. The study examined pressures of 35 patients with severe congenital heart defects undergoing lymphatic interventions. Thoracic duct pressure and central venous pressure were measured in 25 patients during mechanical ventilation and in ten patients during both ventilation and a short pause in ventilation. TD contractions, mechanical ventilation, and arterial pulsations influenced the thoracic duct pressure. The mean pressure of the thoracic duct was 16 ± 5 mmHg. The frequency of the contractions was 5 ± 1 min-1 resulting in an average increase in pressure of 4 ± 4 mmHg. During mechanical ventilation, the thoracic duct pressure correlated closely to the central venous pressure. TD contractions were able to increase thoracic duct pressure by 25%. With thoracic duct pressure correlating closely to the central venous pressure, this intrinsic force may be an important factor in securing a successful return of lymphatic fluid. Future studies are needed to examine the return of lymphatic fluid and the function of the thoracic duct in the absence of both lymphatic complications and mechanical ventilation.


Assuntos
Respiração com Pressão Positiva , Ducto Torácico , Pressão Venosa Central , Humanos , Linfa , Respiração Artificial
6.
Wound Manag Prev ; 68(1): 8-15, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35263273

RESUMO

BACKGROUND: Chronic edema affects millions of people in the United States and worldwide. Edema can result from a variety of diseases, trauma, medications, and other contributing factors; however, all edema is related to lymphatic fluid dysregulation. Additionally, lymphatic impairment and integumentary dysfunction are interrelated, leading to complex clinical presentations that require an integrated medical model of care to maximize outcomes. PURPOSE: This narrative review article will highlight the current evidence that details lymphatic physiology, fluid regulation by the endothelial glycocalyx layer, and the interconnectedness of the vascular and integumentary systems leading to a paradigm shift in our understanding of edema, lymphedema, and chronic wounds. Traditional pedagogy remains siloed with respect to the body systems, whereas current evidence indicates a certain interdependence, particularly between and among the venous, lymphatic, and integumentary systems. METHODS: Comprehensive narrative review of the current and past literature (2010-2021 through PubMed, Google Scholar, MEDLINE Complete, UpToDate) focusing on lymphatic physiology, fluid regulation, the endothelial glycocalyx layer, lymphedema, and venous insufficiency. Review focuses on new evidence supporting the interconnectedness of the systems to support a unified medical management approach. RESULTS: All edema is related to lymphatic dysfunction, whether transient or permanent, thereby creating a lymphedema continuum. Further, lymphatic impairment creates cutaneous regions of skin barrier failure, rendering the skin more susceptible to breakdown and chronic wounds. CONCLUSION: A synthesis of the current evidence suggests an interconnected relationship of the lymphatic, venous, and integumentary systems, highlighting the need for a more integrated medical model of care to provide efficient and comprehensive care and improve patient outcomes.


Assuntos
Vasos Linfáticos , Linfedema , Edema/etiologia , Edema/terapia , Humanos , Linfa , Sistema Linfático/fisiologia , Linfedema/etiologia , Linfedema/terapia
7.
Vet Immunol Immunopathol ; 243: 110363, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34861459

RESUMO

The bovine afferent lymphatic cannulation model allows collection of large volumes of afferent lymph and provides an opportunity to study lymphatic cells trafficking from the periphery directly ex-vivo. The technique requires surgical intervention, but influence of the procedure or time post-surgery on cells trafficking in the lymph has not been well documented. Here, we measured the volume of lymph and number of cells/mL collected daily over a two week time-course. Animal to animal variability was demonstrated but no consistent changes in lymph volume or cell density were observed in relation to time post-cannulation. Cell populations (dendritic cells, αß T-cells, γδ T-cells and NK cells) were analysed by flow cytometry at 1, 3 and 10 days post-cannulation (DPC) and a reduced percentage of γδ T-cells in afferent lymph was observed at 1 DPC. In addition, cell surface molecule expression by afferent lymphatic dendritic cells (ALDC) was assessed due to the key role of these cells in initiating an adaptive immune response. Co-stimulatory molecules CD80 and CD86 were upregulated by CD172a+ve ALDC early in the time-course, suggesting that the cannulation procedure and duration of experiment may impact the activation state of DCs in the naïve host. This should be considered when analysing the response of these cells to vaccines or pathogens.


Assuntos
Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Células Dendríticas , Linfa , Animais , Bovinos , Células Dendríticas/classificação , Citometria de Fluxo/veterinária , Linfa/citologia , Sistema Linfático , Fenótipo
8.
Am Surg ; 88(1): 109-114, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33662220

RESUMO

BACKGROUND: To discuss the prevention and treatment of lymph or chyle leak following neck dissection in patients with thyroid carcinoma. METHODS: A total of 1724 patients with thyroid carcinoma received neck dissection in the Sun Yat-sen University Cancer Center between November 2009 and October 2014. The incidence and management of leak were analyzed. RESULTS: A total of 92 (5.34%) patients developed leak, 28 (1.62%) developed lymph leak, 59 (3.42%) developed chyle leak, and 5 (.29%) developed chylothorax. Medical management to stop postoperative lymph or chyle leak included pressure dressing, reoperation, fasting, or low-fat diet therapy. CONCLUSIONS: Lymph or chyle leak may occur in thyroid carcinoma patients who underwent neck dissection. Clinicians should alert to leak when there were IV + VI region lymph node metastasis and should become aware of chylothorax after pressure dressing. A careful identification and ligation of lymphatic duct may be an effective way to avoid lymph or chyle leak.


Assuntos
Quilo , Linfa , Esvaziamento Cervical/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Neoplasias da Glândula Tireoide/cirurgia , Adolescente , Adulto , Idoso , Criança , Quilotórax/epidemiologia , Quilotórax/prevenção & controle , Feminino , Humanos , Incidência , Linfonodos/lesões , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Adulto Jovem
9.
J Invest Surg ; 35(3): 502-510, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33622163

RESUMO

Background: Biologic therapeutics constitute up to 30% of all drugs approved from 2010 to 2018 and represent a continuous growing market. In contrast to small molecules, biologic therapeutics (>1 kDa MW) are administered parenterally or intravenously due to poor bioavailability when administered orally. The absorption and disposition of biologics that are administered subcutaneously may be absorbed via lymphatic or blood capillaries. Methods: To understand the absorption and distribution of biotherapeutics via the lymphatic system a surgical model was developed in the cynomolgus macaque (Macaca fascicularis) to allow for frequent and chronic collection of lymph fluid. Additionally, the model allowed for the recirculation of the lymph fluid into the blood stream providing true physiologic redistribution of the biologic drug from the bloodstream back into the lymph. Results: To our knowledge, models of lymphatic duct catheterization with recirculation in the NHP have not been reported. The model consisted of two surgically implanted catheters, one in the thoracic lymph duct and one in the azygous vein. These two catheters were then exteriorized and connected to each other to allow for recirculation of lymph back into the venous blood stream. The exteriorized catheters were protected within the pocket of a jacket. Thirty-one surgical procedures were performed with an overall success rate of 70%. Unsuccessful attempts were related to anatomical differences where the lymphatic duct was either not identifiable (n = 3) or too small to catheterize (n = 6). The patency rate was 90% instrumented animals for at least 24 h, up to 168 h. Conclusion: We present the surgical technique, complications, and refinements which resulted in a reliable and reproducible model in the nonhuman primate for the chronic collection and recirculation of lymphatic fluid.


Assuntos
Linfa , Ducto Torácico , Animais , Cateterismo , Sistema Linfático , Primatas , Ducto Torácico/cirurgia
10.
Microvasc Res ; 139: 104228, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34547346

RESUMO

The subcutaneous injection has emerged to become a feasible self-administration practice for biotherapeutics due to the patient comfort and cost-effectiveness. However, the available knowledge about transport and absorption of these agents after subcutaneous injection is limited. Here, a mathematical framework to study the subcutaneous drug delivery of mAbs from injection to lymphatic uptake is presented. A three-dimensional poroelastic model is exploited to find the biomechanical response of the tissue by taking into account tissue deformation during the injection. The results show that including tissue deformability noticeably changes tissue poromechanical response due to the significant dependence of interstitial pressure on the tissue deformation. Moreover, the importance of the amount of lymph fluid at the injection site and the injection rate on the drug uptake to lymphatic capillaries is highlighted. Finally, variability of lymphatic uptake due to uncertainty in parameters including tissue poromechanical and lymphatic absorption parameters is evaluated. It is found that interstitial pressure due to injection is the major contributing factor in short-term lymphatic absorption, while the amount of lymph fluid at the site of injection determines the long-term absorption of the drug. Finally, it is shown that the lymphatic uptake results are consistent with experimental data available in the literature.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Linfa/metabolismo , Modelos Biológicos , Absorção Fisiológica , Anticorpos Monoclonais/metabolismo , Transporte Biológico , Simulação por Computador , Difusão , Módulo de Elasticidade , Humanos , Injeções Subcutâneas , Análise Numérica Assistida por Computador , Porosidade , Pressão , Autoadministração , Fatores de Tempo
11.
Sci Immunol ; 6(66): eabf1152, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34860581

RESUMO

Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell­dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01B in mice, and primed robust germinal center B cell, TFH, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Linfa/efeitos dos fármacos , Saponinas/farmacologia , Receptores Toll-Like/agonistas , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Linfa/fisiologia , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas , Ratos , Ratos Wistar
12.
Cells ; 10(12)2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34943796

RESUMO

The deposition of amyloid-ß (Aß) in the brain is a risk factor for Alzheimer's disease (AD). Therefore, new strategies for the stimulation of Aß clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aß removal from the brain. There is increasing evidence that sleep plays an important role in Aß clearance. Here, we tested our hypothesis that PS at night can stimulate Aß clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aß clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aß accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aß accumulation in the brain of people with disorder of Aß metabolism, sleep deficit, elderly age, and jet lag.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Luz , Animais , Eletroencefalografia , Corantes Fluorescentes/metabolismo , Linfa/metabolismo , Masculino , Memória/efeitos da radiação , Camundongos Endogâmicos BALB C , Fases do Sono/fisiologia , Fases do Sono/efeitos da radiação , Vigília/fisiologia , Vigília/efeitos da radiação
13.
BMC Cancer ; 21(1): 1242, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794409

RESUMO

BACKGROUND: The study aims to evaluate the clinical features and management of postoperative lymphatic leakage (PLL) in patients with cervical cancer who received pelvic lymphadenectomy. METHODS: This retrospective study screened consecutive patients with cervical cancer (stage Ia2-IIb). RESULTS: Among 3427 cases screened, 63 patients (1.8%) were diagnosed with PLL, which manifested as persistent abdominal drainage (42/63, 66.7%), chylous ascites (12/63, 19.0%) or vaginal drainage (9/63, 14.3%). Median time from surgery to onset of PLL was 6 days (range, 4-21 days). All cases resolved in a median 10 days (range, 3-56 days) after conservative treatment; although one case experienced recurrence of vaginal drainage after 26 days, this also resolved after conservative therapy. Multivariate analysis showed that two cycles of neoadjuvant chemotherapy (odds ratio [OR], 3.283; 95% confidence interval [95%CI], 1.289-8.360; P = 0.013), a decrease in hemoglobin level of ≥20 and < 30 g/L (OR, 6.175; 95%CI, 1.033-10.919; P = 0.046) or ≥ 30 g/L (OR, 8.467; 95%CI, 1.248-17.426; P = 0.029), and postoperative albumin level ≥ 30 and < 35 g/L (OR, 2.552; 95%CI, 1.112-5.857; P = 0.027) or < 30 g/L (OR, 5.517; 95%CI, 2.047-18.148; P = 0.012) were associated with PLL. CONCLUSION: Neoadjuvant chemotherapy, postoperative anemia and postoperative hypoproteinemia are risk factors for PLL.


Assuntos
Excisão de Linfonodo/efeitos adversos , Linfa , Doenças Linfáticas/etiologia , Complicações Pós-Operatórias/etiologia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Anemia/complicações , Estudos de Casos e Controles , Ascite Quilosa/etiologia , Tratamento Conservador , Feminino , Humanos , Hipoproteinemia/complicações , Histerectomia/efeitos adversos , Doenças Linfáticas/terapia , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Pelve , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Vagina
14.
Immunity ; 54(12): 2795-2811.e9, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34788601

RESUMO

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 TNFΔARE 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.


Assuntos
Doença de Crohn/imunologia , Células Endoteliais/imunologia , Íleo/imunologia , Linfa/metabolismo , Vasos Linfáticos/imunologia , Mesentério/imunologia , Estruturas Linfoides Terciárias/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Ileíte , Linfangite , Camundongos , Camundongos Knockout , Estresse Mecânico
15.
BMC Cancer ; 21(1): 1231, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789192

RESUMO

BACKGROUND: The correlation between tumor location and lymphatic flow distribution in gastric cancer has been previously reported, and PTD (Proximal - Transitional - Distal) classification was proposed. Our group updated and developed the nPTD classification. METHOD: We retrospectively studied gastric cancer patients who underwent the dye method sentinel node biopsy from 1993 to 2020. The inclusion criteria were a single lesion type 0 cancer of ≤5 cm in the long axis, clinically node-negative, and invasion within the proper muscle layer pathologically. In this study, the distribution of dyed lymphatic flow was evaluated for each occupied area of the tumor. RESULTS: We included 416 patients in this study. The tumors located in the watershed of the right and left gastroepiploic arteries near greater curvature had extensive lymphatic flow; therefore, a newly circular region with a diameter of 5 cm is set on the watershed of the greater curvature between P and T zone as the 'n' zone. In addition, for cancers located in the lesser P curvature, lymphatic flow to the greater curvature was not observed. Therefore, the P zone was divided into two: the lesser curvature side (PL) and the greater curvature side (PG). CONCLUSIONS: The advantage of the nPTD classification is that it provides not only proper nodal dissection but also adequate function-preserving gastrectomy. If the tumor is localized within the PL, the proximal gastrectomy resection area can be further reduced. In contrast, for cancers located in the 'n' zone, near-total gastrectomy is required because of the extensive lymphatic flow.


Assuntos
Gastrectomia/métodos , Excisão de Linfonodo , Linfa/fisiologia , Tratamentos com Preservação do Órgão/métodos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Corantes , Feminino , Humanos , Excisão de Linfonodo/métodos , Metástase Linfática , Vasos Linfáticos/anatomia & histologia , Masculino , Ilustração Médica , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela/métodos , Estômago/irrigação sanguínea , Neoplasias Gástricas/classificação , Neoplasias Gástricas/fisiopatologia
16.
Biosystems ; 210: 104551, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34597710

RESUMO

By analogy with virions, the binding of biologically-inspired nanoparticles (NPs) with ligands to the cellular membrane containing receptors depends on the multivalent ligand-receptor interaction, membrane bending, and cytoskeleton deformation. The interplay of these factors results in the existence of the potential minimum and activation barrier on the pathway towards full absorption of a NP. Herein, I hypothesize and show theoretically that the interaction of a NP, bound to one cell, with another cell can stabilize the potential minimum and increase the corresponding activation barrier, i.e., NPs can mediate the formation of long-living pairs of cells and aggregates containing a few cells inside blood and lymphatic vessels.


Assuntos
Células Sanguíneas/metabolismo , Linfa/citologia , Linfa/metabolismo , Nanopartículas/metabolismo , Multimerização Proteica/fisiologia , Animais , Agregação Celular/fisiologia , Humanos , Bicamadas Lipídicas/metabolismo
17.
J Physiol ; 599(22): 5015-5030, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34648185

RESUMO

Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question in particular is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice. Further analysis revealed that the female mice segregated into two groups: the high group having similar lymphatic TAG transport to the males, and the low group having significantly less lymphatic output, implying the impact of cyclical variation of ovarian hormonal levels. These led us to examine whether oestradiol (E2) and progesterone (P) affect intestinal absorption and lymphatic transport of dietary lipids. In ovariectomized (OVX) rats, E2 treatment significantly reduced [3 H]-TAG lymphatic output through reducing TAG transport; and P treatment decreased [14 C]cholesterol (Chol) lymphatic output by inhibiting Chol absorption, compared to vehicle treatment. Gene expression data suggested that E2 enhances vascular endothelial growth factor-A (VEGF-A) signalling to reduce the permeability of lacteals, leading to reduced CM transport through the lymphatic system. Interestingly, E2 treatment also increased lymphatic output of apolipoprotein A-I (apoA-I), but not apoB-48 and apoA-IV, in the OVX rats. Collectively, these data suggested that ovarian hormone-induced reductions of intestinal lipid absorption and lymphatic transport, as well as increased lymphatic output of apoA-I, may contribute to a beneficial protection from atherosclerosis in females. KEY POINTS: Significant differences in intestinal lipid absorption and lymphatic transport were found between female and male animals. Oestrogen treatment significantly reduced [3 H]triacylglycerol (TAG) lymphatic output through suppressing TAG transport in ovariectomized (OVX) rats, and this effect is associated with enhanced vegfa gene expression in the intestine. Progesterone treatment significantly decreased the output of [14 C]cholesterol in lymph by inhibiting cholesterol absorption in the OVX rats. Oestrogen treatment also increased lymphatic output of apolipoprotein A-I (apoA-I) in the OVX rats, which may contribute to the reduced risk of atherosclerosis in females.


Assuntos
Caracteres Sexuais , Fator A de Crescimento do Endotélio Vascular , Animais , Gorduras na Dieta/metabolismo , Feminino , Absorção Intestinal , Mucosa Intestinal/metabolismo , Linfa , Sistema Linfático , Masculino , Camundongos , Ratos , Triglicerídeos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Inflammation ; 44(6): 2543-2553, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34533673

RESUMO

Severe hemorrhagic shock leads to excessive inflammation and immune dysfunction, which results in high mortality related to mesenteric lymph return. A recent study showed that stellate ganglion block (SGB) increased the survival rate in rats suffering hemorrhagic shock. However, whether SGB ameliorates immune dysfunction induced by hemorrhagic shock remains unknown. The aim of the present study was to verify the favorable effects of SGB on the proliferation and function of splenic CD4 + T cells isolated from rats that underwent hemorrhagic shock and to investigate the mechanism related to the SGB interaction with autophagy and posthemorrhagic shock mesenteric lymph (PHSML). Male rats underwent SGB or sham SGB and conscious acute hemorrhage followed by resuscitation and multiple treatments. After 3 h of resuscitation, splenic CD4 + T cells were isolated to measure proliferation and cytokine production following stimulation with ConA in vitro. CD4 + T cells isolated from normal rats were treated with PHSML drained from SBG-treated rats, and proliferation, cytokine production, and autophagy biomarkers were detected. Hemorrhagic shock reduced CD4 + T cell proliferation and production of interleukin (IL)-2, IL-4, and tumor necrosis factor-α-induced protein 8-like 2 (TIPE2). SGB or administration of the autophagy inhibitor 3-methyladenine (3-MA) normalized these indicators. In contrast, administration of rapamycin (RAPA) autophagy agonist or intravenous injection of PHSML inhibited the beneficial effects of SGB on CD4 + T cells from hemorrhagic shocked rats. Furthermore, PHSML incubation decreased proliferation and cytokine production, increased LC3 II/I and Beclin-1 expression, and reduced p-PI3K and p-Akt expression in normal CD4 + T cells. These adverse effects of PHSML were also abolished by 3-MA administration, as well as incubation with PHSML obtained from SGB-treated rats. SGB improves splenic CD4 + T cell function following hemorrhagic shock, which is related to the inhibition of PHSML-mediated autophagy.


Assuntos
Bloqueio Nervoso Autônomo , Autofagia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Linfa/metabolismo , Ativação Linfocitária , Choque Hemorrágico/terapia , Baço/imunologia , Gânglio Estrelado , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Mesentério , Fenótipo , Ratos Wistar , Choque Hemorrágico/imunologia , Choque Hemorrágico/metabolismo , Choque Hemorrágico/patologia , Baço/metabolismo
19.
Lipids ; 56(6): 579-590, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34409611

RESUMO

Dietary phospholipids have been traditionally known to affect micelle formation. Egg yolk-derived lysophospholipids (LysoPL) are commercially available. We investigated the effects of dietary LysoPL on lymphatic lipid transport. We also compared sn-1 LysoPL and sn-2 LysoPL, which have different fatty acyl esterification positions. Thoracic lymph duct-cannulated rats were fed a diet supplemented with egg yolk-derived sn-1 LysoPL, sn-2 LysoPL, or phospholipids (PL). The amount of lymphatic lipid transport was also evaluated. Time courses of transport were applied to the one-compartment model as one of the pharmacokinetic analyses. The solubility of cholesterol in bile acid micelles was measured. Compared to the PL diet, the sn-1 and sn-2 LysoPL diets significantly reduced the lymphatic transport of cholesterol. There were no differences in the lymphatic PL and TAG transport. There was no difference in cholesterol transport between the sn-1 LysoPL group and the sn-2 LysoPL group; however, the transport rate constant at a decrease in lymphatic cholesterol was lower in the sn-1 LysoPL group than in the sn-2 LysoPL group. Cholesterol solubility in bile acid micelles was significantly decreased in the sn-1 LysoPL and sn-2 LysoPL groups compared to that in the PL group. Dietary LysoPL affects the behavior of intestinal cholesterol and suppresses lymphatic cholesterol transport.


Assuntos
Ácidos Graxos , Linfa , Animais , Colesterol , Dieta , Lisofosfolipídeos , Fosfolipídeos , Ratos
20.
Biomech Model Mechanobiol ; 20(5): 1981-2000, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34363553

RESUMO

A biphasic computational model of a growing, vascularized glioma within brain tissue was developed to account for unique features of gliomas, including soft surrounding brain tissue, their low stiffness relative to brain tissue, and a lack of draining lymphatics. This model is the first to couple nonlinear tissue deformation with porosity and tissue hydraulic conductivity to study the mechanical interaction of leaky vasculature and solid growth in an embedded glioma. The present model showed that leaky vasculature and elevated interstitial fluid pressure produce tensile stress within the tumor in opposition to the compressive stress produced by tumor growth. This tensile effect was more pronounced in softer tissue and resulted in a compressive stress concentration at the tumor rim that increased when tumor was softer than host. Aside from generating solid stress, fluid pressure-driven tissue deformation decreased the effective stiffness of the tumor while growth increased it, potentially leading to elevated stiffness in the tumor rim. A novel prediction of reduced porosity at the tumor rim was corroborated by direct comparison with estimates from our in vivo imaging studies. Antiangiogenic and radiation therapy were simulated by varying vascular leakiness and tissue hydraulic conductivity. These led to greater solid compression and interstitial pressure in the tumor, respectively, the former of which may promote tumor infiltration of the host. Our findings suggest that vascular leakiness has an important influence on in vivo solid stress, stiffness, and porosity fields in gliomas given their unique mechanical microenvironment.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Líquido Extracelular/fisiologia , Glioma/fisiopatologia , Microambiente Tumoral , Animais , Encéfalo , Força Compressiva , Simulação por Computador , Humanos , Linfa/fisiologia , Modelos Biológicos , Modelos Teóricos , Porosidade , Pressão , Estresse Mecânico , Resistência à Tração
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