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1.
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
2.
J Trauma Acute Care Surg ; 91(4): 700-707, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34238858

RESUMO

BACKGROUND: Inflammatory lipid mediators in mesenteric lymph (ML), including arachidonic acid (AA), are considered to play an important role in the pathogenesis of multiple-organ dysfunction after hemorrhagic shock. A previous study suggested that vagus nerve stimulation (VNS) could relieve shock-induced gut injury and abrogate ML toxicity, resulting in the prevention of multiple-organ dysfunction. However, the detailed mechanism of VNS in lymph toxicity remains unclear. The study aimed to investigate the relationship between VNS and inflammatory lipid mediators in ML. METHODS: Male Sprague-Dawley rats underwent laparotomy and superior mesenteric artery obstruction (SMAO) for 60 minutes to induce intestinal ischemia followed by reperfusion and observation. The ML duct was cannulated, and ML samples were obtained both before and after SMAO. The distal ileum was removed at the end of the observation period. In one group of animals, VNS was performed from 10 minutes before 10 minutes after SMAO (5 V, 0.5 Hz). Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of AA was performed for each ML sample. The biological activity of ML was examined using a monocyte nuclear factor κ-light-chain-enhancer of activated B cells activation assay. Western blotting of phospholipase A2 group IIA (PLA2-IIA) was also performed for ML and ileum samples. RESULTS: Vagus nerve stimulation relieved the SMAO-induced histological gut injury. The concentration of AA and level of nuclear factor κ-light-chain-enhancer of activated B cells activation in ML increased significantly after SMAO, whereas VNS prevented these responses. Western blotting showed PLA2-IIA expression in the ML and ileum after SMAO; however, the appearance of PLA2-IIA band was remarkably decreased in the samples from VNS-treated animals. CONCLUSION: The results suggested that VNS could relieve gut injury induced by SMAO and decrease the production of AA in ML by altering PLA2-IIA expression in the gut and ML.


Assuntos
Ácido Araquidônico/metabolismo , Insuficiência de Múltiplos Órgãos/prevenção & controle , Traumatismo por Reperfusão/terapia , Choque Hemorrágico/complicações , Estimulação do Nervo Vago , Animais , Modelos Animais de Doenças , Humanos , Linfa/imunologia , Linfa/metabolismo , Vasos Linfáticos/patologia , Masculino , Mesentério/patologia , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/patologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Choque Hemorrágico/imunologia
3.
Cells ; 10(6)2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204825

RESUMO

Neutrophils are the first immune cells to be recruited from the blood to the tissue site of an infection or inflammation. It has been suggested that neutrophils are capable of migrating from the infected tissue via lymphatic vessels to the draining lymph nodes. However, it remains elusive as to which areas within the lymph nodes can be reached by such reversely migrating cells. To address this question, we applied a model for adoptive neutrophil transfer into the afferent lymphatic vessel that drains towards the popliteal lymph node in mice. We showed that resting and in vitro-activated neutrophils did not enter the lymph node parenchyma but localized primarily in the subcapsular and medullary sinuses. Within the medulla, neutrophils show random migration and are able to sense laser-induced sterile tissue injury by massively swarming to the damaged tissue site. Co-injected dendritic cells supported the entry of resting neutrophils into the lymph node parenchyma via the subcapsular sinus. In contrast, in vivo-activated adoptively transferred neutrophils were capable of migrating into the interfollicular areas of the lymph node. Collectively, the data presented here give further insights into the functional behavior of neutrophils within the lymph nodes.


Assuntos
Movimento Celular/imunologia , Linfonodos/imunologia , Neutrófilos/imunologia , Animais , Linfa/citologia , Linfa/imunologia , Camundongos , Camundongos Endogâmicos C57BL
4.
Cells ; 10(5)2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068712

RESUMO

Fibroblastic reticular cells (FRCs), usually found and isolated from the T cell zone of lymph nodes, have recently been described as much more than simple structural cells. Originally, these cells were described to form a conduit system called the "reticular fiber network" and for being responsible for transferring the lymph fluid drained from tissues through afferent lymphatic vessels to the T cell zone. However, nowadays, these cells are described as being capable of secreting several cytokines and chemokines and possessing the ability to interfere with the immune response, improving it, and also controlling lymphocyte proliferation. Here, we performed a systematic review of the several methods employed to investigate the mechanisms used by fibroblastic reticular cells to control the immune response, as well as their ability in determining the fate of T cells. We searched articles indexed and published in the last five years, between 2016 and 2020, in PubMed, Scopus, and Cochrane, following the PRISMA guidelines. We found 175 articles published in the literature using our searching strategies, but only 24 articles fulfilled our inclusion criteria and are discussed here. Other articles important in the built knowledge of FRCs were included in the introduction and discussion. The studies selected for this review used different strategies in order to access the contribution of FRCs to different mechanisms involved in the immune response: 21% evaluated viral infection in this context, 13% used a model of autoimmunity, 8% used a model of GvHD or cancer, 4% used a model of Ischemic-reperfusion injury (IRI). Another four studies just targeted a particular signaling pathway, such as MHC II expression, FRC microvesicles, FRC secretion of IL-15, FRC network, or ablation of the lysophosphatidic acid (LPA)-producing ectoenzyme autotaxin. In conclusion, our review shows the strategies used by several studies to isolate and culture fibroblastic reticular cells, the models chosen by each one, and dissects their main findings and implications in homeostasis and disease.


Assuntos
Fibroblastos/metabolismo , Linfonodos/patologia , Reticulina/metabolismo , Linfócitos T/citologia , Animais , Autoimunidade , Proliferação de Células , Citocinas/metabolismo , Homeostase , Humanos , Imunofenotipagem , Linfa/metabolismo , Linfonodos/imunologia , Vasos Linfáticos/imunologia , Linfócitos/citologia , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Neoplasias/imunologia
5.
Lab Chip ; 21(11): 2283-2293, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33942040

RESUMO

Lymph transport inside lymphatic vessels is highly complex and not yet fully understood. So far, a consensus has not been reached among existing analytical models on how spatiotemporal coordination of contracting adjacent lymphangions affects lymph transport. To understand complex lymph transport, we created a novel microfluidic valvular chip with flexible bicuspid valves and segmental pneumatic pumps based on a microfluidic device with an inside 3D structure made of hydrogels. Inside the chip, water moved unidirectionally when the microfluidic channel was locally compressed, with its velocity profile closely resembling the waveform of lymph observed in vivo. Furthermore, for a systematic and mechanistic study, we constructed a numerical model based on fluid-structure interaction and validated the model via demonstration of similarities in water transport characteristics between the model and the chip. Using this model, we examined various mechanical and time-dependent parameters, such as period, phase delay, sequence, and strength of contractions, valve compliance, fluid viscosity, and pressure differences, for their effects on water transport. Although our model is simplified, it enabled a parametric study that helped clarify the mechano-temporal correlations between compressions of adjacent chambers via transmissions of hydrodynamic forces, which regulate complex lymph transport. Moreover, our chip demonstrated technical advances that enable unidirectional discrete movement of fluid in the picoliter range by phenumatic pumping. The velocity profile is also similar to the pulse waveform of arteries under pathological conditions such as increased aortic stiffness, allowing our chip to be used for in vitro mechanobiology studies of endothelial cells.


Assuntos
Vasos Linfáticos , Microfluídica , Células Endoteliais , Linfa , Pressão
7.
J Biophotonics ; 14(9): e202100055, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34057296

RESUMO

Multimodal optical coherent tomography grows popularity with researchers and clinicians over the past decade. One of the modalities is lymphangiography, which allows visualization of the lymphatic vessel networks within optical coherence tomography (OCT) imaging volume. In the present study, it is shown that lymphatic vessel visualization obtained from the depth-resolved attenuation coefficient distributions, corrected for the noise, shows improved contrast and detail in comparison with previously proposed approaches. We also argue that the two most popular approaches for lymphatic vessel visualization, namely simple intensity thresholding and vesselness calculation based on local Hessian matrix eigenvalues, imply different definitions of the lymphatic vessel's appearance in the OCT volume and lead to the different networks.


Assuntos
Vasos Linfáticos , Tomografia de Coerência Óptica , Angiografia , Linfa , Vasos Linfáticos/diagnóstico por imagem , Linfografia
8.
Fisioter. Bras ; 22(2): 272-289, Maio 25, 2021.
Artigo em Português | LILACS | ID: biblio-1284188

RESUMO

Introdução: O linfedema é a complicação mais frequente no pós-operatório do câncer de mama. Objetivo: Identificar a efetividade do uso da Terapia Complexa Descongestiva (TCD) na redução do volume e no tratamento intensivo do linfedema em pacientes submetidas ao procedimento cirúrgico com esvaziamento axilar devido ao câncer de mama. Métodos: Trata-se de uma revisão sistemática, para o qual foram consultados os bancos de dados Bireme e Pubmed, utilizando artigos científicos em português e inglês de revistas indexadas nas bases de dados Medline, Scielo, Lilacs, Register of Controlled Trials (Cochrane Central) e Physiotherapy Evidence Database (PEDro), publicados entre os anos de 2004 e 2019. Para a construção do trabalho foram incluídos estudos que estivessem disponíveis na íntegra, que a população alvo fosse composta por mulheres submetidas ao procedimento cirúrgico devido ao câncer de mama, com esvaziamento axilar, que apresentassem linfedema e que incluíssem em seus tratamentos, um protocolo fisioterapêutico de TCD. Também de forma independente, foi avaliada a qualidade metodológica dos estudos selecionados com a Escala de Qualidade de JADAD. Resultados: Atualmente, o padrão-ouro dentre as principais técnicas fisioterapêuticas utilizadas para o tratamento do linfedema é a TCD, a qual é composta por drenagem linfática manual, cuidados com a pele e unhas, bandagem de compressão e exercícios terapêuticos. Conclusão: A TCD é considerada o método mais utilizado e eficiente na redução do volume e no tratamento intensivo do linfedema pósmastectomia. (AU)


Introduction: The lymphedema is the most common postoperative complication of breast cancer. Objective: The present study aims to identify the effectiveness of the use of Complex Decongestive Therapy (CDT) in reducing volume and intensive treatment of lymphedema in patients undergoing axillary emptying due to breast cancer. Methods: This was a systematic review, for which Bireme and Pubmed databases were consulted, using scientific articles in Portuguese and English from journals indexed in Medline, Scielo, Lilacs, Register of Controlled Trials (Cochrane Central) databases and Physiotherapy Evidence Database (PEDro), all of them published between the years 2004 to 2019. For the construction of this study, we included articles available in full, with a target population consisting of women undergoing the surgical procedure due to breast cancer, with axillary emptying, who presented lymphedema and who included in their treatments a physical therapy protocol of CDT. Also, independently, the methodological quality of the studies selected was evaluated using the JADAD Quality Scale. Results: Currently, the gold standard among the main physiotherapeutic techniques used for the treatment of lymphedema is CDT, which consists of manual lymphatic drainage, skin and nail care, compression bandaging and therapeutic exercises. Conclusion: The CDT is considered the most used and efficient method for volume reduction and intensive treatment of post-mastectomy lymphedema. (AU)


Assuntos
Humanos , Modalidades de Fisioterapia , Linfedema , Mastectomia , Neoplasias da Mama , Linfa , Sistema Linfático
10.
Lipids Health Dis ; 20(1): 24, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648494

RESUMO

BACKGROUND: Dietary sphingolipids have various biofunctions, including skin barrier improvement and anti-inflammatory and anti-carcinoma properties. Long-chain bases (LCBs), the essential backbones of sphingolipids, are expected to be important for these bioactivities, and they vary structurally between species. Given these findings, however, the absorption dynamics of each LCB remain unclear. METHODS: In this study, five structurally different LCBs were prepared from glucosylceramides (GlcCers) with LCB 18:2(4E,8Z);2OH and LCB 18:2(4E,8E);2OH moieties derived from konjac tuber (Amorphophallus konjac), from GlcCers with an LCB 18(9Me):2(4E,8E);2OH moiety derived from Tamogi mushroom (Pleurotus cornucopiae var. citrinopileatus), and from ceramide 2-aminoethyphosphonate with LCB 18:3(4E,8E,10E);2OH moiety and LCB 18(9Me):3(4E,8E,10E);2OH moiety derived from giant scallop (Mizuhopecten yessoensis), and their absorption percentages and metabolite levels were analyzed using a lymph-duct-cannulated rat model via liquid chromatography tandem mass spectrometry (LC/MS/MS) with a multistage fragmentation method. RESULTS: The five orally administered LCBs were absorbed and detected in chyle (lipid-containing lymph) as LCBs and several metabolites including ceramides, hexosylceramides, and sphingomyelins. The absorption percentages of LCBs were 0.10-1.17%, depending on their structure. The absorption percentage of LCB 18:2(4E,8Z);2OH was the highest (1.17%), whereas that of LCB 18:3(4E,8E,10E);2OH was the lowest (0.10%). The amount of sphingomyelin with an LCB 18:2(4E,8Z);2OH moiety in chyle was particularly higher than sphingomyelins with other LCB moieties. CONCLUSIONS: Structural differences among LCBs, particularly geometric isomerism at the C8-C9 position, significantly affected the absorption percentages and ratio of metabolites. This is the first report to elucidate that the absorption and metabolism of sphingolipids are dependent on their LCB structure. These results could be used to develop functional foods that are more readily absorbed.


Assuntos
Trato Gastrointestinal/metabolismo , Linfa/metabolismo , Esfingolipídeos/metabolismo , Esfingomielinas/metabolismo , Animais , Ceramidas/química , Ceramidas/metabolismo , Cromatografia Líquida , Suplementos Nutricionais , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Linfa/efeitos dos fármacos , Pleurotus/genética , Ratos , Esfingolipídeos/química , Esfingolipídeos/genética , Esfingomielinas/química , Espectrometria de Massas em Tandem
11.
Sci Rep ; 11(1): 1468, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446832

RESUMO

Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.


Assuntos
Células Endoteliais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Linfa/fisiologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Feto/metabolismo , Cardiopatias Congênitas/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Vasos Linfáticos/metabolismo , Óxido Nítrico/metabolismo , Gravidez , Cultura Primária de Células , Circulação Pulmonar/fisiologia , Ovinos/metabolismo , Transdução de Sinais , Estresse Mecânico , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Int J Pharm ; 596: 120247, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33486039

RESUMO

Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if orlistat absorption could be improved it has the potential to treat diseases such as acute and critical illnesses where PL transport to the systemic circulation via gut lymph promotes organ failure. Orlistat is highly lipophilic and may associate with intestinal lipid absorption pathways into lymph. Here we investigate the potential to improve orlistat lymph and systemic uptake through intestinal administration in lipid formulations (LFs). The effect of lipid type, lipid dose, orlistat dose, and infusion time on lymph and systemic availability of orlistat was investigated. After administration in all LFs, orlistat concentrations in lymph were greater than in plasma, suggesting direct transport via lymph. Lymph and plasma orlistat derivative concentrations were ~8-fold greater after administration in a long-chain fatty acid (LC-FA) compared to a lipid-free, LC triglyceride (LC-TG) or medium-chain FA (MC-FA) formulation. Overall, administration of orlistat in a LC-FA formulation promotes lymph and systemic uptake which may enable treatment of diseases associated with elevated systemic PL activity.


Assuntos
Ácidos Graxos , Linfa , Disponibilidade Biológica , Absorção Intestinal , Orlistate
13.
Lymphat Res Biol ; 19(1): 73-79, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32721266

RESUMO

Background: While performing microsurgery, including lymphaticovenous anastomosis (LVA) for chronic limb lymphedema, it is a common procedure to identify the subcutaneous collecting lymph ducts with near-infrared fluorescence lymphangiography (NIR) using indocyanine green. However, due to limitations such as minimum observable depth, only a few lymphatic ducts can be identified with this procedure. Hence, we developed a new smaller-diameter "lymphatic wire" (LW) that could be inserted directly into lymphatic collecting ducts of the limbs, enabling accurate identification and localization. Methods and Results: First, used the LW on the hind limbs of 6 swine, and 36 porcine lymphatic collecting ducts were identified, the outer diameter of which varied from 0.3-0.7 mm (mean 0.41 ± 0.11 mm). We could insert the LW after creating a side opening in 30 of these ducts. We encountered no difficulties during the procedure. In the pathological examination, adverse events such as valve dysfunction and perforation were not identified. Based on the results, a clinical evaluation of the LW was performed in two patients with lower extremity lymphedema, and the LW helped us identify lymphatic ducts in the subcutaneous layer, even at the sites where the NIR had proved ineffective. Conclusion: Based on our results, we suggest that the procedure for identifying lymphatic vessels using the newly developed LW is a useful technique that can be utilized before performing a LVA for lymphedema. However, further clinical study is required to develop this device and technique, for wider clinical application in the future.


Assuntos
Experimentação Animal , Vasos Linfáticos , Linfedema , Animais , Humanos , Verde de Indocianina , Linfa , Linfografia , Suínos
14.
J Pharm Sci ; 110(1): 489-499, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33069711

RESUMO

Drug delivery to the lymphatic system is gaining increasing attention, particularly in fields such as immunotherapy where drug access to lymphocytes is central to activity. We have previously described a prodrug strategy that facilitates the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA) via incorporation into intestinal triglyceride transport pathways. The current study explored a series of structurally related glyceride and phospholipid mimetic prodrugs of MPA in an attempt to enhance lymph targeting and to better elucidate the design criteria for lipid mimetic prodrugs. MPA was conjugated to a glyceride or phospholipid backbone at various positions using different spacers employing ester, ether, carbonate and amide bonds. Patterns of prodrug hydrolysis were evaluated in rat digestive fluid, and lymphatic transport and plasma pharmacokinetics were assessed in lymph duct cannulated rats. Prodrugs with different spacers between MPA and the glyceride backbone resulted in up to 70-fold differences in gastrointestinal stability. MPA conjugation at the 2 position of the glyceride backbone and via an ester bond were most effective in promoting lymphatic transport. Phospholipid prodrug derivatives, or glyceride derivatives with MPA attached at the 1 position or when linked via ether, carbonate or amide bonds were poorly incorporated into lymphatic transport pathways.


Assuntos
Pró-Fármacos , Animais , Sistemas de Liberação de Medicamentos , Glicerídeos , Linfa , Fosfolipídeos , Ratos
15.
Lymphat Res Biol ; 19(2): 126-128, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33156732

RESUMO

Background: Lymphedema results from inadequate lymphatic function causing swelling in subcutaneous tissues. Lymph is transported proximally through valved lymphatic channels and muscle contraction. The purpose of this study was to determine lymphatic function in nonambulatory patients with lower extremity neuromuscular disease. Methods and Results: Our Lymphedema Program database of 700 patients was reviewed for nonambulatory patients with lower extremity neuromuscular disease. Patient age, gender, disease, body mass index (BMI), and lymphoscintigram result were recorded. Eight patients were included in the study: myelomeningocele (n = 6), spinal muscle atrophy type 2 (n = 1), Charcot Marie Tooth (n = 1). Patient ages were between 15 and 36 years; five were female. BMI range for patients without swelling or a normal lymphoscintigram (n = 4) was 22-27. Four subjects with lymphatic dysfunction by lymphoscintigram all were obese (BMI 36-74; p = 0.03). Conclusions: Nonambulatory patients with lower extremity neuromuscular dysfunction and swelling can exhibit normal lymphatic function. Obesity is associated with abnormal lymphoscintigram result and lymphedema in this patient population. Individuals should be advised to maintain a normal BMI.


Assuntos
Vasos Linfáticos , Doenças Neuromusculares , Adolescente , Adulto , Feminino , Humanos , Extremidade Inferior , Linfa , Linfedema , Linfocintigrafia , Masculino , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-33358925

RESUMO

Anurans have an exceptional capacity for maintaining vascular volume compared with other groups of vertebrates. They can mobilize interstitial fluids via lymphatic return at rates that are ten-fold higher than mammals. This extraordinary capacity is the result of coordination of specialized skeletal muscles and pulmonary ventilation that vary volume and pressure of subcutaneous lymph sacs, thus moving lymph to dorsally located lymph hearts that return lymph to the vascular space. Variation in the capacity to mobilize lymph within anurans varies with the degree of terrestriality, development of skeletal muscles, lung volume and lung compliance, and lymph heart pressure development. This ability enable anurans, which have the highest rates of evaporative water loss among terrestrial vertebrates, to withstand levels of dehydration far exceeding that of other vertebrates, and to successfully occupy virtually all terrestrial environments during their evolution. Maintenance of vascular fluid volume for all vertebrates can be achieved primarily by moving fluid from the interstitial space to the vascular space by transcapillary uptake and mobilization of interstitial (lymphatic) fluid. Transcapillary fluid uptake at the capillary level has been analyzed historically by Krogh and others from a Starling perspective and involves a balance of hydrostatic and oncotic forces. A complete evaluation of blood volume homeostasis also incorporates pressures and compliances of the vascular and interstitial spaces, but has been applied to only a few species. In this review we outline the current understanding of how anurans and other vertebrates maintain blood volume during hypovolemic challenges such as dehydration and hemorrhage which is crucial for maintaining cardiac output.


Assuntos
Volume Sanguíneo/fisiologia , Capilares/fisiologia , Hipovolemia/metabolismo , Linfa/fisiologia , Sistema Linfático/fisiologia , Anfíbios , Animais , Anuros , Transporte Biológico , Peixes , Hemorragia , Humanos , Pulmão/fisiologia , Músculo Esquelético/metabolismo , Ventilação Pulmonar , Ranidae , Especificidade da Espécie , Vertebrados , Viscosidade
17.
J Pharm Sci ; 110(3): 1427-1430, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33359312

RESUMO

Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (fa) via the lymph in the fed state was 0.26, representing 62% of the increase in fa in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport.


Assuntos
Fenantrenos , Administração Oral , Absorção Intestinal , Intestinos , Linfa , Modelos Biológicos , Período Pós-Prandial
18.
AJR Am J Roentgenol ; 216(3): 649-658, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33377793

RESUMO

OBJECTIVE. This article reviews thoracic lymphatic pathways and tributaries, discusses lymphatic anatomic variants and their clinical implications, and emphasizes common patterns of thoracic lymphadenopathy from extrapulmonary malignancies. CONCLUSION. Recognition of common patterns and pathways of thoracic lymphatic drainage can help identify the site of tumor origin and allow a more focused examination of disease extent, both of which are important for disease prognosis and management.


Assuntos
Metástase Linfática , Vasos Linfáticos/anatomia & histologia , Tórax/anatomia & histologia , Diafragma/anatomia & histologia , Humanos , Neoplasias Hepáticas/patologia , Linfa/fisiologia , Vasos Linfáticos/fisiologia , Mesotelioma Maligno/etiologia , Neoplasias Peritoneais/patologia , Pleura/anatomia & histologia , Neoplasias Pleurais/etiologia , Ducto Torácico/anatomia & histologia , Ducto Torácico/embriologia , Parede Torácica/anatomia & histologia
19.
J Surg Res ; 260: 399-408, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33261855

RESUMO

BACKGROUND: We have optimized a technique for cannulation of mesenteric lymph duct (MLD) in mice. Mice have low rates of intestinal lymph production; the MLDs are smaller and associated with fragile vasculature. Previous protocols for lymph collection based on the open lymph fistula model were associated with low success rates in mice. Bariatric surgery procedures worsen success rates due to postoperative adhesions and GI rearrangement. We have used this procedure to collect mesenteric lymph from mice undergoing bile diversion from gall bladder to ileum (GB-IL). HYPOTHESIS: We hypothesize that peptide YY (PYY) levels in mesenteric lymph will increase following nutrient delivery in mice undergoing bile diversion from gall bladder to ileum (GB-IL). METHODS AND RESULTS: We observe that cannulation of the MLD using a needled-catheter maintains lymph vessel integrity, prevents excessive lymph leakage, and is less traumatic, leading to high success rates (>95%). PYY levels in mesenteric lymph after GB-IL were significantly higher post nutrient infusion. The procedure takes approximately 20 min; small rodent surgical experience and practice are required for success. CONCLUSIONS: Intestinal lymph can be collected from mice, including those undergoing bariatric surgical procedures with high success rates by cannulation of the mesenteric lymph duct.


Assuntos
Cirurgia Bariátrica , Procedimentos Cirúrgicos do Sistema Biliar , Cateterismo/métodos , Linfa/metabolismo , Vasos Linfáticos/cirurgia , Mesentério/cirurgia , Peptídeo YY/metabolismo , Animais , Bile , Biomarcadores/metabolismo , Feminino , Vesícula Biliar/cirurgia , Íleo/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais
20.
Arterioscler Thromb Vasc Biol ; 41(1): 87-96, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33028092

RESUMO

Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells. Platelets are anucleate cells derived from megakaryocytes and are primarily known for their role in maintaining hemostasis and vascular integrity. Upon activation by a variety of agonists, platelets readily generate EVs, which were initially identified as procoagulant particles. However, as both platelets and their EVs are abundant in blood, the role of platelet EVs in hemostasis may be redundant. Moreover, findings have challenged the significance of platelet-derived EVs in coagulation. Looking beyond hemostasis, platelet EV cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes. Furthermore, while platelets cannot cross tissue barriers, their EVs can enter lymph, bone marrow, and synovial fluid. This allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. This review highlights the importance of platelet-derived EVs in physiological and pathological conditions beyond hemostasis.


Assuntos
Plaquetas/metabolismo , Comunicação Celular , Micropartículas Derivadas de Células/metabolismo , Hemostasia , Ativação Plaquetária , Animais , Medula Óssea/metabolismo , Micropartículas Derivadas de Células/transplante , Humanos , Mediadores da Inflamação/sangue , Linfa/metabolismo , Líquido Sinovial/metabolismo
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