RESUMO

Background: The goal of fluid resuscitation and the use of inotropes in septic shock has traditionally focused on improving blood pressure and cardiac output, without considering the microcirculatory changes. Reaching macrocirculatory goals but with persistent microcirculatory abnormalities (hemodynamic incoherence) in septic shock has been associated with greater organ dysfunction and mortality. The objective of this study was to evaluate the microcirculation (flow and capillary density) and endothelial glycocalyx changes associated with the use of milrinone in children with septic shock, as well as their relationship with clinical variables and organ dysfunction. Methods: A prospective cohort study from February 2022 to January 2023 at a university hospital (Fundación Cardioinfantil-Instituto de Cardiología). Sublingual video microscopy was used to evaluate capillary density, microvascular flow rates and perfused boundary region (PBR-inverse parameter of glycocalyx thickness-abnormal if >2.0 microns). The primary outcome was the association between microcirculation and endothelial glycocalyx changes related to the use of milrinone. Results: A total of 140 children with a median age of two years [interquartile range (IQR) 0.58-12.1] were included. About 57.9% (81/140) of the patients received milrinone infusions. Twenty-four hours after receiving milrinone, the patients maintained functional capillary density (P<0.01) and capillary recruitment capacity (P=0.04) with no changes in capillary blood volume versus those who did not receive milrinone. Children under two years old who received milrinone had better 4-6-micron capillary density than older children [odds ratio (OR) 0.33; 95% confidence interval (95% CI): 0.12-0.89; P=0.02] and less endothelial glycocalyx degradation [adjusted OR (aOR) 0.34 95% CI: 0.11-0.99; P=0.04]. These changes persisted despite elevated ferritin (aOR 0.41; 95% CI: 0.18-0.93; P=0.03). Prolonged capillary refill and elevated lactate were correlated with microcirculation changes in both groups. The patients who died had the highest PBR levels (P=0.04). Conclusions: Children with septic shock who receive milrinone infusions have microcirculation changes compared with those who do not receive them. The group that received milrinone was found to maintain functional capillary density and capillary recruitment capacity and have less endothelial glycocalyx degradation 24 hours after administration. These changes were present despite the inflammatory response and were more significant in those under two years of age.

RESUMO

Hereditary angioedema (HAE) encompasses a group of diseases characterized by recurrent, genetically mediated angioedema associated with increased vascular permeability primarily due to bradykinin. The disease poses diagnostic challenges, leading to underdiagnosis and delayed therapy. Severe manifestations include laryngeal and intestinal angioedema, contributing to significant morbidity and mortality. If left undiagnosed, the estimated mortality rate of the disease ranges from 25% to 40% due to asphyxiation caused by laryngeal angioedema. There is a pressing need to enhance awareness of hereditary angioedema and its warning signs. The acronym "H4AE" may facilitate the memorization of these signs. This study comprehensively reviews clinical, laboratory, and physiopathological features of documented HAE subtypes. The study advocates for an improved HAE classification based on endotypes, building on the knowledge of angioedema pathophysiology. The proposed endotype classification of HAE offers a clear and applicable framework, encouraging advancements in disease understanding and classification.

RESUMO

Enhanced vascular permeability at the site of injury is a prominent feature in acute inflammatory pain models, commonly assessed through the Evans Blue test. However, this invasive test requires euthanasia, thereby precluding further investigations on the same animal. Due to these limitations, the integration of non-invasive tools such as IRT has been sought. Here, we aimed to evaluate the use of thermography in a common orofacial pain model that employs formalin as a chemical irritant to induce local orofacial inflammation. Male Hannover rats (290-300 g, N = 43) were used. In the first approach, radiometric images were taken before and after formalin administration, assessing temperature changes and extravasated Evans Blue. The second approach included capturing pre- and post-formalin test radiometric images, followed by cytokine measurements in excised vibrissae tissue. Rats were anesthetized for vibrissae tissue collection, allowing correlations between thermographic patterns, nocifensive behavior duration, and cytokine levels in this area. Our findings revealed a positive correlation between local temperature, measured via thermography, and vascular permeability in the contralateral (r2 = 0.3483) and ipsilateral (r2 = 0.4502) side, measured using spectrophotometry. The obtained data supports the notion that thermography-based temperature assessment can effectively evaluate vascular permeability in the orofacial region.

Assuntos

Formaldeído , Termografia , Ratos , Masculino , Animais , Formaldeído/efeitos adversos , Termografia/métodos , Permeabilidade Capilar , Azul Evans/efeitos adversos , Dor Facial/induzido quimicamente , Citocinas

RESUMO

A pioneering study regarding the isolation, biochemical evaluation, functional assays and first PEGylation report of a novel vascular endothelial growth factor from Crotalus durissus terrificus venom (CdtVEGF and PEG-CdtVEGF). CdtVEGF was isolated from crude venom using two different chromatographic steps, representing 2% of soluble venom proteins. Its primary sequence was determined using mass spectrometry analysis, and the molecule demonstrated no affinity to heparin. The Brazilian crotalid antivenom recognized CdtVEGF. Both native and PEGylated CdtVEGF were able to induce new vessel formation and migration, and to increase the metabolic activity of human umbilical endothelial vascular cells (HUVEC), resulting in better wound closure (~50% within 12 h) using the native form. CdtVEGF induced leukocyte recruitment to the peritoneal cavity in mice, with a predominance of neutrophil influx followed by lymphocytes, demonstrating the ability to activate the immune system. The molecule also induced a dose-dependent increase in vascular permeability, and PEG-CdtVEGF showed less in vivo inflammatory activity than CdtVEGF. By unraveling the intricate properties of minor components of snake venom like svVEGF, this study illuminates the indispensable significance of exploring these molecular tools to unveil physiological and pathological processes, elucidates the mechanisms of snakebite envenomings, and could possibly be used to design a therapeutic drug.

Assuntos

Venenos de Crotalídeos , Fator A de Crescimento do Endotélio Vascular , Humanos , Animais , Camundongos , Brasil , Permeabilidade Capilar , Polietilenoglicóis

RESUMO

Coronavirus-induced diseases have afflicted humanity for several decades. This scenario was aggravated by the emergence of the coronavirus disease 2019 (named COVID-19) in Wuhan, China, in December 2019. Since then, COVID-19 has killed millions of people worldwide, probably the most devastating pandemic since HIV/AIDS. This review aimed to bring together important updated aspects related to coronavirus-induced diseases and the enhanced vascular permeability observed mainly in the lungs of affected people. The dysregulated vascular permeability in the lungs is of fundamental importance for coronaviruses-caused morbidity and mortality. Thus, as described in this review, it is a target of new and old drugs.

Assuntos

COVID-19 , Humanos , SARS-CoV-2 , Permeabilidade Capilar , Pulmão , Permeabilidade

RESUMO

The present study aimed to investigate the antioxidant activity of Aniba canelilla (kunth) Mez (Lauraceae) essential oil (AcEO), exploring its potential for prevention and/or treatment of oxidative stress and associated inflammatory process. With this aim, Wistar rats (n = 6/group) were pre-treated intraperitoneally with saline (0.9%) or AcEO (2 or 5 mg/kg) for 5 days. One hour after the last dose, inflammation and oxidative stress were induced by carrageenan (0.3 mg/kg; ip.) administration. Total antioxidant capacity, reduced glutathione (GSH) and lipid peroxidation levels, protein concentration, and leukocyte migration were evaluated in peritoneal fluid. Lipid peroxidation was also evaluated in plasma. Carrageenan strongly reduced the peritoneal antioxidant capacity and GSH concentration, increasing peritoneal and plasma lipid peroxidation. It also promoted increased plasma leakage and leukocyte migration. Treatment with AcEO (2 and 5 mg/kg), whose major constituent was 1-nitro-2-phenylethane (77.5%), increased the peritoneal antioxidant capacity and GSH concentrations, and reduced lipid peroxidation, both peritoneal and plasma, thus inhibiting the carrageenan-induced oxidative imbalance. AcEO also reduced the carrageenan-induced plasma leakage and leukocyte migration. These data demonstrate the AcEO antioxidant activity and its ability to modulate plasma leakage and leukocyte migration, confirming its potential for treating diseases associated with inflammation and oxidative stress.

RESUMO

Coral snakes mainly cause neurotoxic symptoms in human envenomation, but experimental studies have already demonstrated several pharmacological activities in addition to these effects. This investigation was carried out with the aim of evaluating (1) non-neurogenic mechanisms involved in the inflammatory response induced by Micrurus lemniscatus venom (MLV) in rat hind paws, (2) participation of PLA2 in this response, and (3) neutralizing efficiency of commercial anti-elapid antivenom on edema. MLV promoted a rapid, significant increase in vascular permeability, influx of leukocytes, and disorganization of collagen bundles, as demonstrated by histological analysis. Several pretreatments were applied to establish the involvement of inflammatory mediators in MLV-induced edema (5 µg/paw). Treatment of animals with chlorpromazine reduced MLV-induced edema, indicating participation of TNF-α. However, the inefficiency of other pharmacological treatments suggests that eicosanoids, leukotrienes, and nitric oxide have no role in this type of edema formation. In contrast, PAF negatively modulates this venom-induced effect. MLV was recognized by anti-elapid serum, but this antivenom did not neutralize edema formation. Chemical modification of MLV with p-bromophenacyl bromide abrogated the phospholipase activity and markedly reduced edema, demonstrating PLA2 participation in MLV-induced edema. In conclusion, the non-neurogenic inflammatory profile of MLV is characterized by TNF-α-mediated edema, participation of PLA2 activity, and down-regulation by PAF. MLV induces an influx of leukocytes and destruction of collagen fibers at the site of its injection.

RESUMO

Metabolic syndrome is a disorder characterized by a constellation of clinical findings such as elevated blood glucose, hyperinsulinemia, dyslipidemia, hypertension, and obesity. A positive correlation has been found between metabolic syndrome or its components and retinopathy, mainly at microvascular level, in patients without a history of diabetes. Here, we extend the investigations beyond the vascular component analyzing functional changes as well as neuronal and glial response in retinas of Apolipoprotein E knockout (ApoE-KO) mice fed with 10% w/v fructose diet. Given that autophagy dysfunction is implicated in retinal diseases related to hyperglycemia and dyslipidemia, the activation of this pathway was also analyzed. Two months of fructose intake triggered metabolic derangements in ApoE-KO mice characterized by dyslipidemia, hyperglycemia and hyperinsulinemia. An increased number of TUNEL positive cells, in addition to the ganglion cell layer, was observed in the inner nuclear layer in retina. Vascular permeability, evidenced by albumin-Evans blue leakage and extravasation of albumin was also detected. Furthermore, a significant decrease of the glial fibrillary acidic protein expression was confirmed by Western blot analysis. Absence of both Müller cell gliosis and pro-angiogenic response was also demonstrated. Finally, retinas of ApoE-KO FD mice showed defective autophagy activation as judged by LC3B mRNA and p62 protein levels correlating with the increased cell death. These results demonstrated that FD induced in ApoE-KO mice biochemical alterations compatible with metabolic syndrome associated with neuronal impairment and mild vascular alterations in the retina.

RESUMO

We investigated the histology of Duvernoy's venom gland and the biochemical and biological activities of Leptodeira annulata snake venom. The venom gland had a lobular organization, with secretory tubules formed by serous epithelial cells surrounding each lobular duct. The latter drained into a common lobular duct and subsequently into a central cistern. In contrast, the supralabial gland was mucous in nature. SDS-PAGE revealed a profile of venom components that differed from pitviper (Bothrops spp.) venoms. RP-HPLC also revealed greater complexity of this venom compared to Bothrops venoms. The venom had no esterase, l-amino acid oxidase or thrombin-like activity, but was proteolytic towards elastin-Congo red, fibrin, fibrinogen, gelatin and hide powder azure. The venom showed strong α-fibrinogenase and fibrinolytic activities and reduced the rate and extent of plasma recalcification. The proteolytic activity was inhibited by EDTA and 1,10-phenanthroline (metalloproteinase inhibitors) but not by AEBSF and PMSF (serine proteinase inhibitors). The venom had phospholipase A2 (PLA2) activity that was inhibited by varespladib. The venom cross-reacted with antivenoms to lancehead (Bothrops spp.), coralsnake (Micrurus spp.) and rattlesnake (Crotalus durissus terrificus) venoms. The venom did not aggregate rat platelets or inhibit collagen-induced aggregation, but partially inhibited thrombin-induced aggregation. The venom was hemorrhagic (inhibited by EDTA) and increased the vascular permeability (inhibited by varespladib) in rat dorsal skin. In gastrocnemius muscle, the venom caused myonecrosis and increased serum creatine kinase concentrations. In conclusion, L. annulata venom has various enzymatic and biological activities, with the local effects being mediated primarily by metalloproteinases and PLA2.

Assuntos

Colubridae , Venenos de Serpentes , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Wistar , Venenos de Serpentes/química , Venenos de Serpentes/enzimologia

RESUMO

The vascular endothelial growth factor (VEGF) is an essential factor to pathologic angiogenesis. Disruption of VEGF/VEGF receptor interaction in cancer patients inhibits the development of new and pre-existing tumor blood vessels. Consequently, VEGF becomes an important therapeutic target for handling solid tumors. In this work, human VEGF was produced in the culture supernatant of SiHa cells transduced with a replication-defective adenoviral vector (pAdhVEGF121) encoding this molecule. The 35 kDa VEGF121 homodimer was obtained from clarified culture media as a glycosylated protein. VEGF121 expression levels were strictly dependent on the adenoviral viral load used. VEGF121 was produced with purity over 98% after a single step chromatography by immobilized metal affinity chromatography. Additionally, VEGF121 binds Bevacizumab antibody with a KD of 7 nM. Biological characterization by mitogenic assay in HUVEC and ECV-304 cells showed that VEGF121 stimulates cell proliferation in a dose-dependent manner in both cells. Finally, the neovascularization activity of VEGF121 was demonstrated by vascular permeability assays in matrigel plug-bearing mice, showing significantly increased vasculature leakage after treatment with VEGF121. Consequently, transduction of SiHa cells with adenovirus is a suitable alternative for manufacture heterologous proteins of therapeutic interest.

Assuntos

Fator A de Crescimento do Endotélio Vascular/isolamento & purificação , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos

RESUMO

Introducción: Las cirugías arteriales en los pacientes diabéticos permiten disminuir las frecuencias de amputaciones que se realizan en estos pacientes. Objetivo: Exponer los principales tipos de cirugías arteriales en los miembros inferiores que se realizan en pacientes diabéticos y sus resultados. Métodos: Estudio de búsqueda y síntesis bibliográfica en el que consultaron y tamizaron 162 documentos (artículos, registros médicos y tesis) publicados en las bases de datos de sistemas referativos MEDLINE, PubMed y SciELO e indexadas en la Web of Sciencies, Scopus, Redalyc y Latindex, con la utilización de descriptores: cirugía revascularizadora, permeabilidad arterial, pie diabético, cirugía endovascular, endarterectomía, angioplastia transluminal percutánea. Esto generó que se seleccionara 43 artículos y tres registros médicos. Resultados: La técnica en la revascularización del sector aortoiliaco incluye la cirugía derivativa anatómica [by-passaorto-femoral (bi o uni)]y la extraanatómica [by-pass (axilo-femoral, fémoro-femoral), la endarterectomía y la cirugía endovascular en el sector iliaco. Las técnicas quirúrgicas a aplicar en el sector femoropoplíteo y distal son el by-pass secuencial, endarterectomía, simpatectomía, tratamiento endovascular. Es importante tener en cuenta las características de los pacientes por separado para la decisión del tipo de cirugía. Conclusiones: Las cirugías arteriales en el paciente diabético son diversas y para su éxito es necesario valorar siempre el riesgo quirúrgico y la anatomía de las lesiones de cada paciente(AU)

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Introduction: Arterial surgeries in diabetic patients allow reducing the frequency of amputations that are performed in these patients. Objective: To show the main types of arterial surgery in the lower limbs performed in diabetic patients and their results. Methods: Bibliographic search and synthesis study in which 162 materials (articles, medical records and theses) published in the MEDLINE, PubMed and SciELO reference databases were searched and indexed in the Web of Sciencies, Scopus, Redalyc and Latindex, using as descriptors: revascularization surgery, arterial permeability, diabetic foot, endovascular surgery, endarterectomy, percutaneous transluminal angioplasty. This led to the quoting of 43 articles and three medical records. Results: The technique in the revascularization of the aorto iliac sector includes the anatomical derivative surgery [aorto-femoral by-pass (bi or uni)] and extra-anatomical [by-pass (axillo-femoral, femoro-femoral), endarterectomy and endovascular surgery in the iliac sector. The surgical techniques to be applied in the femoro popliteal and distal sectors are the sequential by-pass, endarterectomy, sympathectomy, and endovascular treatment. It is important to consider the characteristics of patients separately to decide the type of surgery. Conclusions: The arterial surgeries in the diabetic patient are diverse and for the success of them it is necessary to always assess the surgical risk and the anatomy of the lesions of each patient(AU)

Assuntos

Humanos , Permeabilidade Capilar , Complicações do Diabetes , Doença Arterial Periférica/cirurgia , Doença Arterial Periférica/epidemiologia , Cuba

RESUMO

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B-2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.Kenne, E., Rasmuson, J., Renne, T., Vieira, M. L., Muller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.

RESUMO

Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate itself has the ability to induce increase in vascular permeability in the skin of mice. Proteomics analysis of exudate revealed the presence of cytokines and chemokines, together with abundant damage associated molecular pattern molecules (DAMPs) resulting from both proteolysis of extracellular matrix and cellular lysis. Moreover, significant differences in the amounts of cytokines/chemokines and DAMPs were detected between exudates collected 1 h and 24 h after envenomation, thus highlighting a complex temporal dynamic in the composition of exudate. Pretreatment of mice with Eritoran, an antagonist of Toll-like receptor 4 (TLR4), significantly reduced the exudate-induced increase in vascular permeability, thus suggesting that DAMPs might be acting through this receptor. It is hypothesized that an "Envenomation-induced DAMPs cycle of tissue damage" may be operating in viperid snakebite envenomation through which venom-induced tissue damage generates a variety of DAMPs which may further expand tissue alterations.

Assuntos

Permeabilidade Capilar , Venenos de Crotalídeos/toxicidade , Exsudatos e Transudatos/metabolismo , Mordeduras de Serpentes/metabolismo , Alarminas/metabolismo , Animais , Bothrops , Citocinas/metabolismo , Camundongos , Proteômica , Receptor 4 Toll-Like/metabolismo

RESUMO

STUDY QUESTION: Are follicular fluid (FF) sphingosine-1-phosphate (S1P) levels in patients at risk of developing ovarian hyperstimulation syndrome (OHSS) altered and in part responsible for the high vascular permeability observed in these patients. STUDY ANSWER: FF S1P levels are lower in FF from patients at risk of OHSS and treatment with S1P may reduce vascular permeability in these patients. WHAT IS KNOWN ALREADY: Although advances have been made in the diagnosis, and management of OHSS and in basic knowledge of its development, complete prevention has proven difficult. STUDY DESIGN, SIZE, DURATION: A total of 40 FF aspirates were collected from patients undergoing ART. The women (aged 25-39 years old) were classified into a control group (n = 20) or a group at risk of OHSS (n = 20). The EA.hy926 endothelial cell line was used to assess the efffects of FF from patients at risk of OHSS with or without the addition of S1P. An animal model that develops OHSS in immature Sprague-Dawley rats were also used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Migration assays, confocal microscopy analysis of actin filaments, immunoblotting and quail chorioallantoic membrane (CAM) assays of in-vivo angiogenesis were performed and statistical comparisons between groups were made. MAIN RESULTS AND THE ROLE OF CHANCE: The S1P concentration was significantly lower in FF from patients at risk of OHSS (P = 0.03). The addition of S1P to this FF decreased cell migration (P < 0.05) and prevented VE-cadherin phosphorylation in endothelial cells (P < 0.05). S1P in the FF from patients at risk of OHSS increased the levels of VE-cadherin (P < 0.05), N-cadherin (P < 0.05) and ß-catenin (P < 0.05), and partially reversed actin redistribution in endothelial cells. The addition of S1P in FF from patients at risk of OHSS also decreased the levels of vascular endothelial growth factor (VEGF121; P < 0.01) and S1P lyase (SPL; P < 0.05) and increased the levels of S1PR1 (P < 0.05) in endothelial cells. In CAMs incubated with FF from patients at risk of OHSS with S1P, the number of vessel branch points decreased while the periendothelial cell coverage increased. Additionally, in a rat OHSS model, we demonstrated that vascular permeability and VEGF121 and its receptor KDR expression were increased in the OHSS group compared to the control group and that S1P administration decreased these parameters. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The results of this study were generated from an in-vitro system. This model reflects the microvasculature in vivo. Even though the ideal model would be the use of human endothelial cells from the ovary, it is obviously not possible to carry out this kind of approach in ovaries of patients from ART. More studies will be necessary to delineate the effects of S1P in the pathogenesis of OHSS. Hence, clinical studies are needed in order to choose the most appropriate method of prevention and management. WIDER IMPLICATIONS OF THE FINDINGS: The use of bioactive sphingolipid metabolites may contribute to finding better and safer therapeutic strategies for the treatment of OHSS and other human diseases that display aberrant vascular leakage. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants ANPCyT (PICT 2012-897), CONICET (PIP 5471), Roemmers and Baron Foundation, Argentina. The authors declare no conflict of interest.

Assuntos

Lisofosfolipídeos/farmacologia , Síndrome de Hiperestimulação Ovariana/metabolismo , Ovário/metabolismo , Esfingosina/análogos & derivados , Adulto , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Feminino , Líquido Folicular/metabolismo , Humanos , Immunoblotting , Lisofosfolipídeos/uso terapêutico , Microscopia Confocal , Síndrome de Hiperestimulação Ovariana/tratamento farmacológico , Ovário/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/uso terapêutico

RESUMO

The barrier properties of endothelial cells are critical for the maintenance of water and protein balance between the intravascular and extravascular compartments. An impairment of endothelial barrier function has been implicated in the genesis and/or progression of a variety of pathological conditions, including pulmonary edema, ischemic stroke, neurodegenerative disorders, angioedema, sepsis and cancer. The altered barrier function in these conditions is often linked to the release of soluble mediators from resident cells (e.g., mast cells, macrophages) and/or recruited blood cells. The interaction of the mediators with receptors expressed on the surface of endothelial cells diminishes barrier function either by altering the expression of adhesive proteins in the inter-endothelial junctions, by altering the organization of the cytoskeleton, or both. Reactive oxygen species (ROS), proteolytic enzymes (e.g., matrix metalloproteinase, elastase), oncostatin M, and VEGF are part of a long list of mediators that have been implicated in endothelial barrier failure. In this review, we address the role of blood borne cells, including, neutrophils, lymphocytes, monocytes, and platelets, in the regulation of endothelial barrier function in health and disease. Attention is also devoted to new targets for therapeutic intervention in disease states with morbidity and mortality related to endothelial barrier dysfunction.

RESUMO

Vanillic acid is found at high concentrations in many plants used in traditional medicine. It has been associated with a variety of pharmacologic activities such as carcinogenesis inhibition, apoptosis and inflammation; however, it has become most popular for its pleasant creamy odor. Since there are few reports concerning the antinociceptive activity of this phenolic compound, the aim of this work was to study this activity in in vivo animal models. Vanillic acid was administered by the intraperitoneal route producing a dose-dependent inhibition of the acetic acid-induced writhing response (ED50: 9.3mg/kg). The antinociceptive activity was inhibited by the pretreatment with ondansetron and yohimbine, indicating that the serotoninergic and adrenergic systems could participate in the mechanism underlying the analgesic activity of vanillic acid. This compound was also demonstrated to interact with ASICs (Acid-sensing Ion Channels) as well as with TPRV1, TRPA1, and TRPM8 receptors in vivo. Furthermore, vanillic acid did not interfere with the locomotor function or motor coordination. The plasmatic phenolic content, analyzed by HPLC, showed that its t1/2 and AUC were 0.123h and 1.38µg·h/mL; respectively. In conclusion, vanillic acid might represent a potential therapeutic option for the treatment of pain.

RESUMO

BACKGROUND: Endothelial cell dysfunction is believed to play an important role in the pathogenesis of plasma leakage in patients with acute dengue virus (DENV) infection. Several factors, produced by activated endothelial cells, have been associated with plasma leakage or severe disease in patients with infectious diseases. OBJECTIVES: The aim of this study was to investigate which of these markers could serve as a surrogate marker for the occurrence of plasma leakage in patients with acute DENV infection. STUDY DESIGN: A case-control study was performed in patients with acute DENV infection in Santos, Brazil. Plasma leakage was detected with X-ray and/or ultrasound examination at admission. Serum levels of soluble endoglin, endothelin-1, angiopoietin-2, VEGF, soluble VEGFR-2, MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined using commercially available ELISAs. RESULTS: Increased levels of angiopoietin-2, endothelin-1 and MMP-2 and decreased levels of soluble VEGFR-2 were significantly associated with the occurrence of plasma leakage. An unsupervised cluster analysis confirmed that angiopoietin-2 and soluble VEGFR-2 were strongly associated with clinical apparent vascular leakage. CONCLUSION: Angiopoietin-2 and soluble VEGFR-2 can serve as surrogate markers for the occurrence of plasma leakage in patients with acute DENV infection.

Assuntos

Angiopoietina-2/sangue , Permeabilidade Capilar/fisiologia , Dengue Grave/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Afinidade de Anticorpos/imunologia , Biomarcadores/sangue , Brasil , Estudos de Casos e Controles , Criança , Vírus da Dengue/patogenicidade , Células Endoteliais/patologia , Células Endoteliais/virologia , Endotelina-1/sangue , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade , Radiografia , Dengue Grave/diagnóstico por imagem , Dengue Grave/virologia , Adulto Jovem

RESUMO

OBJECTIVE: Ischemic preconditioning and some drugs can protect tissues from injury by preserving microcirculation. This study evaluated vascular permeability in a hamster cheek pouch preparation using either short ischemic periods or bradykinin as preconditioning stimuli followed by 30 min of ischemia/reperfusion. METHOD: Sixty-six male hamsters were divided into 11 groups: five combinations of different ischemic frequencies and durations (one, three or five shorts periods of ischemia, separated by one or five minutes) with 10 min intervals between the ischemic periods, followed by 30 min ischemia/reperfusion; three or five 1 min ischemic periods with 10 min intervals between them followed by the topical application of histamine (2 µM); bradykinin (400 nM) followed by 30 min of ischemia/reperfusion; and three control groups (30 min of ischemia/reperfusion or histamine or bradykinin by themselves). Macromolecular permeability was assessed by injection of fluorescein-labeled dextran (FITC-dextran, MW= 150 kDa; 250 mg/Kg body weight), and the number of leaks/cm2 was counted using an intravital microscope and fluorescent light in the cheek pouch. RESULTS: Plasma leakage (number of leaks/cm²) was significantly reduced by preconditioning with three and five 1 min ischemic periods, one and three 5 min ischemic periods and by bradykinin. Histamine-induced macromolecular permeability was also reduced after three periods of 5 min of ischemia. CONCLUSION: Short ischemic periods and bradykinin can function as preconditioning stimuli of the ischemia/reperfusion response in the hamster cheek pouch microcirculation. Short ischemic periods also reduced histamineinduced macromolecular permeability.

Assuntos

Animais , Cricetinae , Masculino , Permeabilidade Capilar/efeitos dos fármacos , Precondicionamento Isquêmico/métodos , Traumatismo por Reperfusão/tratamento farmacológico , Bradicinina/farmacologia , Bochecha/irrigação sanguínea , Modelos Animais de Doenças , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Microcirculação , Plasma/efeitos dos fármacos , Plasma/fisiologia , Traumatismo por Reperfusão/sangue , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/farmacologia

RESUMO

Aiming to compare the effect of different light sources for dental bleaching on vascular permeability of dental pulps, forty-eight incisors were used. The bleaching agent (35 % hydrogen peroxide) was activated by halogen light; LED (Light Emitting Diode) or LED, followed by laser phototherapy (LPT) (λ = 780 nm; 3 J/cm²). After the bleaching procedures, the animals received an intra-arterial dye injection and one hour later were sacrificed. The teeth were diaphanized and photographed. The amount of blue stain content of each dental pulp was quantified using a computer imaging program. The data was statistically compared (p < 0.05). The results showed a significant higher (p < 0.01) dye content in the groups bleached with halogen light, compared with the control, LED and LED plus LPT groups. Thus, tooth bleaching activated by LED or LED plus LPT induces lesser resulted in increased vascular permeability than halogen light.