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 , PermeabilidadeRESUMO
BACKGROUND: Sepsis is an emergency medical condition that can lead to death and it is defined as a life-threatening organ dysfunction caused by immune dysregulation in response to an infection. It is considered the main killer in intensive care units. Sepsis associated-encephalopathy (SAE) is mostly caused by a sepsis-induced systemic inflammatory response. Studies report SAE in 14-63% of septic patients. Main SAE symptoms are not specific and usually include acute impairment of consciousness, delirium and/or coma, along with electroencephalogram (EEG) changes. For those who recover from sepsis and SAE, impaired cognitive function, mobility and quality of life are often observed months to years after hospital discharge, and there is no treatment available today to prevent that. Inflammation and oxidative stress are key players for the SAE pathophysiology. Gold nanoparticles have been demonstrated to own important anti-inflammatory properties. It was also reported 20 nm citrate-covered gold nanoparticles (cit-AuNP) reduce oxidative stress. In this context, we tested whether 20 nm cit-AuNP could alleviate the acute changes caused by sepsis in brain of mice, with focus on inflammation. Sepsis was induced in female C57BL/6 mice by cecal ligation and puncture (CLP), 20 nm cit-AuNP or saline were intravenously (IV) injected 2 h after induction of sepsis and experiments performed 6 h after induction. Intravital microscopy was used for leukocyte and platelet adhesion study in brain, blood brain barrier (BBB) permeability carried out by Evans blue assay, cytokines measured by ELISA and real time PCR, cell adhesion molecules (CAMs) by flow cytometry and immunohistochemistry, and transcription factors, by western blotting. RESULTS: 20 nm cit-AuNP treatment reduced leukocyte and platelet adhesion to cerebral blood vessels, prevented BBB failure, reduced TNF- concentration in brain, and ICAM-1 expression both in circulating polymorphonuclear (PMN) leukocytes and cerebral blood vessels of mice with sepsis. Furthermore, 20 nm cit-AuNP did not interfere with the antibiotic effect on the survival rate of mice with sepsis. CONCLUSIONS: Cit-AuNP showed important anti-inflammatory properties in the brain of mice with sepsis, being a potential candidate to be used as adjuvant drug along with antibiotics in the treatment of sepsis to avoid SAE.
Assuntos
Ceco/metabolismo , Ouro/farmacologia , Inflamação/tratamento farmacológico , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Microvasos/metabolismo , Sepse/tratamento farmacológico , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encefalopatias , Adesão Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/patologia , Neutrófilos/metabolismo , Qualidade de Vida , Sepse/metabolismo , Sepse/patologia , Encefalopatia Associada a Sepse/metabolismoRESUMO
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
The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan) and cyclooxygenase (COX) inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl) gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o.) 1 hour before oral administration of Et/HCl (60%/0.03M). In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME) before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO), as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H(+) in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling neutrophil influx and microcirculatory blood flow mediated by NO.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Gastrite/metabolismo , Gastrite/patologia , Indóis/farmacologia , Microcirculação/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Tiazolidinedionas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Etanol/efeitos adversos , Ácido Gástrico/metabolismo , Gastrite/induzido quimicamente , Gastrite/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Clorídrico/efeitos adversos , Indóis/administração & dosagem , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Tiazolidinedionas/administração & dosagemRESUMO
We recently observed the enhanced serine and matrix metalloproteinase (MMP) activity in the spontaneously hypertensive rat (SHR) compared with its normotensive Wistar-Kyoto (WKY) rat and the cleavage of membrane receptors in the SHR by MMPs. We demonstrate in vivo that MMP-7 and MMP-9 injection leads to a vasoconstrictor response in microvessels of rats that is blocked by a specific MMP inhibitor (GM-6001, 1 microM). Multiple pathways may be responsible. Since the beta(2)-adrenergic receptor (beta(2)-AR) is susceptible to the action of endogenous MMPs, we hypothesize that MMPs in the plasma of SHRs are able to cleave the extracellular domain of the beta(2)-AR. SHR arterioles respond in an attenuated fashion to beta(2)-AR agonists and antagonists. Aorta and heart muscle of control Wistar rats were exposed for 24 h (37 degrees C) to fresh plasma of male Wistar and WKY rats and SHRs with and without doxycycline (30 microM) and EDTA (10 mM) to reduce MMP activity. The density of extracellular and intracellular domains of beta(2)-AR was determined by immunohistochemistry. The density of the extracellular domain of beta(2)-AR is reduced in aortic endothelial cells and cardiac microvessels of SHRs compared with that of WKY or Wistar rats. Treatment of the aorta and the heart of control Wistar rats with plasma from SHRs, but not from WKY rats, reduced the number of extracellular domains, but not intracellular domains, of beta(2)-AR in aortic endothelial cells and cardiac microvessels. MMP inhibitors (EDTA and doxycycline) prevented the cleavage of the extracellular domain. Thus MMPs may contribute to the reduced density of the extracellular domain of beta(2)-AR in blood vessels and to the increased arteriolar tone of SHRs compared with normotensive rats.
Assuntos
Hipertensão/enzimologia , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Processamento de Proteína Pós-Traducional , Receptores Adrenérgicos beta 2/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Aorta/enzimologia , Arteríolas/enzimologia , Arteríolas/fisiopatologia , Pressão Sanguínea , Western Blotting , Vasos Coronários/enzimologia , Modelos Animais de Doenças , Hipertensão/fisiopatologia , Imuno-Histoquímica , Infusões Intra-Arteriais , Masculino , Metaloproteinase 7 da Matriz/administração & dosagem , Metaloproteinase 9 da Matriz/administração & dosagem , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Fatores de Tempo , VasoconstriçãoRESUMO
In addition to reducing blood pressure, hydralazine can reduce the production of inflammatory cytokines and reduce the expression of leukocyte adhesion molecules. Differences in leukocyte behavior and leukocyte adhesion molecule expression in spontaneously hypertensive rats (SHR) compared to normotensive rats have been reported. However, whether hydralazine can reduce leukocyte migration in vivo in hypertension and in normotension remains unknown. To address this question, male SHR and Wistar rats were treated for 15 days with hydralazine at a dose of ~3.5 mg/kg or ~14 mg/kg in their drinking water. The numbers of rollers and adherent and migrated cells were determined by direct vital microscopy, and blood pressure was assessed by tail plethysmography. In addition, following treatment with the higher dose, immunohistochemistry was used to measure the expression of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in endothelial cells, while flow cytometry was used to evaluate the expression of leukocyte CD18 and L-selectin. Hydralazine reduced leukocyte adherence and migration in SHR either at the higher, that reduced blood pressure levels, or lower dose, which did not reduce it. Reduced ICAM-1 expression might be involved in the reduced migration observed in SHR. In Wistar rats, only at the higher dose hydralazine reduced blood pressure levels and leukocyte migration. Reduced P-selectin expression might be involved. We therefore conclude that hydralazine reduces leukocyte migration by different mechanisms in SHR and Wistar rats, specifically by reducing ICAM-1 expression in the former and P-selectin expression in the latter.
Assuntos
Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/farmacologia , Moléculas de Adesão Celular/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Hidralazina/farmacologia , Hipertensão/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Antígenos CD18/metabolismo , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/genética , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Citometria de Fluxo , Hipertensão/imunologia , Hipertensão/fisiopatologia , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/metabolismo , Selectina L/metabolismo , Contagem de Leucócitos , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Masculino , Microscopia de Vídeo , Selectina-P/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pletismografia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The proper use of anesthetics in animal experimentation has been intensively studied. In this study we compared the use of chloral hydrate (500 mg kg(-1)) and ketamine (167 mg kg(-1)) combined with xylazine (33 mg kg(-1)) by the s.c. route in male Wistar rats. Chloral hydrate and ketamine/xylazine produced a depth of anesthesia and analgesia sufficient for surgical procedures. The decrease of systolic and diastolic blood pressure was of a higher magnitude in rats anesthetized with chloral hydrate than with ketamine/xylazine. The initial microvascular diameter and blood flow velocity did not differ between both agents. On the other hand, ketamine/xylazine reduced the heart rate more intensively than chloral hydrate. Both anesthetics promoted an increase in arterial pCO(2) and a decrease in pH levels compared to unanesthetized animals. The blood glucose levels were of a higher magnitude in rats after ketamine/xylazine anesthesia than after chloral hydrate. In mesenteric arterioles studied in vivo, ketamine/xylazine anesthesia reduced the constrictive effect of noradrenaline and the dilator effect of bradykinin. However, both anesthetics did not modify the vasodilator effect promoted by acetylcholine. Based on our data, we concluded that both anesthetics alter metabolic and hemodynamic parameters, however the use of chloral hydrate in studies of microvascular reactivity in vivo is more appropriate since ketamine/xylazine reduces the responses to vasoactive agents and increases blood glucose levels.
Assuntos
Anestesia/métodos , Anestésicos Dissociativos/farmacologia , Anestésicos Intravenosos/farmacologia , Hidrato de Cloral/farmacologia , Ketamina/farmacologia , Xilazina/farmacologia , Animais , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Bradicinina/farmacologia , Dióxido de Carbono/sangue , Antagonismo de Drogas , Combinação de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Injeções Subcutâneas , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/fisiopatologia , Norepinefrina/farmacologia , Troca Gasosa Pulmonar , Ratos , Ratos Wistar , Vasoconstritores/farmacologia , Vasodilatadores/farmacologiaRESUMO
We demonstrated that the decreased response to acetylcholine observed in aorta of male and female spontaneously hypertensive rats is corrected after sustained (15 days) reduction of blood pressure levels by losartan. In order to verify if the same occurs in resistance vessels, vascular diameter changes induced by topical application of acetylcholine and bradykinin (endothelium-dependent vasodilators) and sodium nitroprusside (endothelium-independent vasodilator) to mesenteric arterioles studied in vivo, in situ were determined in rats treated with losartan for 24 h (acute) or 15 days (chronic). Rats that presented similar reduction (in %) of the blood pressure levels after losartan treatment were chosen. Sodium nitroprusside induced similar responses in losartan-treated and untreated male or female SHR. Whereas in female SHR, losartan corrected the diminished arteriolar response to endothelium-dependent vasodilators after acute and chronic treatment, in male SHR this correction only occurred after chronic treatment. Thus, losartan corrected the endothelial dysfunction more easily in female than in male SHR and independently of the normalization or the magnitude of the reduction of the blood pressure levels. In an attempt to explain the difference, we evaluated the losartan effect on nitric-oxide synthase (NOS) activity and angiotensin II AT1 and AT2 receptor gene expression in these animals. In male and female SHR, NOS activity and AT1 receptor expression were not altered by acute or chronic treatment. On the other hand, AT2 receptor expression was augmented only in female SHR by these treatments. Therefore, augmented AT2 receptor expression, but not alteration of NOS activity or AT1 receptor expression, might explain the difference observed.