RESUMO
Hemorrhagic shock (HS) therapy is based on macrohemodynamic improvement, but it is not clear if this therapy correlates directly with increases in tissue perfusion. Aiming to clarify this point, we compared norepinephrine (NE, a vasoconstrictor), sodium nitroprusside (NP, a vasodilator) and levosimendan (LEV, an inodilator) treatments on macro and microvascular parameters using the hamster dorsal skinfold chamber preparation. One hour after HS, animals received Ringer's lactate (RL) solution within 10â¯min, then animals received RL, NP, NE and LEV during 90â¯min via jugular vein. Macrovascular variables: mean arterial pressure (MAP), heart rate (HR), maximal ventricle pressure (MVP), change in ventricular pressure over time (dP/dt) and microvascular variables: arteriolar and venular diameters, functional capillary density (FCD) and red blood cell velocity (RBCV) were evaluated at baseline, 60â¯min after HS, 60 and 90â¯min after treatments. Lactate blood concentrations were evaluated at baseline, 60â¯min after HS and 90â¯min after treatments. Hematocrit (Hct), cardiac output (CO), stroke volume (SV) and number of rolling and adhered leukocytes were assessed at 90â¯min after treatments. Data were considered significant when pâ¯<â¯0.05. NE increased significantly all macrohemodynamic variables compared to baseline (except MAP), and it was the only treatment that increased Hct, CO and SV significantly. NE decreased significantly all microvascular variables in comparison to baseline. NP increased HR, FCD and RBCV and reduced MVP and dP/dt significantly. LEV decreased MVP and dP/dt, arteriolar diameter and FCD and augmented RBCV significantly in comparison to baseline. Blood concentration of lactate increased significantly 60â¯min after HS. Leukocyte rolling and adhesion were not different between groups. We concluded that, early, during hemorrhagic shock, norepinephrine associated to fluid therapy improved macrohemodynamic parameters but failed to improved microvascular flow. Conversely, sodium nitroprusside association had the opposite effect. Despite its inodilator properties, levosimendan did not improve macro or microhemodynamic parameters when combined to fluid therapy.
Assuntos
Endotélio Vascular/fisiopatologia , Hemodinâmica , Microcirculação , Choque Hemorrágico/fisiopatologia , Pele/irrigação sanguínea , Animais , Velocidade do Fluxo Sanguíneo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Hidratação , Hemodinâmica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Migração e Rolagem de Leucócitos , Masculino , Mesocricetus , Microcirculação/efeitos dos fármacos , Choque Hemorrágico/metabolismo , Choque Hemorrágico/terapia , Fatores de Tempo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia , Função Ventricular EsquerdaRESUMO
The Mediterranean diet, rich in olive oil, is beneficial, reducing the risk of cardiovascular diseases and cancer. Olive oil is mostly composed of the monounsaturated fatty acid omega-9. We showed omega-9 protects septic mice modulating lipid metabolism. Sepsis is initiated by the host response to infection with organ damage, increased plasma free fatty acids, high levels of cortisol, massive cytokine production, leukocyte activation, and endothelial dysfunction. We aimed to analyze the effect of omega-9 supplementation on corticosteroid unbalance, inflammation, bacterial elimination, and peroxisome proliferator-activated receptor (PPAR) gamma expression, an omega-9 receptor and inflammatory modulator. We treated mice for 14 days with omega-9 and induced sepsis by cecal ligation and puncture (CLP). We measured systemic corticosterone levels, cytokine production, leukocyte and bacterial counts in the peritoneum, and the expression of PPAR gamma in both liver and adipose tissues during experimental sepsis. We further studied omega-9 effects on leukocyte rolling in mouse cremaster muscle-inflamed postcapillary venules and in the cerebral microcirculation of septic mice. Here, we demonstrate that omega-9 treatment is associated with increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the proinflammatory cytokines TNF-α and IL-1ß in peritoneal lavage fluid of mice with sepsis. Omega-9 treatment also decreased systemic corticosterone levels. Neutrophil migration from circulation to the peritoneal cavity and leukocyte rolling on the endothelium were decreased by omega-9 treatment. Omega-9 also decreased bacterial load in the peritoneal lavage and restored liver and adipose tissue PPAR gamma expression in septic animals. Our data suggest a beneficial anti-inflammatory role of omega-9 in sepsis, mitigating leukocyte rolling and leukocyte influx, balancing cytokine production, and controlling bacterial growth possibly through a PPAR gamma expression-dependent mechanism. The significant reduction of inflammation detected after omega-9 enteral injection can further contribute to the already known beneficial properties facilitated by unsaturated fatty acid-enriched diets.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/fisiopatologia , Ácido Oleico/farmacologia , Sepse/fisiopatologia , Animais , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Camundongos , Azeite de Oliva/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Barks of Ximenia americana are used by the population to treat gastrointestinal inflammatory disorders. Indomethacin is a non-selective non-steroidal anti-inflammatory drug that induces marked gastrointestinal damage. AIMS OF THE STUDIES: To evaluate the gastroprotective activity of total polysaccharides contained in the extract (TPL-Xa) or tea (Tea-Xa) of Ximenia americana barks in the mice gastric damage induced by indomethacin. MATERIALS AND METHODS: TPL-Xa was obtained by a combination of NaOH extraction and ethanol precipitation. Tea-Xa was prepared in distilled water boiled during 5â¯min. Animals received p.o. 0.9% NaCl (saline - control group), TPL-Xa (1-90â¯mg/kg) or Tea-Xa 1â¯h before gastritis induction by indomethacin (20â¯mg/kg). Mice were sacrificed 7â¯h after gastritis induction and analyzed for the following parameters: stomach lesions measurement; histological evaluation; myeloperoxidase (MPO) activity; nitrate/nitrite and cytokine levels; leukocyte adhesion and rolling by intravital microscopy. RESULTS: TPL-Xa reduced macroscopic and microscopic damage, MPO activity (59%), leukocyte rolling (86%) and adhesion (84%), nitrite/nitrate ratio (100%) and IL-8 (69%), but increased IL-4 (50%). Tea-Xa (12.8 yield; 39.3% carbohydrate, including 25.8% uronic acid; 4% protein) reduced macroscopic damage (62%) and MPO activity (50%). CONCLUSION: TPL and Tea of Ximenia americana barks ameliorate the gastric injury induced by indomethacin in mice, an effect that was dependent on the reduction of neutrophil infiltration.
Assuntos
Bebidas , Gastrite/tratamento farmacológico , Olacaceae , Extratos Vegetais , Polissacarídeos , Substâncias Protetoras , Animais , Anti-Inflamatórios não Esteroides , Adesão Celular/efeitos dos fármacos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Gastrite/imunologia , Gastrite/metabolismo , Indometacina , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Nitratos/metabolismo , Nitritos/metabolismo , Peroxidase/metabolismo , Fitoterapia , Casca de Planta , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêuticoRESUMO
Statins are hypocholesterolemic drugs that are prescribed for patients with an increased risk of cardiovascular and cerebrovascular complications. Ezetimibe has an atheroprotective activity through inhibition of the expression of vascular adhesion molecule-I and vascular CD14, a marker of the infiltration of mononuclear leukocytes. Ezetimibe reduces the amount of chemoattractant protein-1 that is available for monocytes and macrophages and alters the activity of nuclear factor κB in leukocytes. The mechanisms of action of statins complement those of ezetimibe. Previous studies have demonstrated that the combination of statins and ezetimibe has beneficial effects, including antiinflammatory activity. The present study evaluated the effects of monotherapy with ezetimibe and simvastatin compared with ezetimibe + simvastatin combined on the evolution of the inflammatory response in a rat model of Complete Freund's Adjuvant-induced arthritis. The animals were treated with 10 mg/kg ezetimibe, 40 mg/kg simvastatin, or 10 mg/kg ezetimibe + 40 mg/kg simvastatin for 1, 7, 14, or 28 days. We analyzed leukocyte rolling behavior, leukocyte adhesion to the endothelium, the number of leukocytes that were recruited to the knee joint cavity, and the concentration of cytokines that are involved in the inflammatory response. The data were analyzed using paired t tests or analysis of variance followed by Bonferroni post hoc test. The treatments reduced leukocyte rolling behavior and leukocyte adhesion. The monotherapies did not change the number of leukocytes that were recruited to the knee joint cavity, whereas the ezetimibe + simvastatin combination significantly reduced this parameter. The treatments reduced the levels of proinflammatory cytokines and increased the levels of the antiinflammatory cytokine IL-10, indicating antiinflammatory properties of these drugs in this experimental model of inflammation.
Assuntos
Artrite Experimental/tratamento farmacológico , Ezetimiba/farmacologia , Inflamação/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Adesão Celular/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Quimioterapia Combinada/métodos , Ezetimiba/administração & dosagem , Articulação do Joelho/patologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Ratos , Sinvastatina/administração & dosagemRESUMO
The fatigue induced by marathon races was observed in terms of inflammatory and immunological outcomes. Neutrophil survival and activation are essential for inflammation resolution and contributes directly to the pathogenesis of many infectious and inflammatory conditions. The aim of this study was to investigate the effect of marathon races on surface molecules related to neutrophil adhesion and extrinsic apoptosis pathway and its association with inflammatory markers. We evaluated 23 trained male runners at the São Paulo International Marathon 2013. The following components were measured: hematological and inflammatory mediators, muscle damage markers, and neutrophil function. The marathon race induced an increased leukocyte and neutrophil counts; creatine kinase (CK), lactate dehydrogenase (LDH), CK-MB, interleukin (IL)-6, IL-10, and IL-8 levels. C-reactive protein (CRP), IL-12, and tumor necrosis factor (TNF)-α plasma concentrations were significantly higher 24 h and 72 h after the marathon race. Hemoglobin and hematocrit levels decreased 72 h after the marathon race. We also observed an increased intercellular adhesion molecule-1 (ICAM-1) expression and decreasedTNF receptor-1 (TNFR1) expression immediately after and 24 h after the marathon race. We observed an increased DNA fragmentation and L-selectin and Fas receptor expressions in the recovery period, indicating a possible slow rolling phase and delayed neutrophil activation and apoptosis. Marathon racing affects neutrophils adhesion and survival in the course of inflammation, supporting the "open-window" post-exercise hypothesis.
Assuntos
Antígenos de Superfície/sangue , Mediadores da Inflamação/sangue , Migração e Rolagem de Leucócitos , Ativação de Neutrófilo , Neutrófilos/metabolismo , Corrida , Adulto , Apoptose , Sobrevivência Celular , Citocinas/sangue , Humanos , Contagem de Leucócitos , MasculinoRESUMO
OBJECTIVE: To evaluate the in vivo anti-inflammatory potential of bovine hyaluronidase (HYAL) using two different models of acute inflammation. METHODS: Air pouches were produced in the dorsal subcutaneous of mice and injected with phosphate saline solution or HYAL. The antiinflammatory action of HYAL was evaluated in carrageenan (Cg)-inflamed air pouches. After 4 and 24 h the cellular influx, protein exudation, cytokines and lipid mediators were evaluated. The action of HYAL on the rolling and adhesion of leukocytes was investigated in the LPS-stimulated mesenteric microcirculation by intravital microscopic. RESULTS: Treatment with HYAL reduced the cellular influx and protein exudation in non-inflamed and inflamed air pouches. HYAL treatment of Cg-inflamed air pouch reduced the production of tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), leukotriene B4 (LTB4) and LTC4, whereas prostaglandins E2 (PGE2) and D2 (PGD2) concentrations were unchanged. Histological analyses showed that HYAL administration diminished cell infiltration in the air-pouch lining. In LPS-stimulated mesenteric microcirculation, HYAL usage decreased rolling and adhesion of leukocytes, but did not affect the blood vessels diameters. CONCLUSION: The results demonstrate that HYAL inhibited cellular recruitment, edema formation and pro-inflammatory mediators production, resulting in decreased adherence of leukocytes to blood vessels and tissue infiltration. Our data suggest that HYAL may be considered an effective candidate to ameliorate acute inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Hialuronoglucosaminidase/farmacologia , Leucócitos/efeitos dos fármacos , Animais , Vasos Sanguíneos , Carragenina , Adesão Celular/efeitos dos fármacos , Citocinas/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Contagem de Leucócitos , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/citologia , Leucócitos/fisiologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BLRESUMO
Leukocyte recruitment to tissues is a highly orchestrated process and is one of the pillars of the inflammatory process. The contribution of leukocytes to tissue damage is very clear, suggesting that targeting leukocyte accumulation in tissue to be relevant for the development of novel therapies to treat chronic inflammatory diseases. Here, we review briefly known mechanisms of leukocyte recruitment and suggest potential targets for the development of novel anti-inflammatory therapies.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Doença Crônica/tratamento farmacológico , Descoberta de Drogas , Humanos , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Terapia de Alvo Molecular , Receptores de Quimiocinas/antagonistas & inibidores , Selectinas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Fish oil, a rich source of n-3 fatty acids, has been studied for its beneficial effects in many diseases. Recent studies have shown the robust anti-inflammatory activity of fish oil (FO), when administered orally to rats, in models of acute inflammation. Herein, we investigated if treatment with fish oil preparation (FOP) could interfere with the recruitment of leukocytes into the joint cavity of arthritic rats. We also evaluated the effect of treatment on rolling behavior and leukocyte adhesion in vivo and on leukocyte chemotaxis in vitro. Treatment with FOP (75, 150, and 300 mg/kg) initiated on the day of induction of arthritis (day 0) and maintained for 21 days reduced the total number of leukocytes recruited into the joint cavity, the number of rolling and adhered leukocytes in arthritic rats, and leukocyte migration in response to stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and leukotriene B4 (LTB4). Together, our data provide evidence that FOP plays an important inhibitory role in the recruitment of leukocytes into the joint cavity of arthritic rats.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Quimiotaxia de Leucócito/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Óleos de Peixe/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucotrieno B4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The transforming growth factor beta 1 (TGF-ß1) is a pleiotropic cytokine with multiple roles in development, wound healing, and immune regulation. TGF-ß1-mediated immune dysfunction may lead to pathological conditions, such as inflammation. Chronic inflammatory process is characterized by a continuous release of pro-inflammatory cytokines, and the inhibition or the blockage of these cytokines signaling pathways are considered a target treatment. In this context, despite the high numbers of TGF-ß-targeted pathways, the inducible regulatory T cells (iTreg) to control inflammation seems to be a promising approach. Our aim was to develop novel peptides through phage display (PhD) technology that could mimic TGF-ß1 function with higher potency. Specific mimetic peptides were obtained through a PhD subtraction strategy from whole cell binding using TGF-ß1 recombinant as a competitor during elution step. We have selected a peptide that seems to play an important role on cellular differentiation and modulation of TNF-α and IL-10 cytokines. The synthetic pm26TGF-ß1 peptide tested in PBMC significantly down-modulated TNF-α and up-regulated IL-10 responses, leading to regulatory T cells (Treg) phenotype differentiation. Furthermore, the synthetic peptide was able to decrease leukocytes rolling in BALB/C mice and neutrophils migration during inflammatory process in C57BL/6 mice. These data suggest that this peptide may be useful for the treatment of inflammatory diseases, especially because it displays potent anti-inflammatory properties and do not exhibit neutrophils' chemoattraction.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Materiais Biomiméticos/farmacologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Neutrófilos/imunologia , Peptídeos/farmacologia , Fator de Crescimento Transformador beta1/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Materiais Biomiméticos/química , Feminino , Humanos , Interleucina-10/imunologia , Migração e Rolagem de Leucócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/patologia , Peptídeos/química , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta1/química , Fator de Necrose Tumoral alfa/imunologiaRESUMO
In this study, the amino acid sequence and anti-inflammatory effect of Bauhinia bauhinioides (BBL) lectin were evaluated. Tandem mass spectrometry revealed that BBL possesses 86 amino acid residues. BBL (1 mg/kg) intravenously injected in rats 30 min prior to inflammatory stimuli inhibited the cellular edema induced by carrageenan in only the second phase (21% - 3 h, 19% - 4 h) and did not alter the osmotic edema induced by dextran. BBL also inhibited carrageenan peritoneal neutrophil migration (51%), leukocyte rolling (58%) and adhesion (68%) and the neutrophil migration induced by TNF-α (64%). These effects were reversed by the association of BBL with galactose, demonstrating that the carbohydrate-binding domain is essential for lectin activity. In addition, BBL reduced myeloperoxidase activity (84%) and TNF-α (68%) and IL1-ß (47%) levels. In conclusion, the present investigation demonstrated that BBL contains highly homologous isolectins, resulting in a total of 86 amino acid residues, and exhibits anti-inflammatory activity by inhibiting neutrophil migration by reducing TNF-α and IL1-ß levels via the lectin domain.
Assuntos
Anti-Inflamatórios/farmacologia , Bauhinia/química , Galectinas/farmacologia , Neutrófilos/fisiologia , Extratos Vegetais/farmacologia , Lectinas de Plantas/farmacologia , Sequência de Aminoácidos , Animais , Anti-Inflamatórios/química , Adesão Celular , Citocinas/fisiologia , Avaliação Pré-Clínica de Medicamentos , Galectinas/química , Migração e Rolagem de Leucócitos , Dados de Sequência Molecular , Neutrófilos/efeitos dos fármacos , Peritonite/imunologia , Extratos Vegetais/química , Lectinas de Plantas/química , Ratos Wistar , Sementes/químicaRESUMO
Inflammation is a local tissue response to attacks characterized by vascular and cellular events, including intense oxidative stress. Riparin A, a compound obtained from Aniba riparia, has been shown to have antioxidant activity and cytotoxicity in vitro. This study was aimed at evaluating the anti-inflammatory effect of riparin A against acute inflammation. The results of our evaluations in various experimental models indicated that riparin A reduced paw edema induced by carrageenan, compound 48/80, histamine, and serotonin. Furthermore, it decreased leukocyte and neutrophil counts, myeloperoxidase activity, thiobarbituric acid reactive substance (TBARS) levels, and cytokine (tumor necrosis factor-α and interleukin-1ß) levels increased by carrageenan-induced peritonitis, and reversed glutathione levels. Riparin A also reduced carrageenan-induced adhesion and rolling of leukocytes on epithelial cells and did not produce gastric-damage as compared with indomethacin. In conclusion, the data show that riparin A reduces inflammatory response by inhibiting vascular and cellular events, modulating neutrophil migration, inhibiting proinflammatory cytokine production, and reducing oxidative stress.
Assuntos
Anti-Inflamatórios/uso terapêutico , Benzamidas/uso terapêutico , Carragenina/efeitos adversos , Edema/tratamento farmacológico , Doenças do Sistema Imunitário/tratamento farmacológico , Transtornos Leucocíticos/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Peritonite/tratamento farmacológico , Fenetilaminas/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Benzamidas/isolamento & purificação , Carragenina/imunologia , Adesão Celular/efeitos dos fármacos , Citocinas/imunologia , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Extremidades/patologia , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Lauraceae/química , Transtornos Leucocíticos/induzido quimicamente , Transtornos Leucocíticos/imunologia , Transtornos Leucocíticos/patologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/imunologia , Neutrófilos/patologia , Estresse Oxidativo/efeitos dos fármacos , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/patologia , Peroxidase/imunologia , Fenetilaminas/isolamento & purificaçãoRESUMO
Inflammation and cancer are related pathologies acting synergistically to promote tumor progression. In both, hematogenous metastasis and inflammation, P-selectin participates in interactions involving tumor cells, platelets, leukocytes and endothelium. Heparin has been shown to inhibit P-selectin and as a consequence it blunts metastasis and inflammation. Some heparin analogs obtained from marine invertebrates are P-selectin inhibitors and do not induce bleeding effects. The present work focuses on the P-selectin blocking activity of a unique heparan sulfate (HS) from the bivalve mollusk Nodipecten nodosus. Initially, we showed that the mollusk HS inhibited LS180 colon carcinoma cell adhesion to immobilized P-selectin in a dose-dependent manner. In addition, we demonstrated that this glycan attenuates leukocyte rolling on activated endothelium and inflammatory cell recruitment in thioglycollate-induced peritonitis in mice. Biochemical analysis indicated that the invertebrate glycan also inhibits heparanase, a key player in cell invasion and metastasis. Experimental metastasis of Lewis lung carcinoma cells was drastically attenuated by the mollusk HS through a mechanism involving inhibition of platelet-tumor-cell complex formation in blood vessels. These data suggest that the mollusk HS is a potential alternative to heparin for inhibiting P-selectin-mediated events such as metastasis and inflammatory cell recruitment.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Heparitina Sulfato/farmacologia , Neoplasias Pulmonares/prevenção & controle , Animais , Anticoagulantes/farmacologia , Antineoplásicos/uso terapêutico , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Carcinoma Pulmonar de Lewis/secundário , Adesão Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glucuronidase/antagonistas & inibidores , Glucuronidase/química , Heparitina Sulfato/uso terapêutico , Humanos , Concentração Inibidora 50 , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Moluscos , Transplante de Neoplasias , Selectina-P/antagonistas & inibidores , Selectina-P/metabolismoRESUMO
BACKGROUND: This study investigated the effects of pentoxifylline (PTX) combined with resuscitation fluids on microcirculatory dysfunctions in a two-hit model of shock and sepsis. MATERIALS AND METHODS: Male Wistar rats (250 g) were submitted to hemorrhagic shock and reperfusion followed by sepsis induced by cecal ligation and puncture. For the initial treatment of shock, rats were randomly divided into: sham, no injury, no treatment; hypertonic saline solution (HS) (7.5%, 4 mL/kg); lactated Ringer's solution (LR, 3 × shed blood volume); HS + PTX (4 mL/Kg + 25 mg/kg PTX); and LR + PTX (3 × shed blood volume + 25 mg/kg PTX). After 48 h of being exposed to the double injury, leukocyte-endothelial interactions were assessed by intravital microscopy of the mesentery. Endothelial expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) was evaluated by immunohistochemistry, as well as lung neutrophil infiltration by histology. RESULTS: Lactated Ringer's solution induced marked increases (P < 0.001) in the number of rolling leukocytes per 10 min (two-fold), adherent leukocytes per 100 µm venule length (six-fold), migrated leukocytes per 5000 µm(2) (eight-fold), P-selectin and ICAM-1 expression (four-fold), and lung neutrophil infiltration (three-fold) compared with sham. In contrast, PTX attenuated leukocyte-endothelial interactions, P-selectin and ICAM-1 expression at the mesentery when associated with either LR (P < 0.001) or HS (P < 0.05). Neutrophil migration into the lungs was similarly reduced by PTX (P < 0.05). CONCLUSIONS: Data presented showed that pentoxifylline attenuates microcirculatory disturbances at the mesenteric bed with significant minimization of lung inflammation after a double-injury model of hemorrhagic shock and reperfusion followed by sepsis.
Assuntos
Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Pentoxifilina/farmacologia , Sepse/tratamento farmacológico , Choque Hemorrágico/tratamento farmacológico , Animais , Ceco/lesões , Modelos Animais de Doenças , Sequestradores de Radicais Livres/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Soluções Isotônicas/farmacologia , Ligadura , Masculino , Microcirculação/efeitos dos fármacos , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/imunologia , Selectina-P/metabolismo , Ratos Wistar , Ressuscitação/métodos , Lactato de Ringer , Sepse/imunologia , Choque Hemorrágico/imunologia , Ferimentos PerfurantesRESUMO
Flavonoids are compounds responsible for several organoleptic characteristics of plant-derived foods. They are also bioactive compounds with antiinflammatory role. Different mechanisms for this activity have been reported, but their effects on cell migration are not fully understood. In the present study, the role of flavonoids on leukocyte migration in vivo was investigated, using the carrageenan-induced pleurisy model and intravital microscopy in rats. It was found that quercetin (1), rutin (2), flavone (5), apigenin (6) and flavonol (7) reduced cell migration to the pleural cavity and inhibited rolling, adhesion and transmigration. Additionally, flow cytometry assays showed that the in vitro treatment with all compounds (15-60 µM) did not cause cell death and 1 inhibited the cleavage of L-selectin and the ß2-integrin expression, whereas 2 and 7 only inhibited the ß2-integrin expression. Together, data herein presented clearly show the ability of flavonoids to inhibit in vivo neutrophil influx into inflamed tissue, by acting in different mechanisms of neutrophil migration.
Assuntos
Antígenos CD18/metabolismo , Flavonoides/farmacologia , Inflamação/metabolismo , Selectina L/metabolismo , Neutrófilos/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Endotélio/citologia , Inflamação/induzido quimicamente , Migração e Rolagem de Leucócitos , Masculino , Neutrófilos/metabolismo , Ratos , Ratos WistarRESUMO
RATIONALE: Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered. OBJECTIVE: The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling. METHODS AND RESULTS: Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P<0.01). AdipoR1-KD markedly reduced globular adiponectin-induced nCDase activation, whereas AdipoR2-KD only slightly reduced. More importantly, small interfering RNA-mediated nCDase-KD markedly blocked the effect of adiponectin on TNFα-induced intercellular adhesion molecule-1 expression. AMP-activated protein kinase-KD failed to block adiponectin-induced nCDase activation and modestly inhibited adiponectin anti-inflammatory effect. In contrast, in caveolin-1 KD (Cav1-KD) cells, >87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNFα-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo. CONCLUSIONS: These results demonstrate for the first time that adiponectin inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.
Assuntos
Adiponectina/metabolismo , Caveolina 1/metabolismo , Ceramidases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vasculite/metabolismo , Adiponectina/imunologia , Caveolina 1/genética , Caveolina 1/imunologia , Ceramidases/genética , Ceramidases/imunologia , Células Endoteliais/imunologia , Ativação Enzimática/imunologia , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Migração e Rolagem de Leucócitos/imunologia , RNA Interferente Pequeno/genética , Espécies Reativas de Nitrogênio/imunologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/imunologia , Receptores de Adiponectina/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Vasculite/imunologiaRESUMO
Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1-7)-Mas receptor axis may contribute to some of the effects of AT1 receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT1 receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1ß and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Angiotensina I/biossíntese , Animais , Artrite Reumatoide/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Quimiocina CXCL1/biossíntese , Modelos Animais de Doenças , Feminino , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Interleucina-1beta/biossíntese , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Fragmentos de Peptídeos/biossíntese , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Several emerging lines of evidence support an anti-inflammatory role for nicotinic acid (niacin); however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Herein, we have examined the effect of nicotinic acid on neutrophil recruitment in experimentally induced inflammation. We demonstrated that nicotinic acid treatment inhibited interleukin (IL)-8-induced, leukotriene (LT)B4-induced, and carrageenan-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence in a mouse cremaster muscle preparation. Surprisingly, nicotinic acid treatment increased the level of the neutrophil chemoattractant KC in response to carrageenan. These results suggest that nicotinic acid plays an important role in the regulation of inflammation due to its ability to inhibit the actions of the neutrophil chemoattractants IL-8 and LTB4. Further inhibition of chemoattractants leads to impairment of leukocyte rolling and adherence to the vascular endothelium in the microcirculation of inflamed tissues.
Assuntos
Anti-Inflamatórios/farmacologia , Doenças do Sistema Imunitário/prevenção & controle , Inflamação/tratamento farmacológico , Transtornos Leucocíticos/prevenção & controle , Niacina/farmacologia , Animais , Carragenina/farmacologia , Adesão Celular/efeitos dos fármacos , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Interleucina-8/farmacologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucotrieno B4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , Cavidade Pleural/efeitos dos fármacos , Cavidade Pleural/metabolismoRESUMO
Melanocortin is a potent anti-inflammatory molecule. However, little is known about the effect of melanocortin on acute inflammatory processes such as neutrophil migration. In the present study, we investigated the ability of [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP-MSH), a semisynthetic melanocortin compound, in the inhibition of neutrophil migration in carrageenin-induced peritonitis model. Herein, subcutaneous pretreatment with NDP-MSH decreased neutrophil trafficking in the peritoneal cavity in a dose-dependent manner. NDP-MSH inhibited vascular leakage, leukocyte rolling, and adhesion and reduced peritoneal macrophage inflammatory protein 2, but not TNF-alpha, IL-1beta, IL-10, and keratinocyte-derived chemokine production. In addition, the effect on neutrophil migration was reverted by the pretreatment with both propranolol (a nonselective beta-adrenergic antagonist) and mecamylamine (a nonselective nicotinic antagonist) but not by splenectomy surgery. Moreover, NDP-MSH intracerebroventricular administration inhibited neutrophil migration, indicating participation of the central nervous system. Our results propose that the NDP-MSH effect may be due to a spleen-independent neuro-immune pathway that efficiently regulates excessive neutrophil recruitment to tissues.
Assuntos
Neutrófilos/efeitos dos fármacos , Peritonite/imunologia , alfa-MSH/análogos & derivados , Animais , Carragenina , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL2/imunologia , Citocinas/imunologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/fisiologia , Peritonite/induzido quimicamente , Receptores Adrenérgicos/fisiologia , Receptores Nicotínicos/fisiologia , alfa-MSH/farmacologiaRESUMO
Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.
Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , GMP Cíclico/metabolismo , Hidroxiureia/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Doenças Vasculares/tratamento farmacológico , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Doença Aguda , Anemia Falciforme/induzido quimicamente , Anemia Falciforme/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Comunicação Celular , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Migração e Rolagem de Leucócitos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/toxicidade , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/metabolismoRESUMO
Sepsis is a severe disorder characterized by systemic inflammatory responses in the presence of an infection and may progress to multiple organ dysfunction and death. Alterations in cerebral microcirculation fulfill a crucial role in the pathogenesis of severe sepsis, and include a decrease in capillary density and disturbances in leukocyte movement along capillaries. Nevertheless, the mechanisms involved in sepsis-associated cerebral microcirculatory alterations have so far not been defined. We investigated the effect of the peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist rosiglitazone on leukocyte/endothelial cell interaction and functional capillary density in the brain in the cecal ligation and puncture (CLP) model of sepsis. Anti-inflammatory effects of rosiglitazone on the cerebral microcirculation were marked. Functional capillary density increased and leukocyte rolling and adhesion were decreased in animals submitted to CLP and treated with rosiglitazone. Our data provide evidence for involvement of PPARγ activation in leukocyte-endothelium interactions and alterations in capillary density. Improved cerebral perfusion in animals treated with rosiglitazone, suggests that PPARγ activation is protective against cerebral microvascular dysfunction in sepsis.