RESUMO
Acute ischemic stroke is associated with pulmonary complications, and often dexmedetomidine and propofol are used to decrease cerebral metabolic rate. However, it is unknown the immunomodulatory actions of dexmedetomidine and propofol on brain and lungs during acute ischemic stroke. The effects of dexmedetomidine and propofol were compared on perilesional brain tissue and lung damage after acute ischemic stroke in rats. Further, the mean amount of both sedatives was directly evaluated on alveolar macrophages and lung endothelial cells primarily extracted 24-h after acute ischemic stroke. In twenty-five Wistar rats, ischemic stroke was induced and after 24-h treated with sodium thiopental (STROKE), dexmedetomidine and propofol. Dexmedetomidine, compared to STROKE, reduced diffuse alveolar damage score [median(interquartile range); 12(7.8-15.3) vs. 19.5(18-24), p = 0.007)], bronchoconstriction index [2.28(2.08-2.36) vs. 2.64(2.53-2.77), p = 0.006], and TNF-α expression (p = 0.0003), while propofol increased VCAM-1 expression compared to STROKE (p = 0.0004). In perilesional brain tissue, dexmedetomidine, compared to STROKE, decreased TNF-α (p = 0.010), while propofol increased VCAM-1 compared to STROKE (p = 0.024). In alveolar macrophages and endothelial cells, dexmedetomidine decreased IL-6 and IL-1ß compared to STROKE (p = 0.002, and p = 0.040, respectively), and reduced IL-1ß compared to propofol (p = 0.014). Dexmedetomidine, but not propofol, induced brain and lung protection in experimental acute ischemic stroke.
Assuntos
Encéfalo/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Pulmão/efeitos dos fármacos , Propofol/administração & dosagem , Animais , Isquemia Encefálica/prevenção & controle , Dexmedetomidina/efeitos adversos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Hipnóticos e Sedativos/efeitos adversos , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Propofol/efeitos adversos , Ratos , Ratos Wistar , Tiopental , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
Leprosy caused by Mycobacterium leprae is characterized by a spectrum of clinical manifestations that are determined by the predominant immunological profile of the host. The recruitment of leukocytes to the sites of injury can influence the development of these profiles. Cell adhesion molecules such as ICAM-1, VCAM-1 and CD62E participate in this process and their expression is regulated by transcriptions factors such as NFκB. To correlate the expression of cell adhesion molecules and NFκB (p65) in leprosy lesions, 30 skin biopsies of patients with leprosy [16 with the tuberculoid (TT) or borderline tuberculoid (BT) forms and 14 with the lepromatous (LL) or borderline lepromatous (BL) forms] were analyzed by immunohistochemistry. A larger mean number of cells expressing VCAM-1 (BT/TT: 18.28 ± 1.4; BL/LL: 10.67 ± 1.2; p = 0.0002), ICAM-1 (BT/TT: 9.92 ± 1.1; BL/LL: 5.87 ± 1.0; p = 0.0084) and CD62E (BT/TT: 13.0 ± 1.5; BL/LL: 2.58 ± 0.3; p = 0.0001) were observed in BT and TT lesions. The mean number of cells expressing NFκB was similar in the two clinical forms (BT/TT: 2.21 ± 2.7; BL/LL: 2.35 ± 3.1;p = 0.9285). No significant correlation was observed between expression of the transcription factor and adhesion molecules analyzed. The synthesis of ICAM-1, VCAM-1 and CD62E depends on the activation of NFκB, which acts synergistically with other transcription factors. Adequate activation of intracellular signaling pathways results in the production of endothelial adhesion molecules, contributing to the recruitment of cells to the site of injury and thus eliciting an effective inflammatory response in the elimination of the bacillus.
Assuntos
Imuno-Histoquímica , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/patologia , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/metabolismo , Biópsia , Selectina E/biossíntese , Endotélio/patologia , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Hanseníase Virchowiana/microbiologia , Leucócitos/imunologia , Leucócitos/microbiologia , Microvasos , Mycobacterium leprae/patogenicidade , NF-kappa B/metabolismo , Pele/patologia , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
This study aimed to investigate the function and signaling pathway of Toll-like receptor 4 (TLR4) in oxidized low-density lipoprotein (oxLDL)-induced up-regulated expressions of oxidized LDL receptor 1 (LOX-1), monocyte chemoattractant protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with different oxLDL concentrations (0, 20, 40, 60, and 80 µg/mL) for 24 and 48 h. The influence of oxLDL on TLR4, LOX-1, MCP-1, and VCAM-1 expressions in HUVECs was detected by real-time polymerase chain reaction and Western blot analysis. HUVECs were transfected with small interfering RNA targeting TLR4 (siTLR4), in which protein expressions of LOX-1, MCP-1, and VCAM-1, and the nuclear translocation of NF-kB (P50) were detected by Western blot. After 48 h of processing HUVECs with pyrrolidine dithiocarbamate (PDTC), protein expressions of TLR4, LOX-1, MCP-1, and VCAM- 1 were detected by Western blot. OxLDL induced a concentration-dependent up-regulation of mRNA and protein expressions of TLR4, LOX-1, MCP-1, and VCAM-1 in HUVECs (P < 0.001). siTLR4 significantly reduced protein expressions of LOX-1, MCP-1, VCAM-1, and reduced the NF-kB (P50) nuclear translocation (P < 0.001). PDTC significantly inhibited protein expressions of TLR4, LOX-1, MCP- 1, and VCAM-1 (P < 0.001). Results of this study demonstrate that the TLR4/NF-κB signaling pathway has an important function in the up-regulation of oxLDL-induced expressions of LOX-1, MCP-1, and VCAM-1 in HUVECs.
Assuntos
Quimiocina CCL2/biossíntese , Lipoproteínas LDL/genética , Receptores Depuradores Classe E/biossíntese , Receptor 4 Toll-Like/genética , Molécula 1 de Adesão de Célula Vascular/biossíntese , Adesão Celular/genética , Quimiocina CCL2/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipoproteínas LDL/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Receptores Depuradores Classe E/genética , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
An inflammatory response induced by high glucose is a cause of endothelial dysfunction in diabetes and is an important contributing link to atherosclerosis. Diabetes is an independent risk factor of atherosclerosis and activation of retinoid X receptor (RXR) has been shown to exert anti-atherogenic effects. In the present study, we examined the effects of the RXR ligands 9-cis-retinoic acid (9-cis-RA) and SR11237 on high glucose-induced inflammation in human umbilical endothelial vein endothelial cells (HUVECs) and explored the potential mechanism. Our results showed that the inflammation induced by high-glucose in HUVECs was mainly mediated by the activation of nuclear factor-B (NF- κB). High glucose-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were in comparison, significantly decreased by treatment with RXR. The effect of RXR agonists was mainly due to the inhibition of NF-κB activation. Using pharmacological inhibitors and siRNA, we confirmed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was an upstream activator of NF-κB. Furthermore, RXR agonists significantly inhibited high glucose-induced activation of NADPH oxidase and significantly decreased the production of reactive oxygen species (ROS). To explore whether the rapid inhibitory effects of RXR agonists were in fact mediated by RXR, we examined the effect of RXR downregulation by RXR siRNA. Our results showed that RXR siRNA largely abrogated the effects of RXR agonists, suggesting the requirement of RXR expression. Therefore, we have shown that RXR is involved in the regulation of NADPH oxidase- NF-κB signal pathway, as the RXR ligands antagonized the inflammatory response in HUVECs induced by high glucose.
Assuntos
Glucose/farmacologia , Inflamação/imunologia , NADPH Oxidases/antagonistas & inibidores , Receptores X de Retinoides/agonistas , Fator de Transcrição RelA/antagonistas & inibidores , Alitretinoína , Antineoplásicos/farmacologia , Aterosclerose , Benzoatos/farmacologia , Células Cultivadas , Diabetes Mellitus , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Molécula 1 de Adesão Intercelular/biossíntese , NADPH Oxidase 4 , NADPH Oxidases/genética , Interferência de RNA , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Receptores X de Retinoides/genética , Receptores X de Retinoides/farmacologia , Retinoides/farmacologia , Tretinoína/farmacologia , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
Sound stress exposure increases fetal loss via inflammatory pathways. Inflammation is known to up-regulate cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), which mediates the adhesion of leukocytes to the vascular endothelium. In this work, we studied the frequency of VCAM-1(+) vessels at the fetomaternal interface in stressed and non-stressed pregnant CBA/J female mice mated with DBA/2J (high fetal loss model) or BALB/c (low fetal loss model) males. The high fetal loss model had fewer large vessels on gestation day 6.5, and stress reduced the frequency of large vessels to a similar number in both high and low fetal loss models. In the high fetal loss model, however, the frequency of VCAM-1+ vessels was dramatically increased. This study shows that VCAM-1 expression is modulated by stress at the fetomaternal interface in abortion-prone cross-breeding.
Assuntos
Aborto Espontâneo/metabolismo , Regulação da Expressão Gênica , Placenta/metabolismo , Estresse Fisiológico , Molécula 1 de Adesão de Célula Vascular/biossíntese , Aborto Espontâneo/patologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Placenta/patologia , GravidezRESUMO
In order to investigate the differential ALCAM, ICAM-1 and VCAM-1 adhesion molecules mRNA expression and the blood-brain barrier (BBB) permeability in C57BL/6 and BALB/c mice in Toxoplasma gondii infection, animals were infected with ME-49 strain. It was observed higher ALCAM on day 9 and VCAM-1 expression on days 9 and 14 of infection in the central nervous system (CNS) of C57BL/6 compared to BALB/c mice. The expression of ICAM-1 was high and similar in the CNS of both lineages of infected mice. In addition, C57BL/6 presented higher BBB permeability and higher IFN-gamma and iNOS expression in the CNS compared to BALB/c mice. The CNS of C57BL/6 mice presented elevated tissue pathology and parasitism. In conclusion, our data suggest that the higher adhesion molecules expression and higher BBB permeability contributed to the major inflammatory cell infiltration into the CNS of C57BL/6 mice that was not efficient to control the parasite.
Assuntos
Molécula de Adesão de Leucócito Ativado/biossíntese , Barreira Hematoencefálica/metabolismo , Encefalite/parasitologia , Toxoplasma/patogenicidade , Toxoplasmose Cerebral/parasitologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula de Adesão de Leucócito Ativado/genética , Animais , Barreira Hematoencefálica/parasitologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/parasitologia , Sistema Nervoso Central/patologia , Encefalite/imunologia , Encefalite/metabolismo , Feminino , Coração/parasitologia , Imuno-Histoquímica , Interferon gama/biossíntese , Interferon gama/genética , Fígado/parasitologia , Fígado/patologia , Pulmão/imunologia , Pulmão/parasitologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Permeabilidade , RNA Mensageiro/metabolismo , Baço/parasitologia , Baço/patologia , Toxoplasma/imunologia , Toxoplasmose Cerebral/imunologia , Toxoplasmose Cerebral/metabolismo , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
BACKGROUND: Although eosinophils co-express multiple integrin receptors, the contributions of integrins to eosinophil development have not been explored. We previously described extensive aggregation and cytological immaturity in eosinophils developing in bone-marrow (BM) cultures exposed to dexamethasone. Here we examined the relationship of alpha 4 integrins with these effects of dexamethasone. OBJECTIVES: We evaluated: (a) the effects of exposure to dexamethasone in BM culture on eosinophil expression of alpha 4 integrin receptors and ligands; (b) the contribution of alpha 4 integrins to eosinophil aggregation and maturation. METHODS: Cultures were established with IL-5 (alone or with dexamethasone) for up to 7 days, and eosinophil production, alpha 4 integrin receptor/ligand expression, aggregation and morphology were evaluated before and after targeting alpha 4 integrin-dependent adhesions. Because prostaglandin E2 (PGE2) modifies the effects of dexamethasone on eosinophilopoiesis, PGE2 effects on alpha 4 integrin expression and function were also evaluated. RESULTS: Dexamethasone increased the yield of eosinophils up to day 7. The frequency of eosinophils expressing alpha 4, beta1 and beta 7 integrin receptors at day 7 was also increased by dexamethasone. Eosinophils also expressed the alpha 4 beta 1 ligand, VCAM-1. Dexamethasone increased the expression of alpha 4 integrin and VCAM-1 in aggregates containing eosinophils as early as day 3. PGE2, added up to day 3, modified the effects of dexamethasone to suppress the expression of alpha 4 integrin, decrease aggregation and promote cytological maturation of eosinophils recovered at day 7. Dissociation of immature eosinophils from clusters present at day 3 by reagents targeting alpha 4 or beta1 integrins or VCAM-1 also induced cytological maturation. The concordant effects of targeting alpha 4 integrins with drugs and antibodies support a relationship between alpha 4-mediated aggregation and maturational arrest. CONCLUSIONS: These observations support a novel role for alpha 4 integrin receptors and ligands in eosinophilopoiesis. In addition, increased alpha 4 expression following glucocorticoid exposure may contribute to the retention and accumulation of eosinophils in haemopoietic tissue.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Dexametasona/farmacologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Integrina alfa4/imunologia , Animais , Células da Medula Óssea/imunologia , Células Cultivadas , Eosinófilos/citologia , Integrina alfa4/efeitos dos fármacos , Integrina alfa4beta1/biossíntese , Integrina alfa4beta1/efeitos dos fármacos , Interleucina-5/farmacologia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Receptores Imunológicos/biossíntese , Receptores Imunológicos/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacosRESUMO
Metabolic syndrome is considered a hyperinsulinemic and inflammatory state closely associated to endothelial dysfunction causing an increased incidence of ischemic cardiovascular events and high mortality. The main objective of the present study was to determine whether leukocitary and soluble cell adhesion molecules were altered in patients with metabolic syndrome in comparison with control subjects. Cell adhesion molecules, mainly of leukocitary location, have been not previously evaluated in specifically designed cross-sectional studies involving male patients with metabolic syndrome. Moreover, other circulating markers of different candidate atherogenic risk parameters were also studied and the potential existence of a progressive relation between the number of metabolic syndrome components and the above mentioned biomarkers was analyzed. Thirty one male patients with metabolic syndrome (ATPIII definition) and 56 male control subjects were studied. We evaluated different markers of insulin resistance, inflammation and atherosclerosis, as well as protective factors. Patients with metabolic syndrome showed (a) hypoadiponectinemia (4551 +/- 2302 ng/ml vs. 5865 +/- 2548 ng/ml, respectively; p<0.05), (b) an atherogenic lipid and lipoprotein profile, (c) altered HDL chemical composition accompanied by higher cholesteryl ester-triglyceride interchange carried out by CETP, (d) diminished Lp-PLA(2) activity (6.5 +/- 1.9 vs. 7.3 +/- 2.2, p<0.05, respectively), antioxidant enzyme related with LDL oxidation, which was positively associated with QUICKI and negatively with VCAM-1 and lymphocyte CD18, and (e) high soluble (VCAM-1: 17 +/-5 vs. 13 +/- 4 ng/ml, respectively; p<0.0005) and leukocyte adhesion molecule expression (monocyte CD54: 52 +/- 15 vs. 45 +/-12 arbitrary units, respectively; p<0.0005; and lymphocyte CD49d: 312 +/- 56 vs. 284 +/- 64 arbitrary units, respectively; p < 0.05). The increment in leukocyte and soluble cell adhesion molecules, crucial for leukocyte interaction with the endothelium and migration into the artery wall, in combination with the other disorders described above reinforce the presence of a clinical status with high propensity to type 2 diabetes and atherosclerotic cardiovascular disease.
Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Moléculas de Adesão Celular/metabolismo , Síndrome Metabólica/metabolismo , Adiponectina/sangue , Antioxidantes/metabolismo , Antígenos CD18/biossíntese , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/classificação , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , HDL-Colesterol/química , Humanos , Insulina/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Lipoproteínas/química , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ETA receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ETA antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ETA antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ETA receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.
Assuntos
Moléculas de Adesão Celular/biossíntese , Desoxicorticosterona/toxicidade , Endotelina-1/fisiologia , Endotélio Vascular/patologia , Hipertensão/patologia , Leucócitos/fisiologia , Receptor de Endotelina A/fisiologia , Cloreto de Sódio na Dieta/toxicidade , Animais , Adesão Celular , Moléculas de Adesão Celular/genética , Quimiotaxia de Leucócito , Compostos de Dansil/farmacologia , Modelos Animais de Doenças , Selectina E/biossíntese , Selectina E/genética , Antagonistas do Receptor de Endotelina A , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão Renovascular/induzido quimicamente , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/patologia , Inflamação , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Macrófagos/fisiologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Nefrectomia , Selectina-P/biossíntese , Selectina-P/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
Central nervous system (CNS) damage can occur during Trypanosoma cruzi infection, especially in immunosuppressed patients. The enhanced susceptibility of C3H/He mice to CD8-mediated acute meningoencephalitis is associated with higher up-regulation of vascular cell adhesion molecule-1 (VCAM-1) on CNS vascular endothelia than in the less susceptible C57BL/6. Further, in vitro adhesion of activated peripheral blood cells to CNS blood vessels was abrogated by anti-VLA-4 antibodies that also inhibited cell migration into the CNS of T. cruzi-infected mice. Lastly, the reactivation of meningoencephalitis in immunosuppressed chronically infected mice was associated with VCAM-1 up-regulation. Therefore, we hypothesize that VLA-4/VCAM-1 pathway plays a pivotal role in the establishment of T. cruzi-elicited encephalitis.