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Mem. Inst. Oswaldo Cruz ; 116: e200417, 2021. tab, graf
Article in English | LILACS | ID: biblio-1154880


BACKGROUND Toxoplasma gondii causes toxoplasmosis and is controlled by activated macrophages. However, infection of macrophages by tachyzoites induces TGF-β signaling (TGF-s) inhibiting nitric oxide (NO) production. NO inhibition may be a general escape mechanism of distinct T. gondii strains. OBJECTIVES To evaluate in activated macrophages the capacity of T. gondii strains of different virulence and genetics (RH, type I; ME-49, type II; VEG, type III; P-Br, recombinant) to evade the NO microbicidal defense system and determine LC3 loading to the parasitophorous vacuole. METHODS Activated peritoneal macrophages were infected with the different T. gondii strains, NO-production was evaluated by the Griess reagent, and inducible nitric oxide synthase expression, TGF-s, and LC3 localisation assayed by immunofluorescence. FINDINGS Only RH persisted in macrophages, while VEG was more resistant than P-Br and ME-49. All strains induced TGF-s, degradation of inducible nitric oxide synthase, and NO-production inhibition from 2 to 24 h of infection, but only RH sustained these alterations for 48 h. By 24 h of infection, TGF-s lowered in macrophages infected by ME-49, and P-Br, and NO-production recovered, while VEG sustained TGF-s and NO-production inhibition longer. LC3 loading to parasitophorous vacuole was strain-dependent: higher for ME-49, P-Br and VEG, lower for RH. All strains inhibited NO-production, but only RH sustained this effect probably because it persisted in macrophages due to additional evasive mechanisms as lower LC3 loading to parasitophorous vacuole. MAIN CONCLUSIONS These results support that T. gondii can escape the NO microbicidal defense system at the initial phase of the infection, but only the virulent strain sustain this evasion mechanism.

Animals , Mice , Toxoplasma/physiology , Macrophages, Peritoneal/parasitology , Nitric Oxide Synthase/metabolism , Macrophages/parasitology , Nitric Oxide/biosynthesis , Toxoplasmosis, Animal/parasitology , Macrophages/metabolism
Braz. j. med. biol. res ; 53(3): e8761, 2020. tab, graf
Article in English | LILACS | ID: biblio-1089339


Nitric oxide (NO) inhibition by high-dose NG-nitro-L-arginine methyl ester (L-NAME) is associated with several detrimental effects on the cardiovascular system. However, low-dose L-NAME increases NO synthesis, which in turn induces physiological cardiovascular benefits, probably by activating a protective negative feedback mechanism. Aerobic exercise, likewise, improves several cardiovascular functions in healthy hearts, but its effects are not known when chronically associated with low-dose L-NAME. Thus, we tested whether the association between low-dose L-NAME administration and chronic aerobic exercise promotes beneficial effects to the cardiovascular system, evaluating the cardiac remodeling process. Male Wistar rats were randomly assigned to control (C), L-NAME (L), chronic aerobic exercise (Ex), and chronic aerobic exercise associated to L-NAME (ExL). Aerobic training was performed with progressive intensity for 12 weeks; L-NAME (1.5 mg·kg-1·day-1) was administered by orogastric gavage. Low-dose L-NAME alone did not change systolic blood pressure (SBP), but ExL significantly increased SBP at week 8 with normalization after 12 weeks. Furthermore, ExL promoted the elevation of left ventricle (LV) end-diastolic pressure without the presence of cardiac hypertrophy and fibrosis. Time to 50% shortening and relaxation were reduced in ExL, suggesting a cardiomyocyte contractile improvement. In addition, the time to 50% Ca2+ peak was increased without alterations in Ca2+ amplitude and time to 50% Ca2+ decay. In conclusion, the association of chronic aerobic exercise and low-dose L-NAME prevented cardiac pathological remodeling and induced cardiomyocyte contractile function improvement; however, it did not alter myocyte affinity and sensitivity to intracellular Ca2+ handling.

Animals , Male , Physical Conditioning, Animal/physiology , Calcium/analysis , Nitric Oxide Synthase/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Enzyme Inhibitors/pharmacology , Myocardial Contraction/drug effects , Body Weight/physiology , Rats, Wistar , Ventricular Pressure/drug effects , Nitric Oxide Synthase/metabolism , NG-Nitroarginine Methyl Ester/administration & dosage , Models, Animal , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Enzyme Inhibitors/administration & dosage , Adiposity , Hemodynamics , Motor Activity/physiology , Myocardium/pathology
Braz. j. med. biol. res ; 52(9): e8525, 2019. tab, graf
Article in English | LILACS | ID: biblio-1011614


Many compounds of ginsenosides show anti-inflammatory properties. However, their anti-inflammatory effects in intervertebral chondrocytes in the presence of inflammatory factors have never been shown. Increased levels of pro-inflammatory cytokines are generally associated with the degradation and death of chondrocytes; therefore, finding an effective and nontoxic substance that attenuates the inflammation is worthwhile. In this study, chondrocytes were isolated from the nucleus pulposus tissues, and the cells were treated with ginsenoside compounds and IL-1β, alone and in combination. Cell viability and death rate were assessed by CCK-8 and flow cytometry methods, respectively. PCR, western blot, and immunoprecipitation assays were performed to determine the mRNA and protein expression, and the interactions between proteins, respectively. Monomeric component of ginsenoside Rd had no toxicity at the tested range of concentrations. Furthermore, Rd suppressed the inflammatory response of chondrocytes to interleukin (IL)-1β by suppressing the increase in IL-1β, tumor necrosis factor (TNF)-α, IL-6, COX-2, and inducible nitric oxide synthase (iNOS) expression, and retarding IL-1β-induced degradation of chondrocytes by improving cell proliferation characteristics and expression of aggrecan and COL2A1. These protective effects of Rd were associated with ubiquitination of IL-1 receptor accessory protein (IL1RAP), blocking the stimulation of IL-1β to NF-κB. Bioinformatics analysis showed that NEDD4, CBL, CBLB, CBLC, and ITCH most likely target IL1RAP. Rd increased intracellular ITCH level and the amount of ITCH attaching to IL1RAP. Thus, IL1RAP ubiquitination promoted by Rd is likely to occur by up-regulation of ITCH. In summary, Rd inhibited IL-1β-induced inflammation and degradation of intervertebral disc chondrocytes by increasing IL1RAP ubiquitination.

Humans , Male , Female , Adult , Middle Aged , Aged , Chondrocytes/drug effects , Ginsenosides/pharmacology , Interleukin-1beta/drug effects , Interleukin-1 Receptor Accessory Protein/metabolism , Intervertebral Disc Degeneration/metabolism , Dinoprostone/metabolism , Cell Survival/drug effects , Tumor Necrosis Factor-alpha/metabolism , Low Back Pain/metabolism , Nitric Oxide Synthase/metabolism , Chondrocytes/cytology , Chondrocytes/metabolism , Ginsenosides/metabolism , Cyclooxygenase 2/metabolism , Aggrecans/metabolism , Interleukin-1beta/metabolism , Ubiquitination , Nucleus Pulposus/cytology , Nucleus Pulposus/drug effects , Nucleus Pulposus/metabolism , Inflammation/metabolism
Acta cir. bras ; 32(11): 935-948, Nov. 2017. graf
Article in English | LILACS | ID: biblio-886187


Abstract Purpose: To investigate the expression of nitric oxide synthase (NOS) and apoptosis associated with ischemic preconditioning (IPC) and pentoxifylline (PTX) in intestinal ischemia (I) and reperfusion (R) injury. Methods: Thirty male rats were assigned to 5 groups: (CG), no clamping of the superior mesenteric artery (90 minutes); (IR-SS) saline + ischemia (30 minutes) + reperfusion (60 minutes); (IR-PTX) PTX + ischemia (30 minutes) + reperfusion (60 minutes); (IPC-IR-SS) 5 minutes of ischemia + 5 minutes of reperfusion (IPC) + saline + I(30 minutes)+R(60 minutes); and (IPC-IR-PTX) IPC + PTX + I(30 minutes)+ R(60 minutes). Results: The application of IPC and PTX showed a significantly lower immunohistochemistry reaction for active caspase-3 (P<0.05) compared to IR+SS. The number of cells immunoreactive to BCL-2 was higher in the IR-PTX group (P>0.05). The NOS-2 expression (qRTPCR) in the IR-PTX group (P<0.05) was higher than the values for the IPC+IR-SS and IPC-IR-PTX groups. The NOS-3 expression was significantly upper in the IPC-IR-PTX group than in the CG (P<0.05), the IR-SS (P<0.05) and the IR-PTX (P<0.05) groups. Conclusions: The BCL-2 and active caspase-3 showed beneficial effects on PTX and IPC. The expression of NOS-2 and NOS-3 in the IPC and IPC-PTX groups showed no synergistic effect.

Humans , Animals , Male , Rats , Pentoxifylline/therapeutic use , Apoptosis/drug effects , Nitric Oxide Synthase/metabolism , Ischemic Preconditioning , Intestinal Diseases/prevention & control , Intestines/blood supply , Vasodilator Agents/therapeutic use , RNA, Messenger/analysis , Immunohistochemistry , Rats, Wistar , Apoptosis/physiology , Disease Models, Animal , Intestinal Diseases/enzymology , Intestines/pathology
Braz. j. med. biol. res ; 50(3): e5556, 2017. graf
Article in English | LILACS | ID: biblio-839268


Muscular atrophy is a progressive degeneration characterized by muscular proteolysis, loss of mass and decrease in fiber area. Tendon rupture induces muscular atrophy due to an intrinsic functional connection. Local inhibition of nitric oxide synthase (NOS) by Nω-nitro-L-arginine methyl ester (L-NAME) accelerates tendon histological recovery and induces functional improvement. Here we evaluate the effects of such local nitrergic inhibition on the pattern of soleus muscle regeneration after tenotomy. Adult male Wistar rats (240 to 280 g) were divided into four experimental groups: control (n=4), tenotomized (n=6), vehicle (n=6), and L-NAME (n=6). Muscular atrophy was induced by calcaneal tendon rupture in rats. Changes in muscle wet weight and total protein levels were determined by the Bradford method, and muscle fiber area and central core lesion (CCL) occurrence were evaluated by histochemical assays. Compared to tenotomized (69.3±22%) and vehicle groups (68.1%±17%), L-NAME treatment induced an increase in total protein level (108.3±21%) after 21 days post-injury. A reduction in fiber areas was observed in tenotomized (56.3±1.3%) and vehicle groups (53.9±3.9%). However, L-NAME treatment caused an increase in this parameter (69.3±1.6%). Such events were preceded by a remarkable reduction in the number of fibers with CCL in L-NAME-treated animals (12±2%), but not in tenotomized (21±2.5%) and vehicle groups (19.6±2.8%). Altogether, our data reveal that inhibition of tendon NOS contributed to the attenuation of atrophy and acceleration of muscle regeneration.

Animals , Male , Rats , Enzyme Inhibitors/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Recovery of Function/drug effects , Regeneration/drug effects , Muscular Atrophy , Nitric Oxide Synthase/metabolism , Rats, Wistar , Recovery of Function/physiology , Regeneration/physiology , Tenotomy
Acta cir. bras ; 30(5): 345-352, 05/2015. tab, graf
Article in English | LILACS | ID: lil-747028


PURPOSE: To evaluated the effects of L-arginine (a NO donor) and L-NAME (Nw-nitro-L-arginine methyl ester - a NOS inhibitor) on ischemia-reperfusion in rat livers. METHODS: One hundred fifty two male Wistar rats were divided into four groups: control (simulated surgery); hepatic IR; pretreatment with L-arginine plus hepatic IR; and L-NAME plus hepatic IR. The hepatocellular damage was evaluated at the first, third and seventh days after the procedures through the alanine-aminotransferase (ALT) and aspartate-aminotransaminase (AST) levels, as well as histopathological features: vascular congestion (VC); steatosis (STE); necrosis (NEC); and inflammatory infiltration (INF). The mortality rate was also evaluated. RESULTS: The pretreatment with L-NAME significantly worsened the AST levels after hepatic IR (p<0.05) at first day and L-arginine demonstrated an attenuating effect on ALT levels at seventh day (p<0.05). Furthermore, the administration of L-arginine was able to reduce the VC and STE in the seventh day after hepatic IR (p<0.05). The analysis of the mortality rates did not demonstrate any difference between the groups. Nevertheless, there was not effect of L-arginine and L-NAME on the mortality of the animals. CONCLUSION: L-arginine/NO pathway has a role in the hepatic IR because the pretreatment with L-arginine partially had attenuated the hepatocellular damage induced by hepatic IR in rats. .

Animals , Male , Arginine/therapeutic use , Enzyme Inhibitors/therapeutic use , Liver/blood supply , Liver/drug effects , NG-Nitroarginine Methyl Ester/therapeutic use , Reperfusion Injury/prevention & control , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Disease Models, Animal , Liver/pathology , Necrosis , Nitric Oxide Synthase/drug effects , Nitric Oxide Synthase/metabolism , Nitric Oxide/metabolism , Random Allocation , Rats, Wistar , Reference Values , Reproducibility of Results , Time Factors , Treatment Outcome
Arq. neuropsiquiatr ; 73(2): 155-158, 02/2015. graf
Article in English | LILACS | ID: lil-741182


Andreas Vesalius (1514-1564) is considered the Father of Modern Anatomy, and an authentic representative of the Renaissance. His studies, founded on dissection of human bodies, differed from Galeno, who based his work on dissection of animals, constituted a notable scientific advance. Putting together science and art, Vesalius associated himself to artists of the Renaissance, and valued the images of the human body in his superb work De Humani Corporis Fabrica.This paper aims to honor this extraordinary European Renaissance physician and anatomist, who used aesthetic appeal to bind text and illustration, science and art. His achievements are highlighted, with an especial attention on neuroanatomy. Aspects about his personal life and career are also focused.

Andreas Vesalius (1514-1564) é considerado o Pai da Anatomia Moderna e um autêntico representante da Renascença. Seus estudos, baseados na dissecação de corpos humanos, diferiam dos de Galeno, que baseava seu trabalho em dissecação de animais, constituiu-se em um notável avanço científico. Reunindo ciência e arte, Vesalius associou-se a artistas da Renascença e valorizou as imagens do corpo humano em seu soberbo trabalho De Humani Corporis Fabrica. Este artigo visa honrar esse extraordinário médico e anatomista da Renascença europeia, que fez uso do apelo estético para coligar texto e ilustração, ciência e arte. Suas realizações são realçadas, com atenção especial na neuroanatomia. Também são colocados em foco aspectos da sua vida pessoal e de sua carreira.

Animals , Female , Pregnancy , Dexamethasone/pharmacology , Endothelium, Vascular/drug effects , Glucocorticoids/pharmacology , Prenatal Exposure Delayed Effects , Vasodilation/drug effects , Blood Pressure/physiology , Endothelium, Vascular/enzymology , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Enzymologic , Microcirculation/drug effects , Microcirculation/physiology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase Type III , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Vascular Resistance/physiology , Vasodilation/physiology
Rev. bras. enferm ; 67(5): 730-736, Sep-Oct/2014. tab
Article in Portuguese | LILACS, BDENF | ID: lil-731206


Avaliou-se o risco para desenvolvimento de eventos coronarianos agudos de acordo com os critérios de Framingham e com as ações de saúde realizadas em hipertensos de uma Unidade de Saúde da Família de Vitória-ES. Estudo observacional, de corte transversal, envolvendo 330 hipertensos. A amostra considerou prevalência do agravo de 50%. Os dados foram coletados dos prontuários e as variáveis constituíram o risco coronariano, a pressão arterial, o número de consultas, de atividades educativas e de medicamentos prescritos. Foi utilizada a ANOVA para comparar as variáveis e o teste t pareado para comparação da pressão no período estudado, com nível de significância de 5%. Respectivamente, 115 (34,8%) sujeitos apresentaram baixo risco de infarto ou morte por doença coronariana nos próximos 10 anos; 67 (20,4%) apresentaram médio risco; e 148 (44,8%) apresentaram alto risco. Somente o quantitativo de medicamentos prescritos mostrou relação significante com o risco coronariano elevado.

The risk of developing acute coronary events was evaluated according to Framingham criteria and health actions performed to hypertensive patients at a Health Unit Family of Vitória-ES. This is a observational, cross-sectional study, involving 330 hypertensive. The sample considered a 50% prevalence of the disease. Data were collected from medical records and the variables were the coronary risk, blood pressure, the number of visits, educational activities and prescribed drugs. ANOVA was used to compare variables and paired t-test for comparison of pressure during the study period, with significance level of 5%. Respectively, 115 (34.8%) subjects had low risk for myocardial infarction or death from coronary heart disease in the next 10 years; 67 (20.4%) had average risk; and 148 (44.8%) had high-risk. Only the amount of prescribed medications showed significant relationship with high coronary risk.

Se evaluó el riesgo de desarrollar eventos coronarios agudos según criterios de Framingham y acciones de salud realizadas en hipertensos de una Unidad de Salud de la Familia de Vitória-ES. Estudio observacional, transversal, envolviendo la participación de 330 hipertensos. La muestra considero la prevalencia del agravo en 50%. Los datos fueron recogidos de las historias clínicas y las variables fueron el riesgo coronario, presión arterial, el número de visitas, actividades educativas y los medicamentos recetados. Fue utilizada ANOVA para comparar las variables y el teste t para la comparación de la presión durante el período de estudio, con un nivel de significación del 5%. Respectivamente, 115 (34,8%) sujetos tenían bajo riesgo de infarto de miocardio o muerte por enfermedad coronaria en los próximos 10 años; 67 (20,4%) tenían un riesgo promedio; y 148 (44,8%) tenían alto riesgo. Sólo la cantidad de medicamentos prescritos mostraron asociación significativa con el riesgo coronario alto.

Animals , Male , Rats , Jejunum/enzymology , Nitric Oxide Synthase/metabolism , Immunohistochemistry , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type III , Rats, Sprague-Dawley , Tissue Distribution
Femina ; 42(4): 179-184, jul-ago. 2014.
Article in Portuguese | LILACS | ID: lil-737134


O trabalho de parto pré-termo (TPPT) assim como as outras causas de prematuridade respondem pela maior parcela da mortalidade e morbidade neonatal no mundo. Várias vias metabólicas já foram estudadas e diversas alterações já foram encontradas em pacientes que desenvolve TPPT. A via metabólica do óxido nítrico (NO) é reconhecida como um dos possíveis mecanismos de desencadeamento fisiopatológico do TPPT. Níveis elevados de dimetil-arginina assimétrica (ADMA), substância endógena inibidora da NO sintetase, estão relacionados com o desencadeamento de TPPT e com maiores taxas de complicações neonatais. O presente estudo aborda as evidências sobre a relação do TPPT e ADMA e as possíveis aplicações clínicas dessa associação.(AU)

Pre-term labor (PTL), as well as the other causes of prematurity, account for the largest portion of neonatal mortality and morbidity in the world. Several metabolic pathways were studied and a significative number of impairments have already been found in patients who develop PTL. The metabolic pathway of nitric oxide (NO) is recognized as one of the possible mechanisms of pathophysiological PTL?s trigger. High levels of asymmetric dimethyl arginine (ADMA), endogenous inhibitory substance of NO synthetase, are related to the triggering of PTL and with higher rates of neonatal complications. The present study addresses the evidence on the relationship of PTL and ADMA and possible clinical applications of this association.(AU)

Female , Pregnancy , Arginine/analogs & derivatives , Arginine/physiology , Arginine/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Obstetric Labor, Premature/physiopathology , Nitric Oxide , Arginine/therapeutic use , Risk Factors , Databases, Bibliographic , Oxidative Stress , Dietary Supplements
Rev. Esc. Enferm. USP ; 48(spe): 109-115, 08/2014.
Article in English | LILACS, BDENF | ID: lil-731297


Objective To analyze the practices of primary care focused on the harmful consumption of drugs. Method This is a qualitative study, developed with a dialectical-critical approach. Data collection was carried out through semi-structured interviews with 10 employees of a basic health unit (UBS). Results The demands are not accepted, and if they go beyond the barriers shaped by the historical absence of health care practices for drug users and moralistic and preconceived ideologies, they are not reinterpreted as health needs; practices that meet these demands and go beyond the barriers are poor; the functionalist approach, which explains drug use as a disease and considers drug users as deviants, supports the few existing practices. Conclusion primary health care is mistakenly focused on addiction; it lacks structural elements of the production process in health and internal dynamics of the working processes that would foster the development of collective practices. .

Objetivo El estudio tiene como objetivo analizar las prácticas de atención primaria dirigidos a lo consumo prejudicial de drogas. Método Se trata de un estudio cualitativo, desarrollado en la perspectiva dialéctica crítica. La recolección de datos se realizó a través de entrevistas semiestructuradas con 10 empleados de una Unidad Básica de Salud. Resultados Muestran que: las demandas no son aceptadas, y si van más allá de las barreras - formadas por la ausencia histórica de la práctica de la atención de salud para los consumidores de drogas y las ideologías morales y preconcebidas -, no son reinterpretados como necesidades de salud; las prácticas que satisfagan esas demandas son pobres; detrás de estas escasas prácticas, está la perspectiva funcionalista, que considera el uso de drogas como una enfermedad y los usuarios de drogas como desviados; los trabajadores valoran la formación clínica y culpan a los usuarios por los problemas que enfrentan. Conclusión Se pode concluir que la atención primaria: es equívoca hacia el objeto de la dependencia; carece de los elementos estructurales del proceso de producción en la salud y las dinámicas internas de los procesos de trabajo que fomenten el desarrollo de las prácticas colectivas.


Objetivo Analisar as práticas de atenção básica voltadas ao consumo prejudicial de drogas. Método Estudo qualitativo, desenvolvido na perspectiva dialético-crítica. A coleta de dados foi realizada através de entrevistas semiestruturadas com 10 trabalhadores de uma Unidade Básica de Saúde (UBS). Resultados As demandas não são acolhidas e, quando ultrapassam as barreiras - conformadas pela ausência histórica de práticas de atenção à saúde ao usuário de drogas e por ideologias moralistas e preconceituosas -, não são reinterpretadas como necessidades de saúde; as práticas que atendem essas demandas são precárias; a perspectiva funcionalista, que compreende o consumo de drogas como doença e considera usuários de drogas como desviantes, embasa as escassas práticas existentes. Conclusão A atenção básica encontra-se equivocamente voltada para a dependência; carece de elementos estruturais do processo de produção em saúde e da dinamicidade interna aos processos de trabalho, que favoreceriam o desenvolvimento de práticas coletivas. .

Adult , Aged , Female , Humans , Male , Middle Aged , Endothelial Growth Factors/metabolism , Lymphokines/metabolism , Nitric Oxide Synthase/metabolism , Stomach Neoplasms/blood supply , Stomach Neoplasms/metabolism , Immunohistochemistry , Microcirculation/pathology , Neoplasm Staging , Neovascularization, Pathologic , Nitric Oxide Synthase Type II , Prognosis , Stomach Neoplasms/pathology , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
Braz. j. med. biol. res ; 47(2): 90-100, 2/2014. tab, graf
Article in English | LILACS | ID: lil-699775


Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON.

Animals , Humans , Rats , Neurons/physiology , Neurosecretory Systems/physiology , Nitric Oxide/physiology , Oxytocin , Supraoptic Nucleus/physiology , Vasopressins , Action Potentials/physiology , Guanylate Cyclase/metabolism , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Water-Electrolyte Balance/physiology
Korean Journal of Urology ; : 677-686, 2014.
Article in English | WPRIM | ID: wpr-192660


PURPOSE: To investigate the effects of estrogen on the expression of the alpha1 receptor and nitric oxide synthase (NOS) in rat urethra and bladder after oophorectomy. MATERIALS AND METHODS: Forty-five mature female Sprague-Dawley rats (aged 10-11 weeks, 235-250 g) were randomly assigned to one of three groups: control group, oophorectomy group (Opx), or oophorectomy and estradiol replacement group (Opx+ Est). The degree of expression of alpha1 receptor (alpha1A and D) and NOS (neuronal NOS [nNOS] and endothelial NOS [eNOS]) in bladder and urethral tissues was investigated by using immunohistochemical staining and Western blotting. RESULTS: In the bladder, the expression rates of alpha1 receptor (alpha1A and alpha1D) increased in the Opx group but decreased in the Opx+Est group. These changes were not statistically significant. The alpha1A and alpha1D receptor of the urethra decreased in the Opx group but increased in the Opx+Est group. These changes were not statistically significant. In the bladder and urethra, the expression rates of nNOS and eNOS significantly increased in the Opx group but decreased in the Opx+Est group (p<0.05). CONCLUSIONS: These data suggest that estrogen depletion increases NOS and alpha1 receptor expression in the rat bladder. However, these changes could be restored by estrogen replacement therapy.

Animals , Collagen/metabolism , Estradiol/analogs & derivatives , Estrogen Replacement Therapy/methods , Female , Muscle, Smooth/pathology , Nitric Oxide Synthase/metabolism , Ovariectomy , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-1/metabolism , Urethra/drug effects , Urinary Bladder/drug effects
Braz. j. med. biol. res ; 46(10): 881-891, 24/set. 2013. tab, graf
Article in English | LILACS | ID: lil-688558


Because histopathological changes in the lungs of patients with systemic sclerosis (SSc) are consistent with alveolar and vessel cell damage, we presume that this interaction can be characterized by analyzing the expression of proteins regulating nitric oxide (NO) and plasminogen activator inhibitor-1 (PAI-1) synthesis. To validate the importance of alveolar-vascular interactions and to explore the quantitative relationship between these factors and other clinical data, we studied these markers in 23 cases of SSc nonspecific interstitial pneumonia (SSc-NSIP). We used immunohistochemistry and morphometry to evaluate the amount of cells in alveolar septa and vessels staining for NO synthase (NOS) and PAI-1, and the outcomes of our study were cellular and fibrotic NSIP, pulmonary function tests, and survival time until death. General linear model analysis demonstrated that staining for septal inducible NOS (iNOS) related significantly to staining of septal cells for interleukin (IL)-4 and to septal IL-13. In univariate analysis, higher levels of septal and vascular cells staining for iNOS were associated with a smaller percentage of septal and vascular cells expressing fibroblast growth factor and myofibroblast proliferation, respectively. Multivariate Cox model analysis demonstrated that, after controlling for SSc-NSIP histological patterns, just three variables were significantly associated with survival time: septal iNOS (P=0.04), septal IL-13 (P=0.03), and septal basic fibroblast growth factor (bFGF; P=0.02). Augmented NOS, IL-13, and bFGF in SSc-NSIP histological patterns suggest a possible functional role for iNOS in SSc. In addition, the extent of iNOS, PAI-1, and IL-4 staining in alveolar septa and vessels provides a possible independent diagnostic measure for the degree of pulmonary dysfunction and fibrosis with an impact on the survival of patients with SSc.

Adult , Female , Humans , Middle Aged , Lung Diseases, Interstitial/pathology , Nitric Oxide Synthase/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Scleroderma, Systemic/pathology , Biomarkers/blood , Cytokines/blood , Immunohistochemistry , /metabolism , /metabolism , Kaplan-Meier Estimate , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/metabolism , Lung Diseases, Interstitial/mortality , Nitric Oxide Synthase Type II/metabolism , Protein Isoforms/blood , Scleroderma, Systemic/complications , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/mortality
Braz. j. pharm. sci ; 49(spe): 57-65, 2013. ilus
Article in English | LILACS | ID: lil-686586


Dendrimers constitute an intriguing class of macromolecules which find applications in a variety of areas including biology. These hyperbranched macromolecules with tailored backbone and surface groups have been extensively investigated as nanocarriers for gene and drug delivery, by molecular encapsulation or covalent conjugation. Dendrimers have provided an excellent platform to develop multivalent and multifunctional nanoconjugates incorporating a variety of functional groups including drugs which are known to be anti-inflammatory agents. Recently, dendrimers have been shown to possess anti-inflammatory properties themselves. This unexpected and intriguing discovery has provided an additional impetus in designing novel active pharmaceutical agents. In this review, we highlight some of the recent developments in the field of dendrimers as nanoscale anti-inflammatory agents.

Dendrímeros constituem uma classe intrigante de macromoléculas que apresentam aplicações em diversas áreas incluindo biologia. Essas macromoléculas extremamente ramificadas com esqueleto planejado e grupos de superfície foram extensivamente investigadas como nanotransportadores de genes e de fármacos, por encapsulamento molecular ou conjugação covalente. Dendrímeros têm proporcionado uma plataforma excelente de desenvolvimento nanoconjugados multivalentes e multifuncionais incorporando uma variedade de grupos funcionais, incluindo fármacos que são conhecidos por atuarem agentes antiinflamatórios. Recentemente, os dendrímeros mostraram propriedades antiinflamatórias. Esta inesperada e intrigante descoberta tem proporcionado um impulso adicional no planejamento de novos agente farmacêuticos ativos. Nesta revisão, nós destacamos alguns dos desenvolvimentos recentes no campo dos dendrímeros como agentes antiinflamatórios em nanoescala.

Anti-Inflammatory Agents/analysis , Dendrimers/analysis , Cytokines , Nitric Oxide Synthase/metabolism
Braz. j. med. biol. res ; 45(11): 1066-1073, Nov. 2012. ilus, tab
Article in English | LILACS | ID: lil-650568


The amino acid arginine (Arg) is a recognized secretagogue of growth hormone (GH), and has been shown to induce GH gene expression. Arg is the natural precursor of nitric oxide (NO), which is known to mediate many of the effects of Arg, such as GH secretion. Arg was also shown to increase calcium influx in pituitary cells, which might contribute to its effects on GH secretion. Although the mechanisms involved in the effects of Arg on GH secretion are well established, little is known about them regarding the control of GH gene expression. We investigated whether the NO pathway and/or calcium are involved in the effects of Arg on GH gene expression in rat isolated pituitaries. To this end, pituitaries from approximately 170 male Wistar rats (~250 g) were removed, divided into two halves, pooled (three hemi-pituitaries) and incubated or not with Arg, as well as with different pharmacological agents. Arg (71 mM), the NO donor sodium nitroprusside (SNP, 1 and 0.1 mM) and a cyclic guanosine monophosphate (cGMP) analogue (8-Br-cGMP, 1 mM) increased GH mRNA expression 60 min later. The NO acceptor hemoglobin (0.3 µM) blunted the effect of SNP, and the combined treatment with Arg and L-NAME (a NO synthase (NOS) inhibitor, 55 mM) abolished the stimulatory effect of Arg on GH gene expression. The calcium channel inhibitor nifedipine (3 µM) also abolished Arg-induced GH gene expression. The present study shows that Arg directly induces GH gene expression in hemi-pituitaries isolated from rats, excluding interference from somatostatinergic neurons, which are supposed to be inhibited by Arg. Moreover, the data demonstrate that the NOS/NO signaling pathway and calcium mediate the Arg effects on GH gene expression.

Animals , Male , Rats , Arginine/pharmacology , Gene Expression Regulation/drug effects , Growth Hormone/genetics , Pituitary Gland/drug effects , Dose-Response Relationship, Drug , Growth Hormone/metabolism , Nitric Oxide Synthase/drug effects , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide/genetics , Nitric Oxide/metabolism , Pituitary Gland/metabolism , Rats, Wistar , Signal Transduction
Arq. bras. cardiol ; 99(3): 780-788, set. 2012. ilus, tab
Article in Portuguese | LILACS | ID: lil-649261


FUNDAMENTO: O programa de biogênese mitocondrial no coração parece apresentar remodelação adaptativa após estresse biomecânico e oxidativo. Os mecanismos adaptativos que protegem o metabolismo do miocárdio durante a hipóxia são coordenados, em parte, pelo óxido nítrico (NO). OBJETIVO: Observar a biogênese mitocondrial e expressão do óxido nítrico sintase (NOS) em corações de cardiopatia congênita com cianose; discutir a resposta mitocondrial à hipóxia crônica do miocárdio. MÉTODOS: Foram investigados 20 pacientes com defeitos cardíacos cianóticos (n = 10) ou acianóticos (n = 10). Foram estudadas amostras do miocárdio na via de saída ventricular direita, tomadas durante a operação. A análise morfométrica de mitocôndrias foi realizada por microscopia eletrônica de transmissão. A relação mtDNA/nDNA foi determinada com PCR em tempo real. Os níveis de transcrição da subunidade I da citocromo c oxidase (COXI), coativador-1α do receptor γ ativado por proliferador de peroxissoma (PGC-1α), o fator respiratório nuclear 1 (NRF1), e fator de transcrição mitocondrial A (Tfam) foram detectados por reação em cadeia da polimerase via transcriptase reversa (RT-PCR) ativado por fluorescência em tempo real. Os níveis proteicos de COXI e nNOS, iNOS e eNOS foram medidos por técnica de Western Blot. RESULTADOS: A densidade volumétrica mitocondrial (Vv) e a densidade numérica (Nv) foram significativamente elevadas em pacientes com cianose, em comparação com a cardiopatia congênita acianótica. MtDNA elevada e suprarregulação dos níveis de COXI, PGC-1 α, NRF1 e Tfam mRNA foram observadas em pacientes cianóticos. Os níveis de proteína de COXI e eNOS foram significativamente maiores no miocárdio de pacientes cianóticos que nos de acianóticos. Os níveis de transcrição do PGC-1α se correlacionam com os níveis de eNOS. CONCLUSÃO: A biogênese mitocondrial é ativada no miocárdio da via de saída ventricular na cardiopatia congênita com cianose, que ...

BACKGROUND: Mitochondrial biogenesis program in heart appears to exhibit adaptive remodeling following biomechanical and oxidative stress. The adaptive mechanisms that protect myocardium metabolism during hypoxia are coordinated in part by nitric oxide (NO). OBJECTIVE: To observe mitochondrial biogenesis and nitric oxide synthase (NOS) expression in hearts of congenital heart disease with cyanosis, discuss mitochondrial response to chronic hypoxia in myocardium. METHODS: 20 patients with cyanotic (n=10) or acyanotic cardiac defects (n=10) were investigated. Samples from the right ventricular outflow tract myocardium taken during operation were studied. Morphometric analysis of mitochondria was performed with transmission electron microscope. Relative mtDNA/nDNA ratio was determined with real-time PCR. Cytochrome c oxidase subunit I (COXI), peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (Tfam) transcript levels were detected by real-time fluorescent RT-PCR. COXI and nNOS, iNOS and eNOS protein levels were measured with western blot. RESULTS: Mitochondrial volume density (Vv) and numerical density (Nv) were significantly elevated in patients with cyanotic compared to acyanotic congenital heart disease. Elevated mtDNA and up-regulated COXI, PGC-1α, NRF1 and Tfam mRNA levels were observed in cyanotic patients. Protein levels of COXI and eNOS were significantly higher in the myocardium of cyanotic than of acyanotic patients. PGC-1α transcript levels correlated with the levels of eNOS. Conclusion: Mitochondrial biogenesis is activated in right ventricular outflow tract myocardium in congenital heart disease with cyanosis, which could be the adaptive response to chronic hypoxia and possibly involves eNOS up-regulation. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

Adolescent , Child , Child, Preschool , Female , Humans , Male , Young Adult , Cyanosis/enzymology , Cyanosis/physiopathology , Heart Defects, Congenital/enzymology , Mitochondrial Turnover/physiology , Myocardium/metabolism , Nitric Oxide Synthase Type III/metabolism , DNA Copy Number Variations , DNA, Mitochondrial/chemistry , Gene Expression Regulation/physiology , Heart Defects, Congenital/physiopathology , Mitochondrial Size , Nitric Oxide Synthase/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/metabolism
Rev. ANACEM (Impresa) ; 6(1): 4-8, abr. 2012. ilus, graf
Article in Spanish | LILACS | ID: lil-640033


INTRODUCCIÓN: La epilepsia del lóbulo temporal se desarrolla como consecuencia de insultos cerebrales como trauma, infartos, infección o convulsiones. Los circuitos neuronales del lóbulo temporal, incluyendo al hipocampo, se reorganizan generando redes hiperexcitables, el foco epiléptico, proceso denominado epileptogénesis; en cambio, la corteza cerebral es más resistente a la reorganización. La epileptogénesis en el hipocampo está mediada en parte por óxido nítrico, sintetizado por la óxido nítrico sintasa neuronal y por la neurotrofina BDNF, cuyo receptor es TrkB. Estas proteínas están localizadas en las sinapsis excitadoras y podrían estar implicadas en la sensibilidad diferencial entre el hipocampo y corteza cerebral a la epileptogénesis. OBJETIVO: Lograr un acercamiento a los mecanismos que participan en la sensibilidad diferencial a la epileptogénesis entre el hipocampo y la corteza, después de convulsiones. MATERIAL Y MÉTODO: Se indujeron convulsiones en ratas mediante inyección de kainato. Se obtuvieron membranas sinápticas reselladas (sinaptosomas) de corteza e hipocampo. En ellas, se cuantificó la co-localización de óxido nítrico sintasa neuronal, TrkB y un marcador de sinapsis excitadoras (Prosap2) mediante técnicas inmunohistoquímicas. Los resultados expresados como por ciento promedio +/- error estándar se sometieron a prueba de t-student. RESULTADOS: TrkB y óxido nítrico sintasa neuronal aumentaron de 20,6 +/- 3,5 por ciento a 35,7 +/- 2,6 por ciento (p = 0,0008) y de 32,4 +/- 3,8 por ciento a 51,5 +/- 3,5 por ciento (p = 0,0003), respectivamente, en sinaptosomas excitadores hipocampales después de convulsiones. En sinaptosomas excitadoras de cerebro corteza no se observaron cambios significativos. DISCUSIÓN: óxido nítrico sintasa neuronal y TrkB se asocian a sinapsis excitadoras hipocampales después de convulsiones, pudiendo contribuir así a la epileptogénesis. La cerebrocorteza es resistente a esta reorganización molecular.

INTRODUCTION: Temporal lobe epilepsy develops as a consequence of brain insults such as trauma, stroke, infection, or seizures. The temporal lobe circuit, including the hippocampus, reorganizes generating hyper-excitable networks and, therefore, the epileptic focus, process called epileptogenesis. Where as, the cerebral cortex is more resistant to the reorganization. Temporal lobe epileptogenesis is mediated partly by neuronal nitric oxide synthase and the neurotrophin BDNF with its receptor TrkB. These proteins are localized at excitatory synapses and might be involved in the differential sensitivity of the hippocampus and cerebral cortex to epileptogenesis. OBJECTIVE: Getting closer to mechanisms involved in epileptogenesis differential sensitivity between the hippocampus and cortex after seizures. MATERIAL AND METHOD: Seizures were induced in rats by injection of kainic acid. Resealed synaptic membranes (synaptosomes) were obtained from cortex and hippocampus. Then the co-localization of neuronal nitric oxide synthase, TrkB and a marker of excitatory synapses (Prosap2/Shank3) was quantified by immunohistochemistry. The results were expressed as mean +/- standard error and subjected to t-student test. RESULTS: TrkB and neuronal nitric oxide synthase increased from 20.6 +/- 3.5 percent to 35.7 +/- 2.6 percent (p = 0.0008) and from 32.4 +/- 3.8 percent to 51.5 +/- 3.5 percent (p = 0.0003), respectively in excitatory hippocampal synaptosomes after seizures. In excitatory cerebrocortical synaptosomes no significant changes were observed. DISCUSSION: neuronal nitric oxide synthase and TrkB associate to excitatory hippocampal synapses after seizures, thereby probably contributing to epileptogenesis. The cerebral cortex is resistant to this molecular reorganization.

Male , Animals , Rats , Cerebral Cortex/metabolism , Epilepsy/metabolism , Hippocampus/metabolism , Nitric Oxide Synthase/metabolism , Receptor, trkB , Kainic Acid/administration & dosage , Carrier Proteins , Epilepsy/chemically induced , Brain-Derived Neurotrophic Factor/metabolism , Temporal Lobe/metabolism , Rats, Sprague-Dawley , Synaptosomes
Braz. j. med. biol. res ; 45(2): 163-171, Feb. 2012. ilus, tab
Article in English | LILACS | ID: lil-614574


The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT1 receptor (AT1-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO2 = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT1-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT1-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT1-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT1-R staining, but C animals showed weak iNOS and AT1-R staining. Macrophages of L and P animals showed moderate and weak AT2-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT1-R blockade. We suggest that AT1-R blockade might act through AT2-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

Animals , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Hypoxia/complications , Antihypertensive Agents/therapeutic use , Hypertension, Pulmonary/drug therapy , Imidazoles/therapeutic use , Nitric Oxide Synthase/drug effects , Tetrazoles/therapeutic use , Animals, Newborn , Chronic Disease , Disease Models, Animal , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/metabolism , Immunohistochemistry , Nitric Oxide Synthase/metabolism , Pulmonary Artery/drug effects , Swine , Vascular Resistance/drug effects
Biol. Res ; 45(1): 51-60, 2012. ilus
Article in English | LILACS | ID: lil-626747


Acute renal failure (ARF) can be caused by injuries that induce tissue hypoxia, which in turn can trigger adaptive or inflammatory responses. We previously showed the participation of basic fibroblast growth factor (FGF-2) in renal repair. Based on this, the aim of this study was to analyze the effect of FGF-2 signaling pathway manipulation at hypoxia-induced protein levels, as well as in key proteins from the vasoactive systems of the kidney. We injected rat kidneys with FGF-2 recombinant protein (r-FGF) or FGF-2 receptor antisense oligonucleotide (FGFR2-ASO) after bilateral ischemia, and evaluated the presence of iNOS, EPO and HO-1, in representation of hypoxia-induced proteins, as well as COX-2, renin, kallikrein, and B2KR, in representation of the vasoactive systems of the kidney. A reduction in iNOS, HO-1, EPO, renin, kallikrein, B2KR, and in renal damage was observed in animals treated with r-FGF. The opposite effect was found with FGF-2 receptor down-regulation. In contrast, COX-2 protein levels were higher in kidneys treated with r-FGF and lower in those that received FGFR2-ASO, as compared to saline treated kidneys. These results suggest that the protective role of FGF-2 in the pathogenesis of ARF induced by I/R is a complex process, through which a differential regulation of metabolic pathways takes place.

Animals , Male , Rats , Acute Kidney Injury/metabolism , Cell Hypoxia/physiology , /metabolism , /pharmacology , Kidney/drug effects , Nitric Oxide Synthase/metabolism , Reperfusion Injury/physiopathology , Acute Kidney Injury/pathology , Disease Models, Animal , Erythropoietin/metabolism , /analysis , /metabolism , Heme Oxygenase-1/metabolism , Kallikreins/analysis , Kidney/blood supply , Rats, Sprague-Dawley , /analysis
Rio de Janeiro; s.n; 2012. 115 p. ilus, tab.
Thesis in Portuguese | LILACS | ID: lil-663605


Este estudo buscou investigar o papel do estresse oxidativo e nitrosativo no enfisema pulmonar induzido por elastase. Foram utilizados camundongos machos C57BL/6 submetidos a dois modelos de indução do enfisema por elastase pancreática suína (PPE): intratraqueal (i.t.) e intranasal (i.n.). No modelo intratraqueal a PPE foi instilada nas doses de 0,05 U ou 0,05 U/camundongo para avaliação temporal do enfisema 7, 14 e 21 dias após instilação de PPE. Em outra etapa, o papel da iNOS foi avaliado através da sua inibição farmacológica por aminoguanidina (AMG) 1% na água de beber ou pela sua exclusão genética em camundongos deficientes em iNOS que tiveram o enfisema induzido por 0,5 U PPE i.t. após 21 dias. No modelo intranasal a dose de PPE foi 3 U/camundongo para avaliação temporal do enfisema (1, 7, 14 e 21 dias após PPE). O papel do estresse oxidativo e nitrosativo foi avaliado com diferentes tratamentos antioxidantes na água de beber: tempol, apocinina+alopurinol, n-acetilcisteína, vitamina C+E, e aminoguanidina durante os 21 dias de indução do enfisema. Os grupos controles foram submetidos à instilação de salina. Lavado broncoalveolar, imunoensaios, análises bioquímicas de estresse oxidativo e ensaios morfométricos foram realizados nos pulmões dos animais. O enfisema foi histologicamente alcançado em 21 dias após 0,5 U PPE i.t., evidenciado pelo aumento do diâmetro alveolar médio - Lm e da densidade de volume dos espaços alveolares - Vvair em comparação ao grupo controle. TNF-a foi aumentado em 7 e 14 dias após 0,05 U PPE comparados ao controle, concomitante com a redução de IL-10 nos mesmos períodos, comparados ao controle. O estresse oxidativo foi observado na fase inicial do enfisema, com aumento dos níveis de nitrito, TBARS e superóxido dismutase no grupo 7 dias após 0,5 U PPE (i.t.) quando comparados ao controle ao passo que no modelo intranasal as alterações típicas do estresse foram vistas no grupo 1 dia após 3 U de PPE. Atividade da glutationa ...

This study investigated the role of oxidative and nitrosative stress in elastase-induced pulmonary emphysema. C57BL/6 male mice were used submitted to two models of emphysema induced by porcine pancreatic elastase (PPE): intratracheal (i.t.) and intranasal (i.n.). In the intratracheal model PPE was instilled at doses of 0.05 U or 0.5 U/mouse (i.t.) to temporal evaluation of emphysema 7, 14 and 21 days post-PPE instillation. Others sets of experiments, the role of iNOS was evaluated through its pharmacology inhibition by 1% aminoguanidine (AMG) into the drinking water or bt iNOS genetic exclusion in iNOS-deficient mice which had induced emphysema by 0.5 U PPE i.t. after 21 days. In the intranasal model the PPE dose was 3 U/mouse to temporal evaluation of emphysema (1, 7, 14 and 21 days after PPE). The role of oxidative and nitrosative stress was evaluated using different antioxidant treatments into the drinking water: tempol, apocynin+allopurinol, N-acetylcysteine, vitamin C+E and aminoguanidine during the 21 days of emphysema induction. Control groups were instilled with saline. Bronchoalveolar lavage, immunoassays, biochemical analysis of oxidative stress and morphometric tests were performed in the lungs of animals. The emphysema was histologically reached 21 days after 0.5 U PPE, as evidenced by an increase in alveolar diameter - Lm and volume density of the alveolar spaces - Vvair compared to the control group. TNF-a was increased in 7 and 14 days after 0.5 U PPE compared to the control, concomitant with reduction of IL-10 at the same time-points compared to the control. Oxidative stress was observed in the early stages of emphysema, with increased levels of nitrite, TBARS and superoxide dismutase in group 7 days after 0.5 U PPE (i.t.) compared to the control, while in the intranasal model the typical stress alterations were seen in group 1 day after 3 U PPE. Glutathione peroxidase activity was increased in all PPE groups (i.t.). Exposure to 0.5 U PPE ...

Animals , Mice , Pulmonary Disease, Chronic Obstructive/chemically induced , Pulmonary Disease, Chronic Obstructive/metabolism , Pancreatic Elastase/administration & dosage , Pancreatic Elastase/metabolism , Pulmonary Emphysema/chemically induced , Pulmonary Emphysema/metabolism , Antioxidants/pharmacology , Oxidative Stress/physiology , Inflammation , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase/metabolism , Lung/pathology