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1.
J Vet Intern Med ; 28(6): 1845-52, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25231643

RESUMEN

BACKGROUND: Systemic oxidative stress in horses with recurrent airway obstruction (RAO) is poorly characterized. OBJECTIVES: The goal of this study was to investigate whether equine RAO is associated with systemic disturbances in the oxidant-antioxidant equilibrium. ANIMALS: Seven healthy horses and 7 horses with symptomatic RAO. METHODS: A prospective study. Healthy and RAO-affected horses were exposed to a 48-hour challenge with moldy hay and straw to induce clinical exacerbation of RAO. Venous blood was collected and the activities of the superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in equine erythrocyte lysates were measured. The concentration of thiobarbituric acid-reactive substances (TBARSs) was assessed both in erythrocyte lysates and in plasma. RESULTS: A significant increase in the activities of GPx and SOD was detected in RAO-affected horses compared with the control animals. There was no significant difference between groups in terms of the erythrocyte lysate activities of CAT, GR, or TBARs or the plasma concentration of TBARs. CONCLUSION AND CLINICAL IMPORTANCE: Our results support the hypothesis that RAO in horses is associated with systemic oxidative stress. Future studies are needed to assess whether horses suffering from RAO can benefit from antioxidant supplementation.


Asunto(s)
Obstrucción de las Vías Aéreas/veterinaria , Enfermedades de los Caballos/sangre , Oxidación-Reducción , Obstrucción de las Vías Aéreas/sangre , Obstrucción de las Vías Aéreas/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/citología , Estudios de Casos y Controles , Catalasa/sangre , Femenino , Glutatión Peroxidasa/sangre , Glutatión Reductasa/sangre , Enfermedades de los Caballos/metabolismo , Caballos/sangre , Caballos/metabolismo , Masculino , Estrés Oxidativo , Estudios Prospectivos , Recurrencia , Superóxido Dismutasa/sangre
2.
Exp Lung Res ; 38(3): 135-46, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22394287

RESUMEN

In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling) assay, and immunohistochemistry for transforming growth factor ß1 (TGFß1), TGFß2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high-dose bleomycin. Increased TUNEL(+) bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFß1 and TGFß2 and accumulation of S100A4(+) fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling.


Asunto(s)
Obstrucción de las Vías Aéreas/inducido químicamente , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Bleomicina/toxicidad , Fibrosis Pulmonar Idiopática/inducido químicamente , Obstrucción de las Vías Aéreas/genética , Obstrucción de las Vías Aéreas/metabolismo , Obstrucción de las Vías Aéreas/patología , Remodelación de las Vías Aéreas (Respiratorias)/genética , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/toxicidad , Bleomicina/administración & dosificación , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína de Unión al Calcio S100A4 , Proteínas S100/genética , Proteínas S100/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta2/genética , Factor de Crecimiento Transformador beta2/metabolismo
3.
Shock ; 28(4): 477-83, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17558346

RESUMEN

Thermal injury results in reduced plasma levels of arginine (Arg). With reduced Arg availability, NOS produces superoxide instead of NO. We hypothesized that Arg supplementation after burn and smoke inhalation (B + S) injury would attenuate the acute insult to the lungs and, thus, protect pulmonary function. Seventeen Suffolk ewes (n = 17) were randomly divided into three groups: (1) sham injury group (n = 6), (2) B + S injury plus saline treatment (n = 6), and (3) B + S injury plus L-ARG infusion at 57 mg.kg(-1).h(-1) (n = 5). Burn and smoke inhalation injury was induced by standardized procedures, including a 40% area full thickness flame burn combined with 48 breaths of smoke from burning cottons. All animals were immediately resuscitated by Ringer solution and supported by mechanical ventilation for 48 h, during which various variables of pulmonary function were monitored. The results demonstrated that Arg treatment attenuated the decline of plasma Arg concentration after B + S injury. A higher plasma Arg concentration was associated with a less decline in Pao2/Fio2 ratio and a reduced extent of airway obstruction after B + S injury. Histopathological examinations also indicated a remarkably reduced histopathological scores associated with B + S injury. Nitrotyrosine stain in lung tissue was positive after B + S injury, but was significantly reduced in the group with Arg. Therefore, L-Arg supplementation improved gas exchange and pulmonary function in ovine after B + S injury via its, at least in part, effect on reduction of oxidative stress through the peroxynitrite pathway.


Asunto(s)
Arginina/farmacología , Quemaduras/tratamiento farmacológico , Pulmón/efectos de los fármacos , Lesión por Inhalación de Humo/tratamiento farmacológico , Obstrucción de las Vías Aéreas/metabolismo , Obstrucción de las Vías Aéreas/patología , Obstrucción de las Vías Aéreas/prevención & control , Animales , Arginina/sangre , Presión Sanguínea/efectos de los fármacos , Quemaduras/patología , Quemaduras/fisiopatología , Femenino , Hematócrito , Lesión Pulmonar , Nitratos/sangre , Nitritos/sangre , Distribución Aleatoria , Ovinos , Lesión por Inhalación de Humo/patología , Lesión por Inhalación de Humo/fisiopatología , Análisis de Supervivencia , Tirosina/análogos & derivados , Tirosina/metabolismo , Micción/efectos de los fármacos
4.
J Med Chem ; 41(13): 2268-77, 1998 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-9632360

RESUMEN

High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).


Asunto(s)
Antiasmáticos , Antiinflamatorios no Esteroideos , Dihidropiridinas , Eosinófilos/enzimología , Isoenzimas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazoles , Obstrucción de las Vías Aéreas/inmunología , Obstrucción de las Vías Aéreas/metabolismo , Obstrucción de las Vías Aéreas/patología , Obstrucción de las Vías Aéreas/prevención & control , Animales , Antiasmáticos/síntesis química , Antiasmáticos/química , Antiasmáticos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Células/efectos de los fármacos , Línea Celular , AMP Cíclico/metabolismo , Citocinas/metabolismo , Dihidropiridinas/síntesis química , Dihidropiridinas/química , Dihidropiridinas/farmacología , Evaluación Preclínica de Medicamentos , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Cobayas , Humanos , Técnicas In Vitro , Macaca fascicularis , Conformación Molecular , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Ovalbúmina/inmunología , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirrolidinonas/farmacología , Rolipram , Relación Estructura-Actividad
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