Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
1.
J Lipid Res ; 57(6): 955-68, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27087439

RESUMEN

Dysfunction of the cerebrovasculature plays an important role in vascular cognitive impairment (VCI). Lipotoxic injury of the systemic endothelium in response to hydrolyzed triglyceride-rich lipoproteins (TGRLs; TGRL lipolysis products) or a high-fat Western diet (WD) suggests similar mechanisms may be present in brain microvascular endothelium. We investigated the hypothesis that TGRL lipolysis products cause lipotoxic injury to brain microvascular endothelium by generating increased mitochondrial superoxide radical generation, upregulation of activating transcription factor 3 (ATF3)-dependent inflammatory pathways, and activation of cellular oxidative stress and apoptotic pathways. Human brain microvascular endothelial cells were treated with human TGRL lipolysis products that induced intracellular lipid droplet formation, mitochondrial superoxide generation, ATF3-dependent transcription of proinflammatory, stress response, and oxidative stress genes, as well as activation of proapoptotic cascades. Male apoE knockout mice were fed a high-fat/high-cholesterol WD for 2 months, and brain microvessels were isolated by laser capture microdissection. ATF3 gene transcription was elevated 8-fold in the hippocampus and cerebellar brain region of the WD-fed animals compared with chow-fed control animals. The microvascular injury phenotypes observed in vitro and in vivo were similar. ATF3 plays an important role in mediating brain microvascular responses to acute and chronic lipotoxic injury and may be an important preventative and therapeutic target for endothelial dysfunction in VCI.


Asunto(s)
Factor de Transcripción Activador 3/genética , Traumatismos Cerebrovasculares/genética , Disfunción Cognitiva/genética , Inflamación/genética , Lipoproteínas/metabolismo , Triglicéridos/metabolismo , Factor de Transcripción Activador 3/biosíntesis , Animales , Cerebelo/irrigación sanguínea , Cerebelo/metabolismo , Cerebelo/patología , Traumatismos Cerebrovasculares/metabolismo , Traumatismos Cerebrovasculares/fisiopatología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Dieta Alta en Grasa/efectos adversos , Dieta Occidental/efectos adversos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Hipocampo/irrigación sanguínea , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inflamación/metabolismo , Inflamación/fisiopatología , Ratones , Estrés Oxidativo/genética , Transducción de Señal/genética
2.
Magn Reson Med ; 76(4): 1246-51, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26485349

RESUMEN

PURPOSE: Previous studies indicated hyperlipidemia may be a risk factor for Alzheimer's disease, but the contributions of postprandial triglyceride-rich lipoprotein (TGRL) are not known. In this study, changes in blood-brain barrier diffusional transport following exposure to human TGRL lipolysis products were studied using MRI in a rat model. METHODS: Male Sprague-Dawley rats (∼180-250 g) received an i.v. injection of lipoprotein lipase (LpL)-hydrolyzed TGRL (n = 8, plasma concentration ≈ 150 mg human TGRL/dL). Controls received i.v. injection of either saline (n = 6) or LpL only (n = 6). The (1) H longitudinal relaxation rate R1 = 1/T1 was measured over 18 min using a rapid-acquired refocus-echo (RARE) sequence after each of three injections of the contrast agent Gd-DTPA. Patlak plots were generated for each pixel yielding blood-to-brain transfer coefficients, Ki , chosen for best fit to impermeable, uni-directional influx or bi-directional flux models using the F-test. RESULTS: Analysis from a 2-mm slice, 2-mm rostral to the bregma showed a 275% increase of mean Ki during the first 20 min after infusion of human TGRL lipolysis product that differed significantly compared with saline and LpL controls. This difference disappeared by 40 min mark. CONCLUSION: These results suggest human TGRL lipolysis products can lead to a transient increase in rat BBB permeability. Magn Reson Med 76:1246-1251, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Lipoproteínas/administración & dosificación , Angiografía por Resonancia Magnética/métodos , Triglicéridos/administración & dosificación , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Inyecciones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley
3.
Inhal Toxicol ; 24(8): 506-17, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22746400

RESUMEN

Increasing evidence suggests a role for a systemic pro-coagulant state in the pathogenesis of cardiac dysfunction subsequent to inhalation of airborne particulate matter (PM). We evaluated platelet activation, systemic cytokines and pulmonary gene expression in mice exposed to concentrated ambient particulate matter (CAPs) in the summer of 2008 (S08) and winter of 2009 (W09) from the San Joaquin Valley of California, a region with severe PM pollution episodes. Additionally, we characterized the PM from both exposures including organic compounds, metals, and polycyclic aromatic hydrocarbons. Mice were exposed to an average of 39.01 µg/m(3) of CAPs in the winter and 21.7 µg/m3 CAPs in the summer, in a size range less than 2.5 µm for 6 h/day for 5 days per week for 2 weeks. Platelets were analyzed by flow cytometry for relative size, shape, CD41, P-selectin and lysosomal associated membrane protein-1 (LAMP-1) expression. Platelets from W09 CAPs-exposed animals had a greater response to thrombin stimulation than platelets from S08 CAPs-exposed animals. Serum cytokines were analyzed by bead based immunologic assays. W09 CAPs-exposed mice had elevations in IL-2, MIP-1α, and TNFα. Laser capture microdissection (LCM) of pulmonary vasculature, parenchyma and airways all showed increases in CYP1a1 gene expression. Pulmonary vasculature showed increased expression of ICAM-1 and Nox-2. Our findings demonstrate that W09 CAPs exposure generated a greater systemic pro-inflammatory and pro-coagulant response to inhalation of environmentally derived fine and ultrafine PM. Changes in platelet responsiveness to agonists, seen in both exposures, strongly suggests a role for platelet activation in the cardiovascular and respiratory effects of particulate air pollution.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Citocinas/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Material Particulado/toxicidad , Activación Plaquetaria/efectos de los fármacos , Estaciones del Año , Animales , California , Monitoreo del Ambiente , Perfilación de la Expresión Génica , Exposición por Inhalación , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de la Partícula
4.
J Immunol ; 183(10): 6767-77, 2009 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-19846878

RESUMEN

Macrophages are activated by IFN-gamma, a proinflammatory and proatherogenic cytokine that mediates its downstream effects primarily through STAT1. IFN-gamma signaling induces phosphorylation of two STAT1 residues: Tyr(701) (Y701), which facilitates dimerization, nuclear translocation, and DNA binding; and Ser(727) (S727), which enables maximal STAT1 transcription activity. Immunosuppressive molecules such as adenosine in the cellular microenvironment can reduce macrophage inflammatory and atherogenic functions through receptor-mediated signaling pathways. We hypothesized that adenosine achieves these protective effects by interrupting IFN-gamma signaling in activated macrophages. This investigation demonstrates that adding adenosine to IFN-gamma-stimulated murine RAW 264.7 and human THP-1 macrophages results in unique modulation of STAT1 serine and tyrosine phosphorylation events. We show that adenosine inhibits IFN-gamma-induced STAT1 S727 phosphorylation by >30% and phosphoserine-mediated transcriptional activity by 58% but has no effect on phosphorylation of Y701 or receptor-associated JAK tyrosine kinases. Inhibition of the adenosine A(3) receptor with a subtype-specific antagonist (MRS 1191 in RAW 264.7 cells and MRS 1220 in THP-1 cells) reverses this adenosine suppressive effect on STAT1 phosphoserine status by 25-50%. Further, RAW 264.7 A(3) receptor stimulation with Cl-IB-MECA reduces IFN-gamma-induced STAT1 transcriptional activity by 45% and STAT1-dependent gene expression by up to 80%. These data suggest that A(3) receptor signaling is key to adenosine-mediated STAT1 modulation and anti-inflammatory action in IFN-gamma-activated mouse and human macrophages. Because STAT1 plays a key role in IFN-gamma-induced inflammation and foam cell transformation, a better understanding of the mechanisms underlying STAT1 deactivation by adenosine may improve preventative and therapeutic approaches to vascular disease.


Asunto(s)
Adenosina/farmacología , Analgésicos/farmacología , Macrófagos/inmunología , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT1/inmunología , Antagonistas del Receptor de Adenosina A3 , Animales , Línea Celular , Dihidropiridinas/farmacología , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/farmacología , Quinasas Janus/inmunología , Quinasas Janus/metabolismo , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Análisis por Micromatrices , Fosforilación/inmunología , Quinazolinas/farmacología , Receptor de Adenosina A3/inmunología , Receptor de Adenosina A3/metabolismo , Factor de Transcripción STAT1/antagonistas & inhibidores , Factor de Transcripción STAT1/metabolismo , Serina/inmunología , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/inmunología , Triazoles/farmacología , Tirosina/inmunología , Tirosina/metabolismo
5.
Brain Res ; 1201: 167-76, 2008 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-18299118

RESUMEN

Ataxia with vitamin E deficiency is caused by mutations in alpha-tocopherol transfer protein (alpha-TTP) gene and it can be experimentally generated in mice by alpha-TTP gene inactivation (alpha-TTP-KO). This study compared alpha-tocopherol (alpha-T) concentrations of five brain regions and of four peripheral organs from 5 months old, male and female, wild-type (WT) and alpha-TTP-KO mice. All brain regions of female WT mice contained significantly higher alpha-T than those from WT males. alpha-T concentration in the cerebellum was significantly lower than that in other brain regions of WT mice. These sex and regional differences in brain alpha-T concentrations do not appear to be determined by alpha-TTP expression which was undetectable in all brain regions. All the brain regions of alpha-TTP-KO mice were severely depleted in alpha-T. The concentration of another endogenous antioxidant, total glutathione, was unaffected by gender but was decreased slightly but significantly in most brain regions of alpha-TTP-KO mice. The results show that both gender and the hepatic alpha-TTP, but not brain alpha-TTP gene expression are important in determining alpha-T concentrations within the brain. Interestingly, functional abnormality (ataxia) develops only very late in alpha-TTP-KO mice in spite of the severe alpha-tocopherol deficiency in the brain starting at an early age.


Asunto(s)
Proteínas Portadoras/genética , Sistema Nervioso Central/metabolismo , alfa-Tocoferol/metabolismo , Animales , Ataxia/genética , Ataxia/metabolismo , Ataxia/fisiopatología , Mapeo Encefálico , Sistema Nervioso Central/anatomía & histología , Sistema Nervioso Central/fisiopatología , Cerebelo/metabolismo , Cerebelo/fisiopatología , Regulación hacia Abajo/genética , Femenino , Alimentos Formulados , Glutatión/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Caracteres Sexuales
6.
Free Radic Biol Med ; 120: 303-310, 2018 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-29551638

RESUMEN

Proteases and reactive oxygen species (ROS) have long been implicated in playing key roles in host tissue injury at sites of inflammation dominated by macrophage activations and/or neutrophil infiltrations. Imbalances between proteases/antiproteases and ROS/antioxidants are recognized to contribute to amplification of inflammatory-based host tissue injury. This has been especially well-documented in such respiratory tract diseases as chronic obstructive pulmonary disease, cystic fibrosis, and acute respiratory distress syndrome. Inflammation-related protease/ROS disequilibria are further confounded by recognition that proteases can increase ROS by several different mechanisms and that ROS can inactivate proteases. The major human antiprotease, alpha-1 antitrypsin (AAT), is dramatically inactivated by ROS. AAT deficiency is the most prevalent genetic predisposing factor leading to emphysema, a condition treated by replacement infusions of plasma-derived AAT (hAAT) at a cost of up to $200,000 per year per patient. An updated method for production of a plant-made recombinant AAT (prAAT) engineered for enhanced oxidation resistance compared to hAAT is presented. Plant-made recombinant AAT shows comparable antiprotease activity to hAAT, and retains full activity under oxidative conditions that would deactivate hAAT. Additionally, we show that prAAT has similar effectiveness in preventing neutrophil elastase-induced cell death in an in vitro human bronchial epithelial cell culture model. We conclude that prAAT is potentially a "biobetter" AAT product that could be made available to individuals with a wide spectrum of inflammatory disorders characterized by overly aggressive neutrophilic infiltrations.


Asunto(s)
Nicotiana , Ingeniería de Proteínas/métodos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , alfa 1-Antitripsina , Humanos , Oxidación-Reducción , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
7.
Toxicol Lett ; 160(2): 127-34, 2006 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-16129572

RESUMEN

Cutaneous tissues are frequently exposed to prooxidative environments, including UV radiation and air pollutants. Among the latter, ozone (O(3)) is of particular concern because of its high and dominating presence in photochemical smog. It is well known that O(3) depletes small molecular weight antioxidants, oxidizes proteins, induces lipid peroxidation and activates cellular responses in various tissues. Using an in vivo model (SKH-1 hairless mice), the interaction between O(3) exposure (0.5ppmx6h/day) and age was examined in relation to cutaneous wound healing. Compared to younger (8 weeks) mice, older (18 months) mice exposed to O(3) (day 0 to day 9 after wounding) exhibited delayed wound closure, increased lipid peroxidation (measured as 4-HNE protein adducts) and protein oxidation (measured as carbonyls concentration) and decreased levels of P-IkappaBalpha and TGFbeta protein. These findings support the hypothesis that oxidant pollutant exposure and age interact so as to disrupt normal wound healing processes.


Asunto(s)
Envejecimiento/fisiología , Ozono/toxicidad , Piel/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Aldehídos/análisis , Aldehídos/química , Animales , Reactivos de Enlaces Cruzados/análisis , Reactivos de Enlaces Cruzados/química , Femenino , Proteínas I-kappa B/biosíntesis , Peroxidación de Lípido/efectos de los fármacos , Ratones , Ratones Pelados , Modelos Animales , Inhibidor NF-kappaB alfa , Unión Proteica , Proteínas/análisis , Proteínas/química , Piel/lesiones , Piel/metabolismo , Factor de Crecimiento Transformador beta/biosíntesis
8.
Redox Rep ; 9(5): 255-61, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15606978

RESUMEN

A study of the involvement of free oxygen radicals in trapping and digestion of insects by carnivorous plants was the main goal of the present investigation. We showed that the generation of oxygen free radicals by pitcher fluid of Nepenthes is the first step of the digestion process, as seen by EPR spin trapping assay and gel-electrophoresis. The EPR spectrum of N. gracilis fluid in the presence of DMPO spin trap showed the superposition of the hydroxyl radical spin adduct signal and of the ascorbyl radical signal. Catalase addition decreased the generation of hydroxyl radicals showing that hydroxyl radicals are generated from hydrogen peroxide, which can be derived from superoxide radicals. Gel-electrophoresis data showed that myosin, an abundant protein component of insects, can be rapidly broken down by free radicals and protease inhibitors do not inhibit this process. Addition of myoglobin to the pitcher plant fluid decreased the concentration of detectable radicals. Based on these observations, we conclude that oxygen free radicals produced by the pitcher plant aid in the digestion of the insect prey.


Asunto(s)
Radicales Libres , Magnoliopsida/fisiología , Oxígeno/metabolismo , Proteínas/metabolismo , Animales , Fenómenos Biomecánicos , Catalasa/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Glándulas Exocrinas/metabolismo , Peróxido de Hidrógeno/farmacología , Insectos , Magnoliopsida/anatomía & histología , Modelos Biológicos , Músculos/metabolismo , Mioglobina/química , Componentes Aéreos de las Plantas/fisiología , Detección de Spin , Superóxidos/química , Factores de Tiempo
9.
Contrib Nephrol ; 170: 165-171, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21659769

RESUMEN

Dyslipidemia is implicated as a risk factor for the development of atherosclerosis. Specifically triglyceride-rich lipoproteins and their lipolysis products are shown to be proinflammatory and proapoptosis in both in vivo and in vitro studies with endothelium. However, the role of triglyceride-rich lipoproteins in the progression of kidney diseases is not clear. Epidemiology studies demonstrated a correlation between renal disease and blood lipids. Recent evidence suggests that the mechanism may involve cellular uptake of lipid and de novo lipogenesis. Further studies are needed to establish the relevance of these mechanistic studies in human pathophysiology.


Asunto(s)
Enfermedades Renales/etiología , Lipoproteínas/fisiología , Triglicéridos/fisiología , Animales , Modelos Animales de Enfermedad , Humanos , Hipertrigliceridemia/complicaciones , Ratones
10.
Eur J Med Chem ; 46(4): 1348-55, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21333407

RESUMEN

A series of 2-aminofluorenes N-alkylated with nitroxides or their precursors were synthesized. The new compounds were tested on hydroxyl radical and peroxyl radical scavenging ability and inflammatory assay on the endothelial brain cells. In agreement with ROS scavenging ability the same compound 7-bromo-N -[(1-Oxyl-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine-4yl)methyl]-9H-fluoren-2-amine (3b) and its hydroxylamine salt (3b/OH/HCl) showed the anti-inflammatory property on the endothelial brain cells.


Asunto(s)
Amiloide/química , Fluorenos/síntesis química , Fluorenos/farmacología , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/farmacología , Óxidos de Nitrógeno/química , Multimerización de Proteína/efectos de los fármacos , Línea Celular , Espectroscopía de Resonancia por Spin del Electrón , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Fluorenos/química , Depuradores de Radicales Libres/química , Humanos , Radical Hidroxilo/química , Lipólisis/efectos de los fármacos , Peróxidos/química , Estructura Secundaria de Proteína
11.
Am J Physiol Heart Circ Physiol ; 295(1): H237-44, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18487440

RESUMEN

Triglyceride-rich lipoprotein (TGRL) lipolysis may provide a proinflammatory stimulus to endothelium. Detergent-resistant plasma membrane microdomains (lipid rafts) have a number of functions in endothelial cell inflammation. The mechanisms of TGRL lipolysis-induced endothelial cell injury were investigated by examining endothelial cell lipid rafts and production of reactive oxygen species (ROS). Lipid raft microdomains in human aortic endothelial cells were visualized by confocal microscopy with fluorescein isothiocyanate-labeled cholera toxin B as a lipid raft marker. Incubation of Atto565-labeled TGRL with lipid raft-labeled endothelial cells showed that TGRL colocalized with the lipid rafts, TGRL lipolysis caused clustering and aggregation of lipid rafts, and colocalization of TGRL remnant particles on the endothelial cells aggregated lipid rafts. Furthermore, TGRL lipolysis caused translocation of low-density lipoprotein receptor-related protein, endothelial nitric oxide synthase, and caveolin-1 from raft regions to nonraft regions of the membrane 3 h after treatment with TGRL lipolysis. TGRL lipolysis significantly increased the production of ROS in endothelial cells, and both NADPH oxidase and cytochrome P-450 inhibitors reduced production of ROS. Our studies suggest that alteration of lipid raft morphology and composition and ROS production could contribute to TGRL lipolysis-mediated endothelial cell injury.


Asunto(s)
Células Endoteliales/metabolismo , Lipólisis , Lipoproteína Lipasa/metabolismo , Lipoproteínas/metabolismo , Microdominios de Membrana/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Triglicéridos/metabolismo , Caveolina 1/metabolismo , Células Cultivadas , Toxina del Cólera , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Células Endoteliales/patología , Inhibidores Enzimáticos/farmacología , Fluoresceína-5-Isotiocianato , Colorantes Fluorescentes , Humanos , Hipertrigliceridemia/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Microdominios de Membrana/patología , Microscopía Confocal , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Transporte de Proteínas
12.
Free Radic Res ; 42(4): 387-96, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18404538

RESUMEN

Allergic asthma is a complex immunologically mediated disease associated with increased oxidative stress and altered antioxidant defenses. It was hypothesized that alpha-tocopherol (alpha-T) decreases oxidative stress and therefore its absence may influence allergic inflammatory process, a pathobiology known to be accompanied by oxidative stress. Therefore, selected parameters of allergic asthma sensitization and inflammation were evaluated following ovalbumin sensitization and re-challenge of alpha-T transfer protein (TTP) knock-out mice (TTP(-/-)) that have greatly reduced lung alpha-T levels (e.g.<5%) compared to their litter mate controls (TTP(+/+)). Results showed that severe alpha-T deficiency result in a blunted lung expression of IL-5 mRNA and IL-5 protein and plasma IgE levels compared with TTP(+/+) mice following immune sensitization and rechallenge, although lung lavage eosinophil levels were comparable in both genomic strains. It is concluded that the initial stimulation of immune responses by the TTP(-/-) mice were generally blunted compared to the TTP(+/+) mice, thus diminishing some aspects of subsequent allergic inflammatory processes.


Asunto(s)
Asma/metabolismo , Asma/patología , Regulación de la Expresión Génica , Deficiencia de Vitamina E/complicaciones , Animales , Asma/genética , Hiperreactividad Bronquial/metabolismo , Proteínas Portadoras/genética , Eosinófilos/metabolismo , Inmunoglobulina E/sangre , Inflamación , Interleucina-5/metabolismo , Pulmón/patología , Ratones , Ratones Noqueados , Ovalbúmina/química , Estrés Oxidativo
13.
Toxicol Appl Pharmacol ; 222(2): 227-34, 2007 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-17602719

RESUMEN

Despite the physiological importance of alpha-tocopherol (AT), the molecular mechanisms involved in maintaining cellular and tissue tocopherol levels remain to be fully characterized. Scavenger receptor B1 (SRB1), one of a large family of scavenger receptors, has been shown to facilitate AT transfer from HDL to peripheral tissues via apo A-1-mediated processes and to be important in the delivery of AT to the lung cells. In the present studies the effects of age and two environmental oxidants ozone (O(3)) (0.25 ppm 6 h/day) and cigarette smoke (CS) (60 mg/m(3) 6 h/day) for 4 days on selected aspects of AT transport in murine lung tissues were assessed. While AT levels were 25% higher (p<0.05) and 15% lower (p<0.05) in plasma and lung tissue, respectively, in aged versus young mice, acute environmental exposure to O(3) or CS at the doses used had no effect. Gene expression levels, determined by RT-PCR of AT transport protein (ATTP), SRB1, CD36, ATP binding cassette 3 (ABCA3) and ABCA1 and protein levels, determined by Western blots for SRB1, ATTP and ABCA1 were assessed. Aged mouse lung showed a lower levels of ATTP, ABCA3 and SRB1 and a higher level CD36 and ABCA1. Acute exposure to either O(3) or CS induced declines in ATTP and SRB1 in both aged and young mice lung. CD36 increased in both young and aged mice lung upon exposure to O(3) and CS. These findings suggest that both age and environmental oxidant exposure affect pathways related to lung AT homeostasis and do so in a way that favors declines in lung AT. However, given the approach taken, the effects cannot be traced to changes in these pathways or AT content in any specific lung associated cell type and thus highlight the need for further follow-up studies looking at specific lung associated cell types.


Asunto(s)
Envejecimiento , Pulmón/efectos de los fármacos , Oxidantes Fotoquímicos/farmacología , Vitamina E/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Western Blotting , Antígenos CD36/genética , Antígenos CD36/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Lipoproteínas/sangre , Pulmón/metabolismo , Ratones , Ratones Pelados , Oxidantes Fotoquímicos/química , Ozono/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores Depuradores de Clase B/genética , Receptores Depuradores de Clase B/metabolismo , Humo , Nicotiana/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA