Hnin Hnin Aung

University of California, Davis, Davis, CA, United States

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Publications (19)73.9 Total impact

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    ABSTRACT: Neurovascular inflammation is associated with a number of neurological diseases including vascular dementia and Alzheimer's disease, which are increasingly important causes of morbidity and mortality around the world. Lipotoxicity is a metabolic disorder that results from accumulation of lipids, particularly fatty acids, in non-adipose tissue leading to cellular dysfunction, lipid droplet formation, and cell death.
    BMC Systems Biology 07/2014; 8(1):80. · 2.98 Impact Factor
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    ABSTRACT: Elevation of triglyceride-rich lipoproteins (TGRLs) contributes to the risk of atherosclerotic cardiovascular disease. Our work has shown that TGRL lipolysis products in high physiological to pathophysiological concentrations cause endothelial cell injury; however, the mechanisms remain to be delineated. We analyzed the transcriptional signaling networks in arterial endothelial cells exposed to TGRL lipolysis products. When human aortic endothelial cells in culture were exposed to TGRL lipolysis products, activating transcription factor 3 (ATF3) was identified as a principal response gene. Induction of ATF3 mRNA and protein was confirmed by qRT-PCR and Western blot. Immunofluorescence analysis showed that ATF3 accumulated in the nuclei of cells treated with lipolysis products. Nuclear expression of phosphorylated c-Jun NH2-terminal kinase (JNK), previously shown to be an initiator of the ATF3 signaling cascade, also was demonstrated. Small interfering RNA (siRNA)-mediated inhibition of ATF3 blocked lipolysis products-induced transcription of E-selectin and interleukin-8, but not interleukin-6 or nuclear factor-κB. c-Jun, a downstream protein in the JNK pathway, was phosphorylated, whereas expression of nuclear factor-κB-dependent JunB was downregulated. Additionally, JNK siRNA suppressed ATF3 and p-c-Jun protein expression, suggesting that JNK is upstream of the ATF3 signaling pathway. In vivo studies demonstrated that infusion of TGRL lipolysis products into wild-type mice induced nuclear ATF3 accumulation in carotid artery endothelium. ATF3(-/-) mice were resistant to vascular apoptosis precipitated by treatment with TGRL lipolysis products. Also peripheral blood monocytes isolated from postprandial humans had increased ATF3 expression as compared with fasting monocytes. This study demonstrates that TGRL lipolysis products activate ATF3-JNK transcription factor networks and induce endothelial cells inflammatory response.
    Arteriosclerosis Thrombosis and Vascular Biology 07/2013; · 6.34 Impact Factor
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    ABSTRACT: 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.
    Inhalation Toxicology 07/2012; 24(8):506-17. · 1.89 Impact Factor
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    ABSTRACT: Environmental particulate matter (PM) exposure has been correlated with pathogenesis of acute airway inflammatory disease such as asthma and COPD. PM size and concentration have been studied extensively, but the additional effects of particulate components such as biological material, transition metals, and polycyclic aromatic hydrocarbons could also impact initial disease pathogenesis. In this study, we compared urban ambient particulate matter (APM) collected from Fresno, California with wildfire (WF) particulate matter collected from Escalon, California on early transcriptional responses in human bronchial epithelial cells (HBE). Global gene expression profiling of APM treated HBE activated genes related to xenobiotic metabolism (CYP 1B1), endogenous ROS generation and response genes (DUOX1, SOD2, PTGS2) and pro-inflammatory responses associated with asthma or COPD such as IL-1α, IL-1β, IL-8, and CCL20. WF PM treatments also induced a pro-inflammatory gene response, but elicited a more robust xenobiotic metabolism and oxidative stress response. Inhibitor studies targeting endotoxin, ROS, and trace metals, found endotoxin inhibition had modest selective inhibition of inflammation while inhibition of hydrogen peroxide and transition metals had broad effects suggesting additional interactions with xenobiotic metabolism pathways. APM induced a greater inflammatory response while WF PM had more marked metabolism and ROS related responses.
    Toxicology in Vitro 06/2011; 25(8):1895-905. · 2.65 Impact Factor
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    ABSTRACT: Epidemiologic studies associate exposure to ambient particulate matter (APM) with increased cardiovascular mortality. Since both pulmonary inflammation and systemic circulation of ultrafine particles are hypothesized as initiating cardiovascular effects, we examined responses of potential target cells in vitro. Human aortic endothelial cells (HAEC) were exposed to 10 μg/ml fine and ultrafine APM collected in an urban setting in summer 2006 or winter 2007 in the San Joaquin Valley, California. RNA isolated after 3 h was analyzed with high-density oligonucleotide arrays. Summer APM treatment affected genes involved in xenobiotic and oxidoreductase activity, transcription factors, and inflammatory responses in HAEC, while winter APM had a robust xenobiotic but lesser inflammatory response. Real-time polymerase chain reaction analysis confirmed that particulate matter (PM)-treated HAEC increased mRNA levels of xenobiotic response enzymes CYP1A1, ALDH1A3, and TIPARP and cellular stress response transcription factor ATF3. Inflammatory response genes included E-selectin, PTGS2, CXCL-2 (MIP-2α), and CCL-2 (MCP-1). Multiplex protein assays showed secretion of IL-6 and MCP-1 by HAEC. Since induction of CYP1A1 is mediated through the ligand-activated aryl hydrocarbon receptor (AhR), we demonstrated APM induced AhR nuclear translocation by immunofluorescence and Western blotting and activation of the AhR response element using a luciferase reporter construct. Inhibitor studies suggest differential influences of polycyclic aromatic hydrocarbon signaling, ROS-mediated responses and endotoxin alter stress and proinflammatory endothelial cell responses. Our findings demonstrate gene responses correlated with current concepts that systemic inflammation drives cardiovascular effects of particulate air pollution. We also demonstrate a unique pattern of gene responses related to xenobiotic metabolism in PM-exposed HAEC.
    Physiological Genomics 06/2011; 43(15):917-29. · 2.81 Impact Factor
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    ABSTRACT: 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.
    European journal of medicinal chemistry 02/2011; 46(4):1348-55. · 3.27 Impact Factor
  • Kit Fai Ng, Hnin Hnin Aung, John C Rutledge
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    ABSTRACT: 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.
    Contributions to nephrology 01/2011; 170:165-71. · 1.49 Impact Factor
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    ABSTRACT: Diabetic nephropathy is an increasingly important cause of morbidity and mortality worldwide. A large body of evidence suggests that dyslipidemia has an important role in the progression of kidney disease in patients with diabetes. Lipids may induce renal injury by stimulating TGF-beta, thereby inducing the production of reactive oxygen species and causing damage to the glomeruli and glomerular glycocalyx. Findings from basic and clinical studies strongly suggest that excess amounts of a variety of lipoproteins and lipids worsens diabetes-associated microvascular and macrovascular disease, increases glomerular injury, increases tubulointerstitial fibrosis, and accelerates the progression of diabetic nephropathy. The increasing prevalence of obesity, type 2 diabetes mellitus, and diabetic nephropathy means that interventions that can interrupt the pathophysiological cascade of events induced by lipoproteins and lipids could enable major life and cost savings. This Review discusses the structural, cellular, and microscopic findings associated with diabetic nephropathy and the influence of lipoproteins, specifically triglyceride-rich lipoproteins (TGRLs), on the development and perpetuation of diabetic nephropathy. Some of the accepted and hypothesized mechanisms of renal injury relating to TGRLs are also described.
    Nature Reviews Nephrology 06/2010; 6(6):361-70. · 7.94 Impact Factor
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    ABSTRACT: Increasingly, evidence suggests a role for a systemic procoagulant state in the pathogenesis of cardiac dysfunction subsequent to inhalation of airborne particulate matter. The authors evaluated blood cell parameters and markers of platelet activation in mice exposed to concentrated ambient particulate matter (CAPs) from the San Joaquin Valley of California, a region with severe particulate matter (PM) pollution episodes. The authors exposed mice to an average of 88.5 microg/m(3) of CAPs in a size range less than 2.5 microm for 6 h/day for 5 days per week for 2 weeks. Platelets were analyzed by flow cytometry for relative size, shape, aggregation, fibrinogen binding, P-selectin, and lysosomal-associated membrane protein-1 (LAMP-1) expression. Serum cytokines were analyzed by bead-based immunologic assays. CAPs-exposed mice had elevations in macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFalpha), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF)-bb, and RANTES (regulated upon activation, normally T-expressed, and presumably secreted). Platelets were the only peripheral blood cells that were significantly elevated in number in CAPs-exposed mice. Flow cytometric analysis of unstimulated platelets from CAPs-exposed mice indicated size and shape changes, and platelets from CAPs-exposed animals had a 54% increase in fibrinogen binding indicative of platelet priming. Stimulation of platelets by thrombin resulted in up-regulation of LAMP-1 expression in CAPs-exposed animals and an increased microparticle population relative to control animals. These findings demonstrate a systemic proinflammatory and procoagulant response to inhalation of environmentally derived fine and ultrafine PM and suggests a role for platelet activation in the cardiovascular and respiratory effects of particulate air pollution.
    Inhalation Toxicology 03/2010; 22(4):267-76. · 1.89 Impact Factor
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    ABSTRACT: 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.
    The Journal of Immunology 11/2009; 183(10):6767-77. · 5.52 Impact Factor
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    ABSTRACT: Male C57BL/6 mice were fed diets supplemented with either β-carotene (BC) or lycopene (LY) that were formulated for human consumption. Four weeks of dietary supplementations results in plasma and lung carotenoid (CAR) concentrations that approximated the levels detected in humans. Bioactivity of the CARs was determined by assaying their effects on the activity of the lung transcriptome (~8,500 mRNAs). Both CARs activated the cytochrome P450 1A1 gene but only BC induced the retinol dehydrogenase gene. The contrasting effects of the two CARs on the lung transcriptome were further uncovered in mice exposed to cigarette smoke (CS) for 3days; only LY activated ~50 genes detected in the lungs of CS-exposed mice. These genes encoded inflammatory-immune proteins. Our data suggest that mice offer a viable in vivo model for studying bioactivities of dietary CARs and their modulatory effects on lung genomic expression in both health and after exposure to CS toxicants.
    Genes & Nutrition 01/2009; 4(1):23-39. · 3.33 Impact Factor
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    ABSTRACT: 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.
    AJP Heart and Circulatory Physiology 08/2008; 295(1):H237-44. · 4.01 Impact Factor
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    ABSTRACT: 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.
    Free Radical Research 05/2008; 42(4):387-96. · 3.28 Impact Factor
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    ABSTRACT: 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.
    Brain Research 04/2008; 1201:167-76. · 2.88 Impact Factor
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    ABSTRACT: While tomato product supplementation, containing antioxidant carotenoids, including lycopene, decreases oxidative stress, the role of purified lycopene as an antioxidant remains unclear. Thus, we tested the effects of different doses of purified lycopene supplementation on biomarkers of oxidative stress in healthy volunteers. This was a double-blind, randomized, placebo-controlled trial, examining the effects of 8-week supplementation of purified lycopene, on plasma lycopene levels, biomarkers of lipid peroxidation {LDL oxidizability, malondialdehyde & hydroxynonenals (MDA & HNE), urinary F(2)-isoprostanes}, and markers of DNA damage in urine and lymphocytes. Healthy adults (n = 77, age > or = 40 years), consumed a lycopene-restricted diet for 2 weeks, and were then randomized to receive 0, 6.5, 15, or 30 mg lycopene/day for 8 weeks, while on the lycopene-restricted diet. Blood and urine samples were collected at the beginning and end of Week 2 of lycopene-restricted diet, and at end of Week 10 of the study. Independent of the dose, plasma lycopene levels significantly increased in all lycopene supplemented groups versus placebo (p < 0.05). ANOVA revealed a significant decrease in DNA damage by the comet assay (p = 0.007), and a significant decrease in urinary 8-hydroxy deoxoguanosine (8-OHdG) at 8 weeks versus baseline (p = 0.0002), with 30 mg lycopene/day. No significant inter- or intra-group differences were noted for glucose, lipid profile, or other biomarkers of lipid peroxidation at any dose/time point. Thus, purified lycopene was bioavailable and was shown to decrease DNA oxidative damage and urinary 8-OHdG at the high dose.
    Journal of the American College of Nutrition 04/2008; 27(2):267-73. · 1.74 Impact Factor
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    ABSTRACT: Angiotensin II (angII) is known to promote atherosclerosis; however, the mechanisms involved are not fully understood. To determine whether angII stimulates proteoglycan production and LDL retention, LDL receptor-deficient mice were infused with angII (1,000 ng/kg/min) or saline via osmotic minipumps. To control for the hypertensive effect of angII, a parallel group received norepinephrine (NE; 5.6 mg/kg/day). Arterial lipid accumulation was evaluated by measuring the retention rate of LDL in isolated carotid arteries perfused ex vivo. Mice infused with angII had increased vascular content of biglycan and perlecan and retained twice as much LDL as saline- or NE-infused mice, although no group developed atherosclerosis at this time. To determine whether this increase in biglycan and perlecan content predisposed to atherosclerosis development, mice were infused with angII, saline, or NE for 4 weeks, then pumps were removed and mice received an atherogenic Western diet for another 6 weeks. Mice that had received angII infusions had 3-fold increased atherosclerosis compared with mice that had received saline or NE, and apolipoprotein B colocalized with both proteoglycans. Thus, one mechanism by which angII promotes atherosclerosis is increased proteoglycan synthesis and increased arterial LDL retention, which precedes and contributes to atherosclerosis development.
    The Journal of Lipid Research 04/2008; 49(3):521-30. · 4.39 Impact Factor
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    ABSTRACT: 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.
    Toxicology and Applied Pharmacology 07/2007; 222(2):227-34. · 3.98 Impact Factor
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    ABSTRACT: Dietary factors and environmental pollutants initiate signaling cascades that converge on AhR:Nrf2:NF-kappaB transcription factor (TF) networks and, in turn, affect the health of the organism through its effects on the expression of numerous genes. Reactive oxygen metabolites (ROMs) have been hypothesized to be common mediators in these pathways. alpha-Tocopherol (AT) is a potent, lipophilic, scavenger of ROMs in vitro and has been hypothesized to be a major chain-breaking anti-oxidant in lipoproteins and biological membranes in vivo. The lung offers a vital organ to test the various postulated actions of AT in vivo. Lung AT concentrations can be manipulated by several methods that include dietary and genetic techniques. In this study we have used mice with severe AT deficiency inflicted at birth by the deletion of AT transfer protein (ATTP) which is abundantly expressed in the liver and regulates systemic concentrations of AT. Mice and humans deficient in ATTP are AT deficient. Female ATTP-deficient (ATTP-KO) mice and their congenic ATTP normal (WT) mice fed a diet containing 35 IU AT/kg diet were used to test our hypothesis. The mice (n=5/group) were exposed to either air or cigarette smoke (CS, total suspended particles 60 mg/m(3), 6h/day), a source of ROM, for 3 or 10 days. Post-exposure lung tissue was dissected, RNA extracted from each lung and it was pooled group-wise and processed for GeneChip analysis (Affymetrix 430A 2.0). Differential analysis of the transcriptomes ( approximately 16,000 mRNAs) identified CS sensitive genes that were modulated by lung AT-concentration. CS activated AhR driven genes such as cyp1b1 whose induction was augmented in CS-exposed, AT-deficient lungs. However, CS-induced expression of some of the Nrf2 driven genes was not potentiated in the AT-deficient lungs. Largest clusters of CS-AT sensitive genes were lymphocyte and leukocyte specific genes. These gene-clusters included those encoding cytokines and immunoglobulins, which were repressed by CS and were modulated by lung AT concentrations. Our genome-wide analysis suggests reciprocal regulation of xenobiotic and immune response genes by CS and a modulatory role of lung AT concentration on the expression of these clusters of genes. These data suggest that in vivo network of AT, AT-metabolites and ATTP affects the transcription of genes driven by AhR, Nrf2 and NF-kappaB, transcription factor networks that transduce cellular metabolic signals and orchestrate adaptive responses of lungs to inhaled environmental pollutants.
    Molecular Aspects of Medicine 01/2007; 28(5-6):453-80. · 10.38 Impact Factor
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    ABSTRACT: 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.
    Toxicology Letters 02/2006; 160(2):127-34. · 3.15 Impact Factor