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      Asthmatics Exhibit Altered Oxylipin Profiles Compared to Healthy Individuals after Subway Air Exposure

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          Abstract

          Background

          Asthma is a chronic inflammatory lung disease that causes significant morbidity and mortality worldwide. Air pollutants such as particulate matter (PM) and oxidants are important factors in causing exacerbations in asthmatics, and the source and composition of pollutants greatly affects pathological implications.

          Objectives

          This randomized crossover study investigated responses of the respiratory system to Stockholm subway air in asthmatics and healthy individuals. Eicosanoids and other oxylipins were quantified in the distal lung to provide a measure of shifts in lipid mediators in association with exposure to subway air relative to ambient air.

          Methods

          Sixty-four oxylipins representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of bronchoalveolar lavage (BAL)-fluid. Validations through immunocytochemistry staining of BAL-cells were performed for 15-LOX-1, COX-1, COX-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Multivariate statistics were employed to interrogate acquired oxylipin and immunocytochemistry data in combination with patient clinical information.

          Results

          Asthmatics and healthy individuals exhibited divergent oxylipin profiles following exposure to ambient and subway air. Significant changes were observed in 8 metabolites of linoleic- and α-linolenic acid synthesized via the 15-LOX pathway, and of the COX product prostaglandin E 2 (PGE 2). Oxylipin levels were increased in healthy individuals following exposure to subway air, whereas asthmatics evidenced decreases or no change.

          Conclusions

          Several of the altered oxylipins have known or suspected bronchoprotective or anti-inflammatory effects, suggesting a possible reduced anti-inflammatory response in asthmatics following exposure to subway air. These observations may have ramifications for sensitive subpopulations in urban areas.

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          Most cited references57

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          Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma.

          Macrophage uptake of oxidized low-density lipoprotein (oxLDL) is thought to play a central role in foam cell formation and the pathogenesis of atherosclerosis. We demonstrate here that oxLDL activates PPARgamma-dependent transcription through a novel signaling pathway involving scavenger receptor-mediated particle uptake. Moreover, we identify two of the major oxidized lipid components of oxLDL, 9-HODE and 13-HODE, as endogenous activators and ligands of PPARgamma. Our data suggest that the biologic effects of oxLDL are coordinated by two sets of receptors, one on the cell surface, which binds and internalizes the particle, and one in the nucleus, which is transcriptionally activated by its component lipids. These results suggest that PPARgamma may be a key regulator of foam cell gene expression.
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            Acute effects of particulate air pollution on respiratory admissions: results from APHEA 2 project. Air Pollution and Health: a European Approach.

            The APHEA 2 project investigated short-term health effects of particles in eight European cities. In each city associations between particles with an aerodynamic diameter of less than 10 microm (PM(10)) and black smoke and daily counts of emergency hospital admissions for asthma (0-14 and 15-64 yr), chronic obstructive pulmonary disease (COPD), and all-respiratory disease (65+ yr) controlling for environmental factors and temporal patterns were investigated. Summary PM(10) effect estimates (percentage change in mean number of daily admissions per 10 microg/m(3) increase) were asthma (0-14 yr) 1.2% (95% CI: 0.2, 2.3), asthma (15-64 yr) 1.1% (0.3, 1.8), and COPD plus asthma and all-respiratory (65+ yr) 1.0% (0.4, 1.5) and 0.9% (0.6, 1.3). The combined estimates for Black Smoke tended to be smaller and less precisely estimated than for PM(10). Variability in the sizes of the PM(10) effect estimates between cities was also investigated. In the 65+ groups PM(10) estimates were positively associated with annual mean concentrations of ozone in the cities. For asthma admissions (0-14 yr) a number of city-specific factors, including smoking prevalence, explained some of their variability. This study confirms that particle concentrations in European cities are positively associated with increased numbers of admissions for respiratory diseases and that some of the variation in PM(10) effect estimates between cities can be explained by city characteristics.
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              Inflammation and immune regulation by 12/15-lipoxygenases.

              12/15-Lipoxygenases (12/15-LOX) are members of the LOX family, which are expressed in mammals by monocytes and macrophages following induction by the T helper type 2 cytokines, interleukins-4 and -13. They oxygenate free polyenoic fatty acids but also ester lipids and even complex lipid-protein assemblies such as biomembranes and lipoproteins. The primary oxidation products are either reduced by glutathione peroxidases to corresponding hydroxy derivatives or metabolized into secondary oxidized lipids including leukotrienes, lipoxins and hepoxilins, which act as lipid mediators. Examination of knockout and transgenic animals revealed important roles for 12/15-LOX in inflammatory diseases, including atherosclerosis, cancer, osteoporosis, angiotension II-dependent hypertension and diabetes. In vitro studies suggested 12/15-LOX products as coactivators of peroxisomal proliferator activating-receptors (PPAR), regulators of cytokine generation, and modulators of gene expression related to inflammation resolution. Despite much work in this area, the biochemical mechanisms by which 12/15-LOX regulates physiological and pathological immune cell function are not fully understood. This review will summarize the biochemistry and tissue expression of 12/15-LOX and will describe the current knowledge regarding its immunobiology and regulation of inflammation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                29 August 2011
                : 6
                : 8
                : e23864
                Affiliations
                [1 ]Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden
                [2 ]Division of Respiratory Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
                [3 ]Department of Entomology and Cancer Research Center, University of California Davis, Davis, California, United States of America
                [4 ]Department of Public Health and Clinical Medicine, Respiratory Medicine and Allergy, Umeå University, Umeå, Sweden
                [5 ]Division of Occupational and Environmental Medicine, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
                National Jewish Health, United States of America
                Author notes

                Conceived and designed the experiments: AK-N JG M. Svartengren B-ML ÅMW CEW. Performed the experiments: SLL BL MN. Analyzed the data: SLL BL BDH ÅMW CEW. Contributed reagents/materials/analysis tools: AK-N JG M. Svartengren JZH M. Sköld BDH B-ML AE ÅMW CEW. Wrote the paper: SLL BL ÅMW CEW. Patient screening and fiberbronchoscopy: M. Sköld AE.

                Article
                PONE-D-11-07277
                10.1371/journal.pone.0023864
                3163588
                21897859
                3224d4c7-5e82-4da2-938b-714c8a76372e
                Lundström et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 25 April 2011
                : 26 July 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Respiratory System
                Biochemistry
                Lipids
                Lipid Mediators
                Lipid Metabolism
                Metabolism
                Lipid Metabolism
                Systems Biology
                Chemistry
                Analytical Chemistry
                Chemical Analysis
                Quantitative Analysis
                Chromatography
                Liquid Chromatography
                Reversed-Phase Chromatography
                Environmental Chemistry
                Atmospheric Chemistry
                Air Quality
                Pollutants
                Mathematics
                Statistics
                Biostatistics
                Statistical Methods
                Medicine
                Clinical Research Design
                Case-Control Studies
                Statistical Methods
                Public Health
                Environmental Health
                Occupational and Industrial Health
                Pulmonology
                Asthma
                Environmental and Occupational Lung Diseases

                Uncategorized
                Uncategorized

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