title: Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD.
abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality; however, the role of inflammatory mediators in its pathobiology remains unclear. The aim of this study was to investigate the influence of gender in COPD on lipid mediator levels.Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers and COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage I-II/A-B) (n=114). 94 lipid mediators derived from the cytochrome-P450, lipoxygenase, and cyclooxygenase pathways were analysed by liquid chromatography-mass spectrometry.Multivariate modelling identified a 9-lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6×10(-6)). No differences were observed for the corresponding male population (p=1.0). These findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxin-diols). These species correlated with lung function (r=0.87; p=0.0009) and mRNA levels of enzymes putatively involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance (r=0.72; p=0.028).These findings suggest a mechanism by which goblet cell-associated cytochrome-P450 and sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype.
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Balgoma
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Sjödin
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stuart
authors.initials: S
authors.lastname: Snowden
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Reza
authors.initials: R
authors.lastname: Karimi
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bettina
authors.initials: B
authors.lastname: Levänen
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Respiratory Unit, Medical Research Center Oulu, Oulu University/UniversityHospital, Medicine and Clinical Research, Pulmonary Division, University of Eastern Finland & Division of Respiratory Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Heta
authors.initials: H
authors.lastname: Merikallio
authors.affiliation: Respiratory Unit, Medical Research Center Oulu, Oulu University/UniversityHospital, Medicine and Clinical Research, Pulmonary Division, University of Eastern Finland & Division of Respiratory Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Kaarteenaho
authors.affiliation: Lung and Airway Research Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Palmberg
authors.affiliation: Lung and Airway Research Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Larsson
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine and Lung Biology Center, University of California San Francisco, San Francisco, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.affiliation: Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Dahlén
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C Magnus
authors.initials: CM
authors.lastname: Sköld
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Both authors contributed equally.
authors.forename: Åsa M
authors.initials: ÅM
authors.lastname: Wheelock
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Both authors contributed equally craig.wheelock@ki.se.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D001992:Bronchoalveolar Lavage Fluid; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D019787:Linoleic Acid / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D058945:Lipoxygenases / Q000737:chemistry; D008297:Male; D008593:Menopause; D008875:Middle Aged; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology*; D012129:Respiratory Function Tests; D012737:Sex Factors; D012907:Smoking
chemical_list: D008055:Lipids; D003577:Cytochrome P-450 Enzyme System; D019787:Linoleic Acid; D058945:Lipoxygenases; D011451:Prostaglandin-Endoperoxide Synthases