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.
Linoleic acid-derived lipids in BALF may indicate the transition from healthy smoker to COPD in a female subphenotype http://ow.ly/XowqN
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Support statement: This study was funded by the Swedish Heart-Lung Foundation, Swedish Foundation for Strategic Research (SSF), VINNOVA (VINN-MER), EU FP6 Marie Curie, Karolinska Institutet, COST BM1201, VINNOVA (CiDAT), AFA Insurance, the King Oscar II Jubilee Foundation, the King Gustaf V and Queen Victoria's Freemasons Foundation, the Finnish Anti-Tuberculosis Association Foundation, the Swedish Research Council, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Centre for Allergy Research, and the Karolinska Institutet and AstraZeneca Joint Research Program in Translational Science. D.B. and M.S. received support from U-BIOPRED, the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Funding information for this manuscript has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received July 6, 2015.
- Accepted January 13, 2016.
- Copyright ©ERS 2016