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- Balgoma, D, et al.
(author)
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Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD
- 2016
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 47:6, s. 1645-1656
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Journal article (peer-reviewed)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.
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- Bood, JR, et al.
(author)
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Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects
- 2015
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In: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 119:3, s. 272-279
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Journal article (peer-reviewed)abstract
- Exercise-induced bronchoconstriction displays refractoriness manifested as a decreased response to repeated exercise challenge within hours. The refractoriness may be attenuated by inhibition of the biosynthesis of prostaglandins (PG). The aim of the study was to determine which PGs and other lipid mediators are excreted during the refractory period. First, 16 subjects with mild stable asthma performed two repeated 4-min challenges with eucapnic voluntary hyperpnea (EVH) 1 and 3 h apart. There was a similar degree of refractoriness in both protocols (∼15% protection). The 1-h interval was too short to study mediator excretion because the urinary levels did not return to baseline before the second challenge. With the 3-h protocol, there was increased urinary excretion of cysteinyl-leukotrienes and metabolites of the mast cell product PGD2after both challenges. Next, another eight subjects performed two 6-min challenges with EVH 3 h apart, which produced a greater bronchoconstrictor response than the 4-min protocol (30.0 ± 5.4 vs. 17.7 ± 1.5%; P = 0.0029) and a greater degree of refractoriness (∼30%). Analysis by ultra-performance liquid chromatography triple quadrupole mass spectrometry confirmed excretion of the bronchoconstrictor cysteinyl-leukotrienes and PGD2during both challenges. In addition, there was increased excretion of the bronchoprotective PGE2, and also of the main metabolite of PGI2. This is the first report of excretion of PGE2and PGI2during the refractory period to EVH challenge, suggesting that they may mediate the refractoriness. Maintained excretion of PGD2and leukotriene E4following the repeat challenge argues against mast cell mediator depletion as the mechanism of refractoriness.
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