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

Abstract

BackgroundAsthma 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.ObjectivesThis 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.MethodsSixty-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.ResultsAsthmatics 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 E2 (PGE2). Oxylipin levels were increased in healthy individuals following exposure to subway air, whereas asthmatics evidenced decreases or no change.ConclusionsSeveral 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.

Lipid Mediator Profiling in Pulmonary Disease

“…In particular, the 12/15-LOX derived 9-and 13-hydroxyoctadecatrienoic acid (HOTE) and their corresponding keto-trienes, oxooctadecatrienoic acids (KOTEs) could be of interest. We observed that the levels of 9-and 13-HOTE in BAL-fluid were significantly increased in healthy individuals compared to mild asthmatics following exposure to subway air, suggesting that these compounds may potentially play a role in the inflammatory response and/or subsequent resolution, and that this response is distinct in healthy individuals versus asthmatics (unpublished data [251]). …”

“…However, these compounds warrant analysis because alterations may occur that are due to active biological functions or effects caused by alterations in the 13-and/or 9-HODE precursors. We have for instance observed elevated levels of these compounds in BAL-fluid from healthy individuals following subway air exposure that correlate with shifts in HODE and KODE levels (unpublished data [251]). …”

Lipid mediator profiles differ between lung compartments in asthmatic and healthy humans

“…The role of lipid mediators in the pathogenesis of asthma has been extensively studied [4][5][6][7][8][9][10]. Lipid mediators are included in a group of compounds broadly called oxylipins, a term that includes eicosanoids derived from arachidonic acid as well as compounds derived from other related v-3 and v-6 fatty acids.…”

“…Oxylipin profiles have previously been investigated in large-volume bronchoalveolar lavage fluid (BALF), mainly reflecting profiles in the peripheral lung [7,8], but not in small-volume bronchial wash samples, which better reflect the proximal airways. To test the hypothesis that asthmatics, due to their underlying asthmatic inflammation, have altered oxylipin profiles in both distal (BALF) and proximal (bronchial wash) regions of the lung compared with healthy individuals, bronchoscopies were performed.…”

Application of ’omics technologies to biomarker discovery in inflammatory lung diseases

“…DHA and EPA), most of which have as of yet undetermined biological roles. The use of LC with low particle size and MRM mass spectrometry has recently made it possible to quantify hundreds of these molecules simultaneously [98,99], providing new insights into their role in respiratory disease [80]. A particular advantage of analysing eicosanoids is that measurement of indicative urinary metabolites is usually a sensitive approach to monitoring pulmonary biosynthesis.…”