Exploration of the Sphingolipid Metabolite, Sphingosine-1-phosphate and Sphingosine, as Novel Biomarkers for Aspirin-exacerbated Respiratory Disease.

Hoang Kim Tu Trinh,Kumsun Cho,Ga-Young Ban,Seung-Hyun Kim,Joo-Youn Cho,Hyun-Ju Yoo,Su-Chin Kim,Hae-Sim Park,Su-Jung Kim

doi:10.1038/srep36599

Abstract

Sphingolipid (SL) metabolites have been suggested to be important inflammatory mediators in airway inflammation and asthma. However, little is known about SL metabolites in aspirin-exacerbated respiratory disease (AERD). We aimed to explore the potential AERD biomarkers by conducting lipidomics targeting SL metabolites. The levels of SL metabolites in serum and urine samples from 45 AERD patients and 45 aspirin-tolerant asthma (ATA) patients were quantified through mass spectrometry. During the lysine-aspirin bronchoprovocation test (ASA-BPT), the levels of serum sphingomyelin (SM) were significantly decreased in AERD (P < 0.05) but not in ATA. The serum SM levels were positively correlated with airway responsiveness to methacholine. At the basal status before the ASA-BPT, the levels of serum sphingosine-1-phosphate (S1P) and urine sphingosine were significantly higher in the AERD patients compared with that of ATA patients (P < 0.001) and were positively correlated with a greater decrease in FEV1 (%) values following the ASA-BPT test (P < 0.001 for each), and with serum periostin level (P < 0.05 for each). This study is the first to evaluate serum S1P and urine sphingosine as potential biomarkers of AERD as well as to examine the metabolic disturbance of SL in AERD patients.

Highlights

Previous studies linking asthma to SL have focused on airway inflammation and allergic responses related to S1P
aspirin-exacerbated respiratory disease (AERD), termed “aspirin sensitive asthma”, is a syndrome triggered by ingesting non-steroidal anti-inflammatory drugs (NSAIDs) that is associated with an increased production of cysteinyl leukotrienes (CysLTs)
We examined the association of S1P and sphingosine with HLA-DBP1*0301 and cysteinyl leukotriene receptor type 1 (CYSLTR1)-634C >T polymorphism in 89 asthmatic patients comprising of patients with AERD and with ATA (Table E3)

Summary

Introduction

Previous studies linking asthma to SL have focused on airway inflammation and allergic responses related to S1P. Asthma is a common and clinically heterogeneous disorder that is characterized by intermittent airflow obstruction, airway hyperreactivity, chronic airway inflammation, and increased mucus production[13]. Given that SLs, S1P, could contribute to the pathogenesis of airway inflammation and asthma, we aimed to investigate the SL profiles of AERD patients and its association with clinical outcomes. The serum and urine samples from AERD and ATA patients were analyzed for SL metabolites using lipid chromatograpy- mass spectrometry. We searched for a correlation between SL metabolites and key AERD biomarkers, 15-hydroxyeicosatetraenoic acid (15-HETE)[18], human leukocyte antigen HLA-DBP1*030119, cysteinyl leukotriene receptor type 1 (CYSLTR1) gene polymorphism[20] and periostin[21]. To discriminate AERD from ATA, receiver operating characteristics (ROC) curve analysis for serum S1P and urine sphingosine were analyzed

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