Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers

Higashi, Noritaka; Mita, Haruhisa; Ono, Emiko; Fukutomi, Yuma; Yamaguchi, Hiromichi; Kondo, Keiichi; Tanimoto, Hidenori; Sekiya, Kiyoshi; Akiyama, Kazuo; Taniguchi, Masami

doi:10.1016/j.jaci.2009.12.977

Cited by 82 publications

(76 citation statements)

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“…Alternatively, it could enhance other proinflammatory cytokines and cysteinyl leukotrienes from inflammatory cells. 22 It was previously noted that the suppression of tumor necrosis factor-a protein and mRNA expression by PGE2 8 while EP4 agonist significantly reduced levels of proinflammatory cytokines and chemokines, indicating the role of EP4 activation in systemic inflammation. 23 Despite the genetic and functional study data provided here, replication studies in larger and different cohorts must be in consideration to validate these findings.…”

Section: Discussionmentioning

confidence: 94%

Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria

et al. 2012

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Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria-and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at À1254 G4A showed significantly higher frequency compared with NC (P ¼ 0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P ¼ 0.031). In vitro functional study demonstrated that the À1254 G allele had lower luciferase activity (Po0.001) in HMC-1 cells. EMSA finding showed that PTGER4 À1254 G produced a specific band. Significantly decreased PTGER4 expression (P ¼ 0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P ¼ 0.001). The PTGER4 À1254 G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.

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Section: Discussionmentioning

confidence: 94%

Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria

et al. 2012

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“…Overproduction of cysteinyl leukotrienes (Cys-LTs) has been implicated as major pathogenetic feature. In AERD, free radical-mediated prostaglandin generation has also been demonstrated by measuring the urinary enantiomer PGF (2) alpha (46). Although both COX-1 and COX-2 are expressed in the airways, COX-1 is the functionally dominant enzyme, which explains some of the clinical observations related to drug specificity in patients with aspirin-sensitive asthma (tolerance of COX-2 inhibitors) (47).…”

Section: Aspirin-intolerant Asthmamentioning

confidence: 99%

Untangling asthma phenotypes and endotypes

Agache

Akdiş

Jutel

et al. 2012

Allergy

286

235

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Asthma phenotypes have been developed to address the complexities of the disease. However, owing to a lack of longitudinal studies, little is known about the onset as well as the stability of phenotypes. Distinguishing phenotypes with regard to the severity or duration of the disease is essential. A phenotype covers the clinically relevant properties of the disease, but does not show the direct relationship to disease etiology and pathophysiology. Different pathogenetic mechanisms might cause similar asthma symptoms and might be operant in a certain phenotype. These putative mechanisms are addressed by the term 'endotype'. Classification of asthma based on endotypes provides advantages for epidemiological, genetic, and drug-related studies. A successful definition of endotypes should link key pathogenic mechanisms with the asthma phenotype. Thus, the identification of corresponding molecular biomarkers for individual pathogenic mechanism underlying phenotypes or subgroups within a phenotype is important. Whether newly defined asthma endotypes predict the individual course of asthma has to be validated in longitudinal studies. The accurate endotyping reflects natural history of asthma and should help to predict treatment response. Thus, understanding asthma endotypes might be useful in clinical practice.

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“…Previous studies [24,25,35,37,39,40] showed changes in LT levels in urine, EBC, or saliva after oral or inhaled aspirin challenge tests. Some types of samples, such as EBC [35,40] or saliva [25], are inappropriate for monitoring changes in metabolites after provocation.…”

Section: Discussionmentioning

confidence: 98%

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin‐exacerbated respiratory disease

Ban

Cho

Kim

et al. 2016

Clin Experimental Allergy

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SummaryBackground To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). Objective To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. Methods An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/QToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. Results A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE 4 and LTE 4 /PGF 2 a ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE 4 and LTE 4 /PGF 2 a ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE 4 levels were significantly correlated with the fall in FEV 1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). Conclusions and Clinical Relevance Serum metabolite level of LTE 4 and LTE 4 /PGF 2 a ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/QToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.

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Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers

Cited by 82 publications

References 49 publications

Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria

Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria

Untangling asthma phenotypes and endotypes

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin‐exacerbated respiratory disease

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