Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses

Daffern, Pamela J.; Muilenburg, Diego J.; Hugli, Tony E.; Stevenson, Donald D.

doi:10.1016/s0091-6749(99)70324-6

Cited by 129 publications

(107 citation statements)

References 26 publications

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“…46 Thus, platelets probably augment systemic overproduction of cysLTs in AERD by several mechanisms. Urinary concentrations of LTE 4 correlate strongly with certain clinical outcomes in AERD, 47 and the remarkable correlation between steady-state urinary excretion of LTE 4 and the frequencies of platelet-adherent neutrophils, eosinophils, and monocytes in the peripheral blood ( Figure 5), combined with the contribution of platelets to the pool of LTC 4 S activity in granulocytes (Figure 4), strongly supports the pathogenetic relevance of our findings. The increases in platelet-leukocyte complexes in AERD are probably not because of enhanced production of thromboxane ( Figure 5A) or isoprostanes, because their respective urinary metabolites (unlike LTE 4 levels) did not discriminate subjects with AERD from aspirin-tolerant controls.…”

Section: Platelet-wbc Adherence Causes Cyslts In Aerd 3795supporting

confidence: 80%

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Laidlaw

Kidder

Bhattacharyya

et al. 2012

Blood

221

209

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Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocytederived precursor leukotriene (LT)A 4 to LTC 4 , the parent cysLT, through the terminal enzyme LTC 4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirintolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC 4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC 4 generation by activated granulocytes from subjects with AERD compared with aspirintolerant controls. Urinary LTE 4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in plateletleukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD. (Blood. 2012;119(16):3790-3798) IntroductionAspirin-exacerbated respiratory disease (AERD) is a distinctive syndrome characterized clinically by a triad of asthma, nasal polyposis, and aspirin sensitivity. It is a chronic inflammatory disease associated with eosinophilic infiltration of respiratory tissues, peripheral eosinophilia, and excessive production of cysteinyl leukotrienes (cysLTs), a class of inflammatory lipid mediators that are thought to contribute to several of the characteristic features of AERD. Individuals with this syndrome account for 4% to 11% of all adult patients with asthma, and for a disproportionate share (ϳ 30%) of patients with severe asthma. 1 The confirmatory diagnostic feature of AERD is an idiosyncratic respiratory reaction, including symptoms of acute bronchoconstriction, nasal congestion, and eye watering, on ingestion of aspirin or another nonselective cyclooxygenase (COX) inhibitor. Despite the strikingly consistent clinical phenotype of AERD, the pathogenesis of the disease remains unclear.CysLTs derive from the metabolism of arachidonic acid by effector cells of the innate immune system. In inflammatory leukocytes (neutrophils, monocytes, eosinophils, mast cells, and basophils), arachidonic acid is oxidized by 5-lipoxygenase (5-LO) to form the unstable intermediate leukotriene (LT)A 4 . 2 In neutrophils, LTA 4 is preferentially hydrolyzed by LTA 4 hydrolase to form LTB 4 , whereas in monocytes, mast cells, eosinophils, and basophils, it i...

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Section: Platelet-wbc Adherence Causes Cyslts In Aerd 3795supporting

confidence: 80%

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Laidlaw

Kidder

Bhattacharyya

et al. 2012

Blood

221

209

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“…In the present study, urine baseline LTE 4 levels were correlated with decreases in FEV 1 % after the Lys-ASA BPT in line with previous studies [26,30]. However, baseline LTE 4 levels were not correlated with baseline FEV 1 % or asthma severity, which is inconsistent with results of previous studies [27,31].…”

Section: Discussionsupporting

confidence: 53%

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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“…AERD is a disorder characterized by severe eosinophilic infiltrate into the sinus and respiratory tract, a baseline over-production of CysLTs and a unique sensitivity to LTE 4 following ingestion of aspirin 1,15,24,25 . Expression of LTC 4 S in eosinophils drives much of the over-production of CysLTs 24 with additional components driven by the activation of mast cells 3,5,26,27 and platelet-adherent neutrophils 28 .…”

Section: Discussionmentioning

confidence: 99%

“…AERD comprises as many as 7% of adult-onset asthmatics and up to 12-14% of adult asthmatics with severe asthma 1,2 . During aspirin reactions, many mediators are released including cysteinyl leukotrienes (CysLT), tryptase, ECP and prostaglandin D 2 (PGD 2 ) suggesting both mast cell and eosinophil activation [3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

Eosinophil Production of PGD2 in Aspirin-Exacerbated Respiratory Disease

Steinke

Negri

Baker

et al. 2016

Journal of Allergy and Clinical Immunology

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Background-Aspirin-exacerbated respiratory disease (AERD) differs from aspirin tolerant disease due in part to eosinophilic tissue infiltration and over-expression of arachidonic acid metabolic pathway components that lead to enhanced secretion of cysteinyl leukotrienes (CysLT) and prostaglandin D 2 (PGD 2 ) observed constitutively and, paradoxically, in response to aspirin and other cyclooxygenase inhibitors. We have previously demonstrated the capacity of interferon (IFN)-γ to drive CysLT expression and response.

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Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses

Cited by 129 publications

References 26 publications

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

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

Eosinophil Production of PGD2 in Aspirin-Exacerbated Respiratory Disease

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