Recovery of Leukotriene E<sub>4</sub>from the Urine of Patients with Airway Obstruction

Drazen, Jeffrey M.; O’Brien, Jeanne; Sparrow, David; Weiss, Scott T.; Martins, Mílton A.; Israel, Elliot; Fanta, Christopher H.

doi:10.1164/ajrccm/146.1.104

Cited by 183 publications

(111 citation statements)

References 13 publications

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“…Besides mast cells, eosinophils are the main source of CysLTs which contribute not only to bronchoconstriction and airway hyperreactivity 39, but as in the case of LTE 4 also to eosinophil recruitment 40. Increased levels of LTE 4 can be detected in urine 41, BALF 42, and exhaled breath condensate 43 of patients after allergen challenge. Accordingly, mass spectrometric analysis of BALF from OVA‐challenged mice revealed slightly increased LTC4 levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Frei

Luschnig

Parzmair

et al. 2016

Allergy

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BackgroundAccumulation of activated eosinophils in tissue is a hallmark of allergic inflammation. The endocannabinoid 2‐arachidonoylglycerol (2‐AG) has been proposed to elicit eosinophil migration in a CB 2 receptor/Gi/o‐dependent manner. However, it has been claimed recently that this process may also involve other mechanisms such as cytokine priming and the metabolism of 2‐AG into eicosanoids. Here, we explored the direct contribution of specific CB 2 receptor activation to human and mouse eosinophil effector function in vitro and in vivo.Methods In vitro studies including CB 2 expression, adhesion and migratory responsiveness, respiratory burst, degranulation, and calcium mobilization were conducted in human peripheral blood eosinophils and mouse bone marrow‐derived eosinophils. Allergic airway inflammation was assessed in mouse models of acute OVA‐induced asthma and directed eosinophil migration.Results CB 2 expression was significantly higher in eosinophils from symptomatic allergic donors. The selective CB 2 receptor agonist JWH‐133 induced a moderate migratory response in eosinophils. However, short‐term exposure to JWH‐133 potently enhanced chemoattractant‐induced eosinophil shape change, chemotaxis, CD11b surface expression, and adhesion as well as production of reactive oxygen species. Receptor specificity of the observed effects was confirmed in eosinophils from CB 2 knockout mice and by using the selective CB 2 antagonist SR144528. Of note, systemic application of JWH‐133 clearly primed eosinophil‐directed migration in vivo and aggravated both AHR and eosinophil influx into the airways in a CB 2‐specific manner. This effect was completely absent in eosinophil‐deficient ∆dblGATA mice.ConclusionOur data indicate that CB 2 may directly contribute to the pathogenesis of eosinophil‐driven diseases. Moreover, we provide new insights into the molecular mechanisms underlying the CB 2‐mediated priming of eosinophils. Hence, antagonism of CB 2 receptors may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophilic disorders.

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Section: Resultsmentioning

confidence: 99%

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Frei

Luschnig

Parzmair

et al. 2016

Allergy

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“…A quantitative RT-PCR analysis in the mouse revealed that GPR99 mRNA is highly expressed in kidney, testis, and smooth muscle (23). Given that CysLT 1 R and CysLT 2 R are also expressed on smooth muscle cells in airways and blood vessels (3,4,28,29), expression and function of GPR99 on smooth muscle may be affected by the presence of CysLT 1 R and CysLT 2 R. LTE 4 has a sufficient biologic half-life to be excreted into the urine (30), and urinary LTE 4 excretion is significantly increased in spontaneous acute asthma flares (22). Asthmatic individuals show LTE 4 -induced bronchoconstriction as an aerosol in the same concentration range as LTD 4 and LTC 4 (31,32), and LTE 4 potentiates airway hyperresponsiveness to histamine (33).…”

Section: Gpr99 Mediates Lte 4 -Induced Ear Edema In the Cysltr1/ Cysltr2mentioning

confidence: 99%

“…Unexpectedly, LTE 4 elicited more edema in the Cysltr1/Cysltr2 Ϫ/Ϫ mice than LTD 4 or LTC 4 at the same dose and showed a 64-fold increase in potency in the Cysltr1/Cysltr2 Ϫ/Ϫ mice as compared with WT mice, revealing a ligand preference for an unidentified receptor (19). Such a receptor could be important in asthma both because there is heterogeneity to the benefit of CysLT 1 R antagonists (20,21) and because LTE 4 , unlike transient LTC 4 and LTD 4 , is sustained at levels that even * This work was supported, in whole or in part, by National Institutes of Health provide a urinary biomarker for the 5-lipoxygenase/LTC 4 synthase pathway (22).…”

mentioning

confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

162

154

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Background: A most stable cysteinyl leukotriene, LTE 4 , mediates vascular permeability in mice lacking the two known receptors. Results: GPR99 deficiency abolishes LTE 4 -induced vascular permeability in mice also lacking the two known receptors. Conclusion: GPR99 is a potential third cysteinyl leukotriene receptor. Significance: GPR99 may be a therapeutic target for inflammatory diseases.The cysteinyl leukotrienes (cys-LTs), leukotriene C 4 (LTC 4 ), a conjugation product of glutathione and eicosatetraenoic acid, and its metabolites, LTD 4 and LTE 4 , are lipid mediators of smooth muscle constriction and inflammation in asthma. LTD 4 is the most potent ligand for the type 1 cys-LT receptor (CysLT 1 R), and LTC 4 and LTD 4 have similar lesser potency for CysLT 2 R, whereas LTE 4 has little potency for either receptor. Cysltr1/Cysltr2 ؊/؊ mice, lacking the two defined receptors, exhibited a comparable dose-dependent vascular leak to intradermal injection of LTC 4 or LTD 4 and an augmented response to LTE 4 as compared with WT mice. As LTE 4 retains a cysteine residue and might provide recognition via a dicarboxylic acid structure, we screened cDNAs within the P2Y nucleotide receptor family containing CysLTRs and dicarboxylic acid receptors with trans-activator reporter gene assays. GPR99, previously described as an oxoglutarate receptor (Oxgr1), showed both a functional and a binding response to LTE 4 in these transfectants. We generated Gpr99 ؊/؊ and Gpr99/Cysltr1/Cysltr2 ؊/؊ mice for comparison with WT and Cysltr1/Cysltr2 ؊/؊ mice. Strikingly, GPR99 deficiency in the Cysltr1/Cysltr2 ؊/؊ mice virtually eliminated the vascular leak in response to the cys-LT ligands, indicating GPR99 as a potential CysLT 3 R active in the Cysltr1/Cysltr2 ؊/؊ mice. Importantly, the Gpr99 ؊/؊ mice showed a dose-dependent loss of LTE 4 -mediated vascular permeability, but not to LTC 4 or LTD 4 , revealing a preference of GPR99 for LTE 4 even when CysLT 1 R is present. As LTE 4 is the predominant cys-LT species in inflamed tissues, GPR99 may provide a new therapeutic target.Leukotriene C 4 (LTC 4 ), 2 LTD 4 , and LTE 4 , collectively called cysteinyl leukotrienes (cys-LTs), are proinflammatory mediators derived from arachidonic acid through the 5-lipoxygenase/ LTC 4 synthase pathway (1, 2). Intracellularly synthesized LTC 4 is exported via multidrug resistance-associated proteins and is rapidly metabolized in the extracellular space by cleavage removal of glutamic acid and then glycine to LTD 4 and LTE 4 , respectively. The type 1 cys-LT receptor (CysLT 1 R) is the high affinity receptor for LTD 4 , whereas the type 2 receptor (CysLT 2 R) can bind both LTC 4 and LTD 4 with one-log less affinity than that of CysLT 1 R for LTD 4 in transfected cells (3, 4). The cys-LTs are mediators of bronchial asthma on the basis of their potent bronchoconstrictive activity via the CysLT 1 R in pharmacologic studies and the clinical effectiveness of CysLT 1 R antagonists (5, 6).LTE 4 , the most abundant cys-LT at sites of inflammation due to its stab...

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“…Cysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE 4 , the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma.…”

mentioning

confidence: 99%

“…LTE 4 , the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE 4 that mediates cutaneous vascular permeability.…”

mentioning

confidence: 99%

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Bankova

Lai

Yoshimoto

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE 4 , the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE 4 that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC 4 synthase (LTC 4 S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE 4 . GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE 4 one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC 4 S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE 4 and of GPR99 may have therapeutic benefits in asthma.C ysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are lipid mediators detected during asthma exacerbations triggered by allergen (1), aspirin (2, 3), and respiratory viruses (4). The cysLTs elicit vascular permeability, inflammation, and bronchoconstriction through three G-protein-coupled receptors. The type 1 cysLT receptor (CysLTR), CysLT 1 R, is the highaffinity receptor for LTD 4 and the dominant CysLTR mediating airway smooth muscle constriction (5-8). The type 2 CysLTR, CysLT 2 R, has prominent effects on the vascular endothelium (9-12) and also elicits bronchial constriction (13,14). LTE 4 , the stable cysLT (15-18), is a weak agonist for CysLT 1 R and CysLT 2 R in transfected cells (5, 19), but elicits airflow obstruction in patients with asthma (20-22). Moreover, LTE 4 has comparable activity to LTC 4 and LTD 4 in eliciting a wheal and flare response in human skin (23), and LTE 4 elicits cutaneous vascular permeability in mice lacking both CysLT 1 R and CysLT 2 R, suggesting the existence of a high-affinity receptor for LTE 4 , which was recently identified as GPR99 (24,25). However, the mechanism by which LTE 4 induces lung pathobiology and the role of GPR99 remain poorly understood.The cysLTs are derived from arachidonate through the serial enzymatic actions of 5-lipoxygenase and leukotriene C 4 synthase (LTC 4 S). LTC 4 , the terminal product of intrac...

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Recovery of Leukotriene E₄from the Urine of Patients with Airway Obstruction

Cited by 183 publications

References 13 publications

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

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Recovery of Leukotriene E4from the Urine of Patients with Airway Obstruction

Cited by 183 publications

References 13 publications

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Leukotriene E4elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

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About

Recovery of Leukotriene E₄from the Urine of Patients with Airway Obstruction

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99