Release of leukotrienes in patients with bronchial asthma

Lam, Stephen; Chan, Henry; LeRiche, Jean; Chan‐Yeung, Moira; Salari, Hassan

doi:10.1016/0091-6749(88)91043-3

Cited by 229 publications

(83 citation statements)

References 23 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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“…LTE 4 , the most abundant cys-LT at sites of inflammation due to its stability (7,8), was only a weak agonist for the CysLT 1 R and CysLT 2 R in studies with transfectants (3,4), suggesting that it might lack agonist activity. In contrast, pretreatment with LTE 4 , but not LTC 4 or LTD 4 , enhanced the response of guinea pig trachea (9) or human bronchial smooth muscle to histamine (10).…”

mentioning

confidence: 99%

“…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 stability (7,8), was only a weak agonist for the CysLT 1 R and CysLT 2 R in studies with transfectants (3, 4), suggesting that it might lack agonist activity. In contrast, pretreatment with LTE 4 , but not LTC 4 or LTD 4 , enhanced the response of guinea pig trachea (9) or human bronchial smooth muscle to histamine (10).…”

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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

160

158

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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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“…mL -1 , and the cells were then stimulated with 1 mg calcium ionophore A23187. LTC 4 and LTB 4 were quantified by means of high-performance liquid chromatography, as described by LAM et al [12].…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

Enhanced peripheral leukocyte leukotriene production and bronchial hyperresponsiveness in asthmatics

et al. 2000

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Leukotrienes (LTs) are pro-inflammatory mediators that contribute to the pathophysiological features of asthma. The relationship between the amounts of LTB 4 and LTC 4 produced by the leukocytes of asthmatic patients on the one hand and immunoglobulin E (IgE)-mediated allergy, asthma exacerbations and bronchial hyperresponsiveness was studied.Leukocytes were obtained from peripheral blood drawn from 29 atopic and 27 nonatopic asthmatics during exacerbations and clinically controlled periods, as well as from 20 control individuals. The leukocytes were stimulated with calcium ionophore A23187 to induce LTB 4 and LTC 4 production. Allergy was assessed by means of specific serum IgE or by positive skin tests, whereas bronchial hyperresponsiveness was measured by methacholine challenge.The leukocytes of the asthmatics generated significantly more LTB 4 (p<0.05) and LTC 4 (p<0.01) than those of controls. The leukocytes of patients with atopic asthma generated significantly more LTC 4 than those of patients with nonatopic asthma (p<0.01). Significantly more LTC 4 was produced by leukocytes obtained during exacerbations, than by those obtained during clinically controlled periods (p<0.01). In addition, there was a significant correlation between LTB 4 generation by leukocytes and the degree of bronchial hyperresponsiveness to methacholine (r=-0.792, p<0.0001).These results suggest that leukotriene C 4 production by leukocytes is associated with immunoglobulin E-mediated allergy and asthma exacerbations, and further that generation of leukotriene B 4 is closely related to bronchial hyperresponsiveness in patients with asthma. Eur Respir J 2000; 16: 504±508.

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Release of leukotrienes in patients with bronchial asthma

Cited by 229 publications

References 23 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

Enhanced peripheral leukocyte leukotriene production and bronchial hyperresponsiveness in asthmatics

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