Leukotriene E4: Perspective on the forgotten mediator

Lee, Tak H.; Woszczek, Grzegorz; Farooque, Sophie

doi:10.1016/j.jaci.2009.04.020

Cited by 51 publications

(43 citation statements)

References 43 publications

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“…However, it is clear that LTE 4 can stimulate inflammatory responses in mice deficient in both CysLT 1 and CysLT 2 (57), so it is possible that the enhancing effect observed is mediated by a montelukast-sensitive receptor that is distinct from either CysLT 1 or CysLT 2 and may fall in the P2Y class of receptors but is not P2Y 12 . Indeed, it has been established that LTE 4 can elicit inflammatory responses that are qualitatively distinct from other cysLTs (30,31). Inhalation of LTE 4 , but not LTD 4 , promotes airway eosinophilia in human volunteers (58), and, interestingly, this persistent eosinophilia is suppressed by treatment with the CysLT 1 antagonist zafirlukast (27).…”

Section: Discussionmentioning

confidence: 99%

“…LTD 4 binds CysLT 1 with higher affinity than LTC 4 , whereas CysLT 2 binds these cysLTs with equal affinity. LTE 4 has only weak activity on either CysLT 1 (23,24) or CysLT 2 (25,26) and has therefore been generally considered to be a stable inactive breakdown product, although there is accumulating evidence that LTE 4 can stimulate inflammatory responses through mechanisms independent of CysLT 1 or CysLT 2 (27)(28)(29)(30)(31) CysLT 1 mediates bronchoconstriction and also a range of proinflammatory effects including activation and migration of leukocytes (21,32,33), whereas CysLT 2 may mediate the vasoactive effects of LTC 4 and LTD 4 . The leukotriene antagonists approved for use in asthma and allergic rhinitis, most notably montelukast, block the action of cysLTs (predominantly LTD 4 ) on CysLT 1 but do not inhibit CysLT 2 -mediated effects.…”

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confidence: 99%

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Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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PGD2 exerts a number of pro-inflammatory responses through a high affinity interaction with chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflammation. Since cysteinyl leukotrienes (cysLTs) are also produced during the allergic response we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD2. PGD2 induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D4 (LTD4) and E4 (LTE4) also stimulated the cytokine production but were much less active than PGD2. However, when combined with PGD2, cysLTs caused a greater than additive enhancement of the response, with LTE4 being most effective in activating Th2 cells. LTE4 enhanced calcium mobilisation in response to PGD2 in Th2 cells without affecting endogenous PGD2 production or CRTH2 receptor expression. The effect of LTE4 was inhibited by montelukast but not by the P2Y12 antagonistmethylthioadenosine 5′-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells since inhibition of cysLT action by montelukast or cysLT sythesis by MK886, an inhibitor of 5-LO-activating protein, reduced the response of Th2 cells to the levels produced by PGD2 alone. These findings reveal that cysLTs, in particular LTE4, have a significant pro-inflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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“…This, in turn, is transformed into LTE 4 by the cleavage of the glycine moiety by dipeptidase enzyme [19] . The LTE 4 is the most stable CysLT and is a weak agonist for CysLT 1 /CysLT 2 receptors [21,22] .…”

Section: Biosynthesis Of Cysltsmentioning

confidence: 99%

“…Out of all the CysLTs, LTE 4 binds poorly to the classical CysLT 1 and CysLT 2 receptors and is much less active on normal airways [21,22] . However, earlier studies have reported that LTE 4 caused skin swelling in human subjects with similar potency as other CysLTs and the airways of asthmatic subjects (particularly those that were aspirin sensitive) were hyperresponsive to LTE 4 .…”

Section: Evidence For Further Cyslt Receptor Subtypesmentioning

confidence: 99%

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

Singh¹,

Gupta²,

Dastidar³

et al. 2010

Pharmacology

184

143

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The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C₄ (LTC₄), leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT₁ and CysLT₂. The CysLT₁ receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT₂ receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT₁-receptor-mediated effects, and the role of the CysLT₂ receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT₂-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.

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“…Cysteinyl leukotrienes are potent inflammatory mediators that elicit bronchoconstriction, leading to air-flow limitation, [1][2][3] which could be blocked by leukotriene receptor antagonists. 4 Unfortunately, a simple and feasible measure for predicting the efficacy in asthma is lacking.…”

Section: Introductionmentioning

confidence: 99%

Impulse Oscillometry for Leukotriene D₄Inhalation Challenge in Asthma

et al. 2013

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BACKGROUND: The value of impulse oscillometry (IOS) for bronchial provocation testing is poorly defined. We investigated the positive threshold derived from the parameters and diagnostic power of IOS for asthma with the leukotriene D 4 bronchial provocation test. METHODS: We enrolled 62 subjects with asthma and 21 healthy subjects. IOS was employed to perform the leukotriene D 4 bronchial provocation test, followed by spirometry. The positive threshold was determined based on the cutoff point in the receiver operating characteristic curve, from which the parameters with the highest diagnostic power were obtained. RESULTS: Airway impedance at 5 Hz (Z 5 ), resistance at 5 Hz (R 5 ), and resonance frequency had the highest diagnostic power (areas under curve 0.82, 0.82, and 0.81, respectively), with increases of 57%, 43%, and 63%, corresponding to a 20% decrease in FEV 1 , respectively. IOS indices yielded assay sensitivity and specificity similar to that of spirometry. The positive threshold for IOS, defined as either a 57% increase in Z 5 or a 63% increase in resonance frequency in the bronchial provocation test, yielded an assay accuracy of 0.6 in subjects with asthma. CONCLUSIONS: IOS during the leukotriene D 4 bronchial provocation test has a diagnostic power similar to that of spirometry. Either a 57% increase in Z 5 or a 63% increase in resonance frequency may be regarded as a surrogate of FEV 1 decrease to determine airway hyper-responsiveness in asthma.

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Leukotriene E4: Perspective on the forgotten mediator

Cited by 51 publications

References 43 publications

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

Impulse Oscillometry for Leukotriene D₄Inhalation Challenge in Asthma

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Leukotriene E4: Perspective on the forgotten mediator

Cited by 51 publications

References 43 publications

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

Impulse Oscillometry for Leukotriene D4Inhalation Challenge in Asthma

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Impulse Oscillometry for Leukotriene D₄Inhalation Challenge in Asthma