The 5‐lipoxygenase‐activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma

Kent, Sandra E; Boyce, Malcolm; Diamant, Zuzana; Singh, Dave; O’Connor, Brian; Saggu, Parminder; Norris, Virginia

doi:10.1111/cea.12002

Cited by 30 publications

(34 citation statements)

References 26 publications

(63 reference statements)

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“…GATA3 is also expressed in mast cells, 41 eosinophils, 43 and airway epithelial cells, where it controls type 2 cytokine expression and effector mechanisms associated with the allergen-induced allergic response. 44,45 After an allergen challenge, the early asthmatic response depends on mast-cell degranulation, whereas the late asthmatic response is considered to be preferentially T-cell dependent and accompanied by a marked influx of eosinophils into the airways and the airway lumen. Mast-cell tryptase represents a reliable and robust marker of mast-cell activation and mast-cell degranulation.…”

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confidence: 99%

Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

et al. 2015

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confidence: 99%

Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

et al. 2015

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“…More recently, a 5-lipoxygenase–activating protein (FLAP) (Fig. 1) inhibitor (GSK2190915) has been shown to be effective in inhibiting allergic responses to inhaled allergen in patients with mild asthma (Kent et al, 2013). The continued development and refinement of compounds that modulate receptors and signaling associated with mast cell-derived lipid mediators will continue to aid in the treatment of human disease and our understanding of the biology these molecules influence.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate and other lipid mediators generated by mast cells as critical players in allergy and mast cell function

Kulinski

Muñoz-Cano

Olivera

2016

European Journal of Pharmacology

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Sphingosine-1phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments.

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“…In a randomized, double-blind, crossover design, 19 males with mild asthma were enrolled and they received either GSK2190915 or placebo for 5 days. The early and late asthma response to inhaled allergen challenge measured with the fall in the FEV1 (L) was evaluated and it was found that the active treatment significantly reduced the early asthma response (0 --2 h post-challenge value of the FEV1), treatment difference 0.408 l versus placebo between brackets, treatment difference over placebo 0.229 l. The active treatment was also found to significantly reduce the allergen-induced sputum eosinophil count and the sputum LTB4 levels [30].…”

Section: Flap Inhibitorsmentioning

confidence: 99%