A dual Cys<scp>LT</scp><sub>1/2</sub> antagonist attenuates allergen‐induced airway responses in subjects with mild allergic asthma

Gauvreau, Gail M.; Lp, Boulet; FitzGerald, J. Mark; Cockcroft, Donald W.; Davis, Beth E.; Leigh, Richard; Tanaka, Masaya; Ja, Fourre; Nabata, Toshiya; O'Byrne, Paul M.

doi:10.1111/all.12987

Cited by 17 publications

(11 citation statements)

References 45 publications

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“…CysLTs released in response to allergen challenges in atopic subjects elicit bronchoconstriction primarily through CysLT 1 R (64). Although no studies have directly contrasted the effects of CysLT 1 R antagonists with those of 5-LO inhibition, a recent study demonstrated that a dual CysLT 1 R/CysLT 2 R antagonist, but not a CysLT 1 R-selective antagonist, prevented the increase in sputum eosinophils occurring in atopic asthmatic subjects following allergen inhalation, even though both drugs blocked the attendant changes in lung function (65). The markedly dysregulated cysLT synthesis, strong IL-33 expression, and high levels of tissue eosinophilia observed in AERD may reflect, in part, immunopathologic contributions from CysLT 2 R. The findings support the potential therapeutic utility of drugs with the capacity to block CysLT 2 R, alone or in combination with the other cysLT receptors, in AERD and other conditions characterized by robust type 2 immunopathology and cysLT production.…”

Section: Discussionmentioning

confidence: 99%

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Liu

Barrett

Kanaoka

et al. 2018

The Journal of Immunology

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Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLTR), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease-like mice. These responses were mitigated by deletions of either or leukotriene C synthase (). Administrations of either LTC (the parent cysLT) or the selective CysLTR agonist N-methyl LTC to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLTR-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLTR-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of blunted LTC-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLTR prior to inhalation challenge of mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLTR signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLTR-targeted drugs may interrupt these processes.

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Section: Discussionmentioning

confidence: 99%

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Liu

Barrett

Kanaoka

et al. 2018

The Journal of Immunology

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“…Interestingly, angiotensin II receptor 1 (AT1R) has been shown to activate NOX1 likely via Gαq and PLCβ which activate PKC [29]. Evidence showed that thrombin can increase NOX1-dependent ROS generation by mechanisms involving PAR4 or EGFR transactivation [24,30,31]. Several studies have reported an upregulation of NOX4 in response to GPCR ligands such as angiotensin II (AT-II), urotensin-II, β-adrenergic agonists, renin and thrombin [32][33][34][35][36][37].…”

Section: Recently Described Roles Of G Protein Mutations In Tumorigenmentioning

confidence: 99%

Update on GNA Alterations in Cancer: Implications for Uveal Melanoma Treatment

Larribère

Utikal

2020

Cancers

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Tumorigenesis is correlated with abnormal expression and activity of G protein-coupled receptors (GPCRs) and associated G proteins. Oncogenic mutations in both GPCRs and G proteins (GNAS, GNAQ or GNA11) encoding genes have been identified in a significant number of tumors. Interestingly, uveal melanoma driver mutations in GNAQ/GNA11 were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for BRAF mutations in cutaneous melanoma which saw enormous success. Moreover, new immunotherapies strategies such as immune checkpoint inhibitors have given underwhelming results. In this review, we summarize the current knowledge on cancer-associated alterations of GPCRs and G proteins and we focus on the case of uveal melanoma. Finally, we discuss the possibilities that this signaling might represent in regard to novel drug development for cancer prevention and treatment.

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“…With respect to testing of investigational therapies, allergen inhalation test was initially used to assess the first monoclonal antibody, omalizumab, directed at IgE, in the treatment of allergic asthma [61,62]. This study was followed by several others using inhaled allergen challenge as a proof of concept to evaluate small molecule inhibitors [63][64][65][66][67][68][69], novel corticosteroids, oligonucleotides and monoclonal antibodies [70][71][72][73][74][75][76][77].…”

Section: Assessment Of Potential New Asthma Therapiesmentioning

confidence: 99%

Allergen bronchoprovocation test: an important research tool supporting precision medicine

Boulet

Côté

Abd‐Elaziz

et al. 2020

Current Opinion in Pulmonary Medicine

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Purpose of reviewAllergen bronchoprovocation test (ABT) has been used to study asthma pathophysiology and as a diseasemodelling tool to assess the properties and efficacy of new asthma drugs. In view of the complexity and heterogeneity of asthma, which has driven the definition of several phenotypes and endotypes, we aim to discuss the role of ABT in the era of precision medicine and provide guidance for clinicians how to interpret and use available data to understand the implications for the benefits of asthma treatment. Recent findingsIn this review, we summarize background knowledge and applications of ABT and provide an update with recent publications on this topic. In the past years, several studies have been published on ABT in combination with non-invasive and invasive airway samplings and innovative detection techniques allowing to study several inflammatory mechanisms linked to Th2-pathway and allergen-induced pathophysiology throughout the airways. SummaryABT is a valuable research tool, which has strongly contributed to precision medicine by helping to define allergen-triggered key inflammatory pathways and airway pathophysiology, and thus helped to shape our understanding of allergen-driven asthma phenotypes and endotypes. In addition, ABT has been instrumental to assess the interactions and effects of new-targeted asthma treatments along these pathways.

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A dual CysLT_1/2 antagonist attenuates allergen‐induced airway responses in subjects with mild allergic asthma

Abstract: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT blockade. Whether dual cysLT antagonism offers additional benefit for treatment of asthma requires further study.

Cited by 17 publications

References 45 publications

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Update on GNA Alterations in Cancer: Implications for Uveal Melanoma Treatment

Allergen bronchoprovocation test: an important research tool supporting precision medicine

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A dual CysLT1/2 antagonist attenuates allergen‐induced airway responses in subjects with mild allergic asthma

Abstract: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT blockade. Whether dual cysLT antagonism offers additional benefit for treatment of asthma requires further study.

Cited by 17 publications

References 45 publications

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Update on GNA Alterations in Cancer: Implications for Uveal Melanoma Treatment

Allergen bronchoprovocation test: an important research tool supporting precision medicine

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A dual CysLT_1/2 antagonist attenuates allergen‐induced airway responses in subjects with mild allergic asthma