Effects of mediator antagonism on mannitol and adenosine monophosphate challenges

Currie, Graeme P.; Haggart, K.; Lee, D. K C; Fowler, Stephen J.; Wilson, Andrew M.; Brannan, John D.; Anderson, Sandra D.; Lipworth, Brian J.

doi:10.1046/j.1365-2222.2003.01688.x

Cited by 56 publications

(41 citation statements)

References 27 publications

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“…The gene expression, immunostaining in airway epithelial cells and bronchial macrophages, and the level of the sPLA 2 -X protein in the airways all increased in response to exercise challenge in the asthma group, whereas the levels remained constant after challenge in nonasthmatic control subjects. These results indicate that sPLA 2 -X may play a role in regulating the levels of proinflammatory eicosanoids in asthma, particularly in manifestations of indirect BHR, in which increased production of proinflammatory eicosanoids is critical (7)(8)(9).…”

Section: Discussionmentioning

confidence: 97%

“…A major manifestation of asthma is exercise-induced bronchoconstriction (EIB), which reflects the degree of indirect bronchial hyperresponsiveness (BHR) (6). Dysregulated eicosanoid synthesis is prominent in indirect BHR (7)(8)(9). The levels of CysLTs in the airways, measured in exhaled breath condensate (10) or in induced sputum (11), are higher in patients with asthma with EIB than in patients with asthma without EIB.…”

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confidence: 99%

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Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Hallstrand

Emil

Singer

et al. 2007

Am J Respir Crit Care Med

103

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Rationale: Secreted phospholipase A 2 enzymes (sPLA 2 s) play key regulatory roles in the biosynthesis of eicosanoids, such as the cysteinyl leukotrienes, but the role of these enzymes in the pathogenesis of asthma is not known. Objectives: To establish if sPLA 2 s are overexpressed in the airways of patients with asthma, and to determine if these enzymes may play a role in the generation of eicosanoids in exercise-induced bronchoconstriction. Methods: Induced sputum samples were obtained from subjects with asthma with exercise-induced bronchoconstriction and nonasthmatic control subjects at baseline, and on a separate day 30 minutes after exercise challenge. The expression of the PLA 2 s in induced sputum cells and supernatant was determined by quantitative polymerase chain reaction, immunocytochemistry, and Western blot. Measurements and Main Results: The sPLA 2 s expressed at the highest levels in airway cells of subjects with asthma were groups X and XIIA. Group X sPLA 2 (sPLA 2 -X) was differentially overexpressed in asthma and localized to airway epithelial cells and bronchial macrophages. The gene expression, immunostaining in airway epithelial cells and bronchial macrophages, and the level of the extracellular sPLA 2 -X protein in the airways increased in response to exercise challenge in the asthma group, whereas the levels were lower and unchanged after challenge in nonasthmatic control subjects. Conclusions: Increased expression of sPLA 2 -X may play a key role in the dysregulated eicosanoid synthesis in asthma.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Hallstrand

Emil

Singer

et al. 2007

Am J Respir Crit Care Med

103

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“…In other words, there was little difference between 1 and 4 weeks on BHR to methacholine. Indeed, even single doses of montelukast have been shown to attenuate BHR [21]. Asano et al evaluated the effects of pranlukast for 4 weeks in 48 patients with moderate-to-severe persistent asthma [20].…”

Section: Discussionmentioning

confidence: 99%

Leukotriene C₄ synthase polymorphisms and responsiveness to leukotriene antagonists in asthma

Currie

Lima

Sylvester

et al. 2003

Brit J Clinical Pharma

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Aim Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C 4 synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild-type (A) polymorphism of this enzyme. Methods We carried out a retrospective analysis of 8 randomised, placebo-controlled trials performed in our department in mild-to-moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils . Results For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) ( n = 78): 2.21 and 2.07-fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36-fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold-differences of 1.07 (95%CI 0.63-1.81) and 1.02 (95%CI 0.70-1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes. Conclusion Polymorphisms of leukotriene C 4 synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists in mild-to-moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide.

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“…After exercise challenge, histamine and the mast cell protease tryptase are released into the airways, and inhibition of EIB with a cysLT 1 -receptor inhibitor plus an antihistamine reduced the amount of histamine released after exercise challenge [21]. In an analogous situation using mannitol challenge, pharmacologic inhibitors indicated that histamine was responsible for bronchoconstriction soon after challenge, whereas the release of cysLTs was responsible for sustained bronchoconstriction [28].…”

Section: Role Of Leukotrienes In the Pathophysiology Of Eibmentioning

confidence: 99%

Role of leukotrienes in exercise-induced bronchoconstriction

Hallstrand

Henderson²

2008

Curr Allergy Asthma Rep

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Exercise-induced bronchoconstriction (EIB) refers to acute airflow obstruction that is triggered by a period of physical exertion. EIB occurs mainly in individuals with other features of asthma but is especially prominent in a subset of asthmatics with pronounced indirect airway hyperresponsiveness. Leukotrienes (LTs) play a critical role in the pathophysiology of EIB. Asthmatics who are susceptible to EIB have increased levels of cysteinyl LTs (cysLTs [ie, LTs C4, D4, and E4]) in induced sputum and exhaled breath condensate. Exercise challenge in individuals susceptible to this disorder initiates the sustained increase in cysLTs in the airways and an increase in the ratio of cysLTs to prostaglandin E(2). The effects of cysLTs leading to secreted mucin release and smooth muscle constriction may be mediated in part through activation of sensory nerves. Therapies that block cysLT production or the cysLT(1) receptor effectively reduce the severity of EIB.

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Effects of mediator antagonism on mannitol and adenosine monophosphate challenges

Cited by 56 publications

References 27 publications

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Leukotriene C₄ synthase polymorphisms and responsiveness to leukotriene antagonists in asthma

Role of leukotrienes in exercise-induced bronchoconstriction

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Effects of mediator antagonism on mannitol and adenosine monophosphate challenges

Cited by 56 publications

References 27 publications

Secreted Phospholipase A2Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Secreted Phospholipase A2Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma

Role of leukotrienes in exercise-induced bronchoconstriction

Contact Info

Product

Resources

About

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Leukotriene C₄ synthase polymorphisms and responsiveness to leukotriene antagonists in asthma