Fluticasone propionate attenuates platelet-activating factor-induced gas exchange defects in mild asthma

Acuña, Adelaida; Gabrijelcic, J; Uribe, Esteban; Rabinovich, Roberto; Roca, Josep; Barberà, Joan Albert; Chung, Kian Fan; Rodríguez-Roisín, Robert

doi:10.1183/09031936.02.00268802

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…Anthropometric and functional data were within normal limits and close to those reported in previous studies [15]. There were no differences between the placebo and the formoterol subjects (table 2 and fig.…”

Section: Baseline Findings (Before Platelet-activating Factor)supporting

confidence: 67%

“…In contrast, formoterol was unable to modulate either facial flushing or neutrophil kinetics. Based on previous work by the authors in both normal subjects [3,8,9] and mild asthmatics [4,10,15], the authors postulate that PAF-induced pulmonary gas exchange defects and increases of Rrs are related to airway narrowing secondary to abnormally increased microvascular leakage, rather than to a primary constrictor effect on airway smooth muscle. SABAs were among the first agents to exhibit anti-oedema effects by preventing separation of endothelial cells at postcapillary venular sites [16].…”

Section: Discussionmentioning

confidence: 99%

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Formoterol protects against platelet-activating factor-induced effects in asthma

Gabrijelcic

Casas²,

Rabinovich

et al. 2003

Eur Respir J

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Platelet-activating factor (PAF) is an inflammatory mediator that provokes neutropaenia, bronchoconstriction and gas exchange defects due to exudation of bulk plasma within the airways. While the inhibitory effects of short-acting b 2 -agonists on PAF-induced disturbances have been consistently shown, those of longacting b 2 -agonists are less convincing.To further explore the mechanisms involved in PAF challenge in asthma, 12 patients (forced expiratory volume in one second, 90¡4% predicted) were investigated 2 h after inhaled formoterol (18 mg), in a double-blind, placebo-controlled, crossover design following PAF (18 mg) inhalation.Compared with the placebo, at 5 min, premedication with formoterol reduced PAFinduced cough and dyspnoea, and attenuated increased respiratory system resistance (by 67%) and arterial deoxygenation (by 50%). Likewise, ventilation-perfusion (V9A/Q9) inequality improved, as reflected by the dispersion of pulmonary blood flow (by 63%) and an overall index of V9A/Q9 heterogeneity (by 71%). In contrast, PAF-induced facial flushing, neutropaenia and subsequent rebound neutrophilia remained unchanged.The improvement in gas exchange abnormalities shown after platelet-activating factor in patients with asthma pretreated with formoterol at the recommended clinical dose may reflect, in addition to its class effects, an anti-exudative effect of formoterol in the airways. Eur Respir J 2004; 23: 71-75.

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Section: Baseline Findings (Before Platelet-activating Factor)supporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Formoterol protects against platelet-activating factor-induced effects in asthma

Gabrijelcic

Casas²,

Rabinovich

et al. 2003

Eur Respir J

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“…In this study, we found that activation of the PAF-receptor-mediated signaling pathway may be one mechanism by which (S) -albuterol induces HBSMC proliferation. PAF is an endogenous lipid mediator with mitogenic properties [40, 41], and has been reported to aggravate asthmatic conditions [42,43,44,45]. In our study, the specific PAF receptor antagonist CV-3988, at a low concentration of 1 µ M , inhibited (S) -albuterol-induced cell growth, but neither reversed levalbuterol-induced inhibition of cell growth, nor produced additive inhibition with levalbuterol.…”

Section: Discussionmentioning

confidence: 64%

Levalbuterol Inhibits Human Airway Smooth Muscle Cell Proliferation: Therapeutic Implications in the Management of Asthma

Ibe¹,

Portugal²,

Raj³

2006

Int Arch Allergy Immunol

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Background: Racemic albuterol is a mixture of (R)- and (S)-enantiomers of albuterol. Its pharmacological activity and clinical efficacy reside in the (R)-enantiomer (levalbuterol), but the (S)-enantiomer exacerbates airway reactivity in nonclinical models. The role of albuterols in airway smooth muscle cell (SMC) proliferation is not well understood. Methods: The effect of levalbuterol on human bronchial SMC growth was compared with the effects of racemic albuterol and (S)-albuterol. Cells were fed albuterols and ³H-thymidine in 5% FBS and incubated for 24 h. The effect of (S)-albuterol on levalbuterol actions was also studied and so were the effects of cAMP/PKA, PI-3 kinase, NK-ĸB, and retinoblastoma (Rb) proteins on albuterols and human bronchial SMC proliferation. Results: Levalbuterol inhibited cell proliferation at low concentrations. The growth-inhibitory effect of levalbuterol occurs via activation of the cAMP/PKA pathway. Addition of (S)-albuterol to levalbuterol decreased the growth-inhibitory effect of levalbuterol, and (S)-albuterol attenuated levalbuterol-induced cAMP release by 65%. Levalbuterol inhibited NF-ĸB and Rb protein expressions. ICI-118551 abrogated the inhibitory properties of levalbuterol. The PAF receptor antagonist CV-3988 inhibited (S)-albuterol-induced cell growth, with no effect on levalbuterol. Conclusions: Levalbuterol inhibits cell growth by activating the cAMP/PKA pathway and inhibiting PI-3 kinase, NF-ĸB and Rb protein expression, and (S)-albuterol induces cell growth by activating PAF-receptor-mediated cell signaling.

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“…However, fewer clinical studies have addressed a possible effect of ICS on the pulmonary circulation. In asthmatics, inhalation of platelet aggregation factor (PAF) has been used for acute induction of a perfusion-ventilation mismatch in asthmatics [19]. Within 45 minutes after inhalation of fluticasone propionate, the corticosteroid ameliorated the PAF induced gas exchange mismatch, measured as improved systemic arterial oxygen tension.…”

Section: Discussionmentioning

confidence: 99%

Vasoconstriction after inhalation of budesonide: A study in the isolated and perfused rat lung

Ewing

Ryrfeldt

Sjöberg

et al. 2010

Pulmonary Pharmacology & Therapeutics

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Abstract:Clinical studies have shown that inhaled corticosteroids can induce rapid vasoconstriction in the airways, leading to decreased mucosal blood flow. The aim of this study was to investigate whether vasoconstriction of the pulmonary circulation after short inhalation of a corticosteroid can be detected in the isolated and perfused rat lung (IPL) -a model which could serve as a substitute or a complement to clinical models.Methods: IPLs were briefly exposed to dry powder aerosol of budesonide. The pulmonary perfusate flow rate was assessed during 100 minutes post exposure. A reduction in perfusion flow rate was interpreted as vasoconstriction.Main Results: Vasoconstriction was more pronounced after brief inhalation of 10 and 50 μg budesonide than 2 μg. The onset of vasoconstriction became statistically significant within 10-40 minutes after inhalation. Co-administration of a selective α 1 -adrenoceptor antagonist (prazosin 50 nM added to the perfusate) reduced vasoconstriction by approximately 50% during 100 minutes of perfusion (p=0.003).Conclusions: Inhaled budesonide rapidly induces pulmonary vasoconstriction suggesting a nongenomic mechanism probably related to disposition of noradrenaline at the neuro-muscular junction. This ex vivo model could serve as a substitute or a complement to clinical models for investigating rapid effects of glucocorticoid receptor agonists on the pulmonary/bronchial circulation. Word count abstract: 202

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Fluticasone propionate attenuates platelet-activating factor-induced gas exchange defects in mild asthma

Cited by 17 publications

References 29 publications

Formoterol protects against platelet-activating factor-induced effects in asthma

Formoterol protects against platelet-activating factor-induced effects in asthma

Levalbuterol Inhibits Human Airway Smooth Muscle Cell Proliferation: Therapeutic Implications in the Management of Asthma

Vasoconstriction after inhalation of budesonide: A study in the isolated and perfused rat lung

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