Dataset Information

Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.

ABSTRACT:

Background

In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown.

Methods

In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) 2 h after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three-week courses. We examined the effect of the leukotriene C(4) synthase (LTC(4)S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner.

Results

In 37 subjects, 2 h after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV(1) (HS-PD(20)) increased by 59% (9.17 ml after placebo vs. 14.55 ml after montelukast, p=0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD(20) by 84% (10.97 vs. 20.21 ml, p=0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper-responsiveness (2 h vs. three-week HS-PD(20) values 14.55 vs. 20.21 ml respectively, p=0.0898). We did not observe an effect of the LTC(4)S polymorphism on the response to CysLTR1 antagonism in this cohort.

Conclusions

A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism. Clinicaltrials.gov registration number NCT00116324.

SUBMITTER: Kazani S

PROVIDER: S-EPMC3080101 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.

Kazani Shamsah S Sadeh Jonathan J Bunga Sreedhar S Wechsler Michael E ME Israel Elliot E

Respiratory medicine 20101218 5

<h4>Background</h4>In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown.<h4>Methods</h4>In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate as ...[more]

PMID: 21169002

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Project description:Rationale: Acute exposure to ambient particle matter is associated with increased levels of the cysteinyl leukotriene (CysLT) biomarker, urinary leukotriene E4 (uLTE4), in subjects with asthma. Objectives: The role of CysLTs in mediating asthma worsening after particulate matter exposures was explored. Methods: Daily concentrations of particulate matter of 2.5 ?m and smaller diameter (PM2.5) and repeated measurements of albuterol use over a 5-month period were collected in 44 urban school children with persistent asthma. DNA was analyzed for gene polymorphisms on genes involved in the CysLT pathway to identify gene–environment interactions. An experimental challenge study in 16 adults with mild, nonpersistent asthma was performed to define biological pathways explaining these gene–environment interactions. Subjects in the challenge study were exposed on two different days to filtered air or diesel exhaust (300 ?g PM2.5/m3). FEV1 and CysLT-related gene DNA methylation and messenger RNA expression changes were measured before and 6 hours after exposure challenges. Results: In school children with asthma, associations between PM2.5 and school-time albuterol usage were significantly greater in those with the variant C allele in the CysLT receptor 1 (CysLTR1) rs320995 locus (5.4% increase per interquartile range PM2.5 increase) compared with those homozygous for the wild-type T allele (1.6% decrease; P?=?0.005 for allele?×?PM2.5 interaction). In the challenge study, declines in forced expiratory volume in 1 second after diesel exhaust exposure were associated with lower CysLTR1 expression (r2?=?0.52; P?=?0.01), which, in turn, was associated with decreased leukotriene C4 synthase cg1631890 (P?=?0.02) and increased CysLTR1 cg26848126 (P?=?0.01) methylation, as assessed in a multivariable model (r2?=?0.69). Conclusions: Health effects of acute particulate exposure on asthma are associated with changes in CysLTR1 expression and methylation of CpG sites on CysLTR1 and leukotriene C4 synthase genes.

Project description:IntroductionIn series of cases and animal models suffering hemorrhagic shock, the use of vasopressors has shown potential benefits regarding hemodynamics and tissue perfusion. Terlipressin is an analogue of vasopressin with a longer half-life that can be administered by bolus injection. We have previously observed that hypertonic albumin improves resuscitation following controlled hemorrhage in piglets. The aim of the present study was to analyze whether the treatment with the combination of terlipressin and hypertonic albumin can produce better hemodynamic and tissular perfusion parameters than normal saline or hypertonic albumin alone at early stages of hemorrhagic shock in an infant animal model.MethodsExperimental, randomized animal study including 39 2-to-3-month-old piglets. Thirty minutes after controlled 30 ml/kg bleed, pigs were randomized to receive either normal saline (NS) 30 ml/kg (n = 13), 5% albumin plus 3% hypertonic saline (AHS) 15 ml/kg (n = 13) or single bolus of terlipressin 15 μg/kg i.v. plus 5% albumin plus 3% hypertonic saline 15 ml/kg (TAHS) (n = 13) over 30 minutes. Global hemodynamic and tissular perfusion parameters were compared.ResultsAfter controlled bleed a significant decrease of blood pressure, cardiac index, central venous saturation, carotid and peripheral blood flow, brain saturation and an increase of heart rate, gastric PCO2 and lactate was observed. After treatment no significant differences in most hemodynamic (cardiac index, mean arterial pressure) and perfusion parameters (lactate, gastric PCO2, brain saturation, cutaneous blood flow) were observed between the three therapeutic groups. AHS and TAHS produced higher increase in stroke volume index and carotid blood flow than NS.ConclusionsIn this pediatric animal model of hypovolemic shock, albumin plus hypertonic saline with or without terlipressin achieved similar hemodynamics and perfusion parameters than twice the volume of NS. Addition of terlipressin did not produce better results than AHS.

Dataset Information

Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.

Background

Methods

Results

Conclusions

Publications

Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.

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