Saliva is one likely source of leukotriene B4 in exhaled breath condensate.

Leukotriene (LT)B4 in exhaled breath condensate (EBC) has been reported to be elevated in airway inflammation. The origin of leukotrienes in EBC is, however, not established. The aims of this study are to measure LTB4 levels in EBC collected in two challenges characterised by a strong neutrophilic airway inflammation and to compare LTB4 levels in EBC with levels in sputum and saliva.

The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo.

Lipoxins (LXs) and aspirin-triggered LX (ATL) are trihydroxytetraene-containing eicosanoids generated from arachidonic acid that are distinct in structure, formation, and function from the many other proinflammatory lipid-derived mediators. These endogenous eicosanoids have now emerged as founding members of the first class of lipid/chemical mediators involved in the resolution of the inflammatory response. Lipoxin A(4) (LXA(4)), ATL, and their metabolic stable analogs elicit cellular responses and regulate leukocyte trafficking in vivo by activating the specific receptor, ALX.

Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate.

Background: Inhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved.

Characterisation of guinea pig precision-cut lung slices: comparison with human tissues.

Precision-cut lung slices (PCLS) allow comparison of the airway responses of different species under identical experimental conditions. The aim of this study was to establish and characterise PCLS from guinea pigs (GPs) and to compare them with human PCLS. GP PCLS were prepared according to previously published procedures with the exception that the agarose solution and the initial incubation medium contained isoproterenol to avoid post mortem airway contraction.

Treatment of asthma with antileukotrienes: first line or last resort therapy?

Twenty five years after the structure elucidation of slow reacting substance of anaphylaxis, antileukotrienes are established as a new therapeutic modality in asthma. The chapter reviews the biochemistry and pharmacology of leukotrienes and antileukotrienes with particular focus on the different usage of antileukotrienes for treatment of asthma and rhinitis in Europe and the US. Further research needs and new areas for leukotriene involvement in respiratory diseases are also discussed.

Aggregates of ultrafine particles impair phagocytosis of microorganisms by human alveolar macrophages.

We investigated whether exposure of alveolar macrophages to aggregates of ultrafine carbon particles affected subsequent phagocytosis of microorganisms. Human alveolar macrophages were obtained by bronchoalveolar lavage and exposed to aggregates of ultrafine carbon particles or diesel exhaust particles (DEP) for 20 h before measurements of phagocytosis. The particle loads were estimated to be comparable to those of air pollution exposure with established health effects in humans.

Leukotriene D4-induced hypoxaemia in asthma is mediated by the cys-leukotriene1 receptor.

Bronchoprovocation with cysteinyl-leukotrienes (LTs) induces airflow obstruction and gas exchange abnormalities, namely ventilation-perfusion ratio (V'(A)/Q') imbalance. However, it is unknown which of the two different receptors for cysteinyl-LTs mediate these V'(A)/Q' disturbances. In a double-blinded, crossover design, 10 patients with mild asthma were randomised to receive an oral single dose of the selective cysteinyl-LT1 receptor antagonist montelukast (40 mg) or placebo before leukotriene (LT)D4 inhalation challenge.

Relation between bronchial responsiveness to inhaled leukotriene D4 and markers of leukotriene biosynthesis.

Background: While clinical trials with antileukotrienes have shown overall beneficial effects in asthma, the factors that determine leukotriene dependent asthma are still unclear. A study was undertaken to determine whether or not leukotriene responsiveness in the airways correlates with endogenous leukotriene biosynthesis.

Methods: Bronchial responsiveness to leukotriene (LT) D4 was assessed as PD20FEV1 in 20 subjects with mild asthma and 10 healthy controls, and compared with bronchial responsiveness to methacholine and two global measures of leukotriene production-urinary LTE4 and ex vivo production of LTB4 in whole blood.

Inhibition of nitric-oxide synthase enhances antigen-induced contractions and increases release of cysteinyl-leukotrienes in guinea pig lung parenchyma: nitric oxide as a protective factor.

Nitric oxide (NO) in exhaled air is a biomarker of airway inflammation. However, the role of NO in the peripheral lung is not known. The aim of this study was to determine the role of endogenous NO in antigen-induced contractions of ovalbumin (OVA)-sensitized guinea pig lung parenchyma (GPLP).

Effects of 5-lipoxygenase inhibitor zileuton on airway responses to inhaled swine house dust in healthy subjects.

Background: Inhalation of swine house dust induces acute airway inflammation and increased bronchial responsiveness in healthy subjects.

Objective: The aim of the study was to investigate whether 5-lipoxygenase products such as leukotrienes may have a role in this reaction.

Methods: Twenty-three healthy subjects were randomised into two groups receiving treatment with either zileuton (600 mg) or placebo four times a day.

International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor.

Oxoeicosanoids are a family of biologically active arachidonic acid derivatives that have been intimately linked with cellular migration. These metabolites are not only potent chemotaxins but also elicit oxygen radical production as well as induce secretory events in different cells. The most potent native ligand reported is 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and the cell membrane receptor activated has now been cloned.

The contractile action of leukotriene B4 in the guinea-pig lung involves a vascular component.

Leukotriene B4 (LTB4) is a potent leukocyte chemoattractant, acting on specific receptors, BLT receptors. The aim of this study was to examine the mechanism of action of LTB4 in the guinea-pig lung, using strips of lung parenchyma (GPLP), spirals of trachea (GPT) and bronchus (GPB) and rings of pulmonary artery (GPPA). Mechanical responses were studied in organ baths, and mediator release was assessed using enzyme immuno assay.

High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma.

Urinary LTE4 reflects the whole body production of the cysteinyl-leukotrienes (LTC4, LTD4 and LTE4) that are established mediators in asthma. The influence of chronic inhaled and oral glucocorticoid treatment on urinary excretion of leukotriene (LT) E4 was investigated in subjects with asthma. Enzyme immunoassay analysis of LTE4 was performed in spot urine samples collected from 40 patients with severe asthma, 25 patients with mild-moderate asthma and 20 non-asthmatic control subjects.

Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung.

Intravascular challenge of isolated perfused and ventilated guinea pig lung (IPL) from actively sensitized guinea pigs, with cumulatively increasing (10-10,000 microg) doses of ovalbumin (OVA), resulted in dose-dependent and reproducible reductions in lung conductance. The antihistamines mepyramine (1 microM) and metiamide (1 microM), the leukotriene antagonist zafirlukast (0.1 microM), or the cyclooxygenase enzyme (COX) inhibitor diclofenac (10 microM) each caused a parallel and rightward shift in the dose-response relation for OVA, providing evidence for contributions of histamine, cysteinyl-leukotrienes, and COX products to the OVA-induced bronchoconstriction in the IPL.

Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib.

Background: Subjects with aspirin-intolerant asthma (AIA) respond with bronchoconstriction and extrapulmonary adverse reactions to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit the cyclooxygenase (COX) step in the biosynthesis of prostaglandins. Recently, 2 isotypes of COX have been identified, and COX-2-selective NSAIDs have been developed for treatment of inflammatory disorders.

Objective: We investigated whether 33 subjects with a typical history of AIA tolerated the new COX-2-selective NSAID celecoxib.

International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors.

The leukotrienes and lipoxins are biologically active metabolites derived from arachidonic acid. Their diverse and potent actions are associated with specific receptors. Recent molecular techniques have established the nucleotide and amino acid sequences and confirmed the evidence that suggested the existence of different G-protein-coupled receptors for these lipid mediators.

Pharmacological evidence for a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle.

1. To characterize the cysteinyl-leukotriene receptors (CysLT receptors) in isolated human pulmonary arteries, ring preparations were contracted with leukotriene C(4) (LTC(4)) and leukotriene D(4) (LTD(4)) in either the absence or presence of the selective CysLT(1) receptor antagonists, ICI 198615, MK 571 or the dual CysLT(1)/CysLT(2) receptor antagonist, BAY u9773. 2.

Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction.

Background: Airway obstruction induced by physical exercise is a common feature in asthma, and conventional treatments do not offer optimal protection. There is thus a need for additional therapies for optimal control of exercise-induced bronchoconstriction (EIB).

Objective: The influence of treatment with the antihistamine loratadine and the antileukotriene zafirlukast alone and in combination on EIB was investigated.

Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial.

Leukotriene antagonists block the proinflammatory actions of leukotrienes (LT) and have been introduced as new treatments for asthma. Conventional therapy with glucocorticosteroids does not inhibit the biosynthesis of leukotrienes. We therefore tested whether addition of the leukotriene receptor antagonist montelukast was of therapeutic benefit in a group of aspirin-intolerant patients with asthma of whom 90% already were treated with moderate to high doses of glucocorticosteroids.

An alternative pathway for metabolism of leukotriene D(4): effects on contractions to cysteinyl-leukotrienes in the guinea-pig trachea.

Contractions of guinea-pig tracheal preparations to cysteinyl-leukotrienes (LTC(4), LTD(4) and LTE(4)) were characterized in organ baths, and cysteinyl-leukotriene metabolism was studied using radiolabelled agonists and RP-HPLC separation. In the presence of S-hexyl GSH (100 microM) the metabolism of [(3)H]-LTC(4) into [(3)H]-LTD(4) was inhibited and the LTC(4)-induced contractions were resistant to CysLT(1) receptor antagonism but inhibited by the dual CysLT(1)/CysLT(2) receptor antagonist BAY u9773 (0.3 - 3 microM) with a pA(2)-value of 6.

Pulmonary gas exchange and sputum cellular responses to inhaled leukotriene D(4) in asthma.

Inhalational challenges with inflammatory mediators may provoke lung function disturbances similar to those shown in spontaneous acute asthma. Cysteinyl leukotrienes (CysLTs) have recently been established as mediators of bronchoconstriction in asthma but their effects on pulmonary gas exchange in asthma have not been assessed. We therefore investigated the effects of leukotriene D(4) (LTD(4)) challenge resulting in a significant decrease in FEV(1) (mean +/- SE, by 32 +/- 3%) in 13 nonsmoking, mild asthmatics.

Health effects of diesel exhaust emissions.

Epidemiological studies have demonstrated an association between different levels of air pollution and various health outcomes including mortality, exacerbation of asthma, chronic bronchitis, respiratory tract infections, ischaemic heart disease and stroke. Of the motor vehicle generated air pollutants, diesel exhaust particles account for a highly significant percentage of the particles emitted in many towns and cities. This review is therefore focused on the health effects of diesel exhaust, and especially the particular matter components.

Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids.

Some patients with severe asthma cannot be controlled with high doses of inhaled steroids (ICS), which may be related to ongoing environmental allergen exposure. We investigated whether 10 weeks of high altitude allergen avoidance leads to sustained benefits regarding clinical and inflammatory markers of disease control in adolescents with persistent asthma despite treatment with high dose ICS. Eighteen atopic asthmatic adolescents (12-18 yr, 500-2000 microg ICS daily) with established house dust mite allergy, participated in a parallel-group study.