Effects of (a Combination of) the Beta-Adrenoceptor Agonist Indacaterol and the Muscarinic Receptor Antagonist Glycopyrrolate on Intrapulmonary Airway Constriction.

Expression of bronchodilatory β-adrenoceptors and bronchoconstrictive muscarinic M-receptors alter with airway size. In COPD, (a combination of) β-agonists and muscarinic M-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β-agonists and anticholinergics in COPD.

Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices.

The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk.

The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease.

COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, β2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD.

Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease.

Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown.

Bronchoprotection by olodaterol is synergistically enhanced by tiotropium in a guinea pig model of allergic asthma.

The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen.

Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD.

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling.

Increased arginase activity contributes to airway remodelling in chronic allergic asthma.

Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and l-proline downstream of the arginase product l-ornithine, and via reduced nitric oxide synthesis. Using the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma.

Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation.

Rationale: In a guinea pig model of allergic asthma, using perfused tracheal preparations ex vivo, we demonstrated that L-arginine limitation due to increased arginase activity underlies a deficiency of bronchodilating nitric oxide (NO) and airway hyperresponsiveness (AHR) after the allergen-induced early and late asthmatic reaction.

Objectives: Using the same animal model, we investigated the acute effects of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) and of L-arginine on AHR after the early and late reaction in vivo. In addition, we investigated the protection of allergen-induced asthmatic reactions, AHR, and airway inflammation by pretreatment with the drug.

The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation.

Recently, we have shown that allergen-induced airway hyperresponsiveness (AHR) after the early (EAR) and late (LAR) asthmatic reaction in guinea pigs could be reversed acutely by inhalation of the Rho kinase inhibitor Y-27632. The present study addresses the effects of pretreatment with inhaled Y-27632 on the severity of the allergen-induced EAR and LAR, the development of AHR after these reactions, and airway inflammation. Using permanently instrumented and unrestrained ovalbumin (OA)-sensitized guinea pigs, single OA challenge-induced EAR and LAR, expressed as area under the lung function (pleural pressure, P(pl)) time-response curve, were measured, and histamine PC(100) (provocation concentration causing a 100% increase of P(pl)) values were assessed 24 h before, and at 6 and 24 h after, the OA challenge (after the EAR and LAR, respectively).

Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison.

Chronic inflammation in asthma and chronic obstructive pulmonary disease drives pathological structural remodelling of the airways. Using tiotropium bromide, acetylcholine was recently identified as playing a major regulatory role in airway smooth muscle remodelling in a guinea pig model of ongoing allergic asthma. The aim of the present study was to investigate other aspects of airway remodelling and to compare the effectiveness of tiotropium to the glucocorticosteroid budesonide.

A guinea pig model of acute and chronic asthma using permanently instrumented and unrestrained animals.

To investigate mechanisms underlying allergen-induced asthmatic reactions, airway hyperresponsiveness and remodeling, we have developed a guinea pig model of acute and chronic asthma using unanesthetized, unrestrained animals. To measure airway function, ovalbumin (IgE)-sensitized animals are permanently instrumented with a balloon-catheter, which is implanted inside the pleural cavity and exposed at the neck of the animal. Via an external cannula, the balloon-catheter is connected to a pressure transducer, an amplifier, an A/D converter and a computer system, enabling on-line measurement of pleural pressure (P(pl))-closely correlating with airway resistance-for prolonged periods of time.

Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction.

Background: In guinea pigs, we have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA). Using conscious, unrestrained OA-sensitized guina pigs, we now investigated the role of Rho-kinase in the development of airway hyperresponsiveness (AHR) after the allergen-induced early (EAR) and late asthmatic reaction (LAR) in vivo.

Methods: Histamine and PGF2alpha PC100-values (provocation concentrations causing 100% increase in pleural pressure) were assessed before OA-challenge (basal airway responsiveness) and after the OA-induced EAR (5 h after challenge) and LAR (23 h after challenge).

Inhibition of Rho-kinase normalizes nonspecific hyperresponsiveness in passively sensitized airway smooth muscle preparations.

Currently, little is known about mechanisms underlying passive sensitization-induced nonspecific airway hyperresponsiveness. We sought to determine whether the nonspecific airway hyperresponsiveness observed after passive sensitization involves an increased role of Rho-kinase in airway smooth muscle contraction. In addition, the contribution of Rho-kinase to specific allergen-induced airway smooth muscle contraction was studied.

Effects of salbutamol and enantiomers on allergen-induced asthmatic reactions and airway hyperreactivity.

Salbutamol consists of a racemic mixture of R- and S-salbutamol. R-salbutamol (levalbuterol) is the active bronchodilating enantiomer, whereas S-salbutamol is thought to be pharmacologically inactive or to exert adverse effects. This study evaluated the bronchoprotective effects of inhalation of therapeutically relevant doses of the racemate and individual enantiomers in guinea pigs.

Inflammatory cell distribution in guinea pig airways and its relationship to airway reactivity.

Although airway inflammation and airway hyperreactivity are observed after allergen inhalation both in allergic humans and animals, little is known about the mechanisms by which inflammatory cells can contribute to allergen-induced airway hyperreactivity. To understand how inflammatory cell infiltration can contribute to airway hyperreactivity, the location of these cells within the airways may be crucial Using a guinea pig model of acute allergic asthma, we investigated the inflammatory cell infiltration in different airway compartments at 6 and 24 h (i.e.

Relatives of hospitalized stroke patients: their needs for information, counselling and accessibility.

Aim Of The Study: The purpose of this study is to explore the needs of stroke patients' relatives during the hospitalization period.

Background: In the Netherlands, the consequences of a stroke, and the needs of stroke patients and their relatives are becoming increasingly important. In hospital, however, nursing care is still focused on the patients.

(1-->3)-beta-D-glucan and endotoxin in house dust and peak flow variability in children.

House dust-associated bacterial endotoxins have been shown to be associated with asthma severity, and a similar role has been suggested for fungal (1-->3)-beta-D-glucans. In this study the relation between these agents and peak expiratory flow (PEF) variability was investigated in 148 children 7 to 11 yr of age of whom 50% had self- or parent-reported chronic respiratory symptoms. All children self-monitored twice daily their PEF for a period of 16 wk.

Role of tachykinin NK2-receptor activation in the allergen-induced late asthmatic reaction, airway hyperreactivity and airway inflammatory cell influx in conscious, unrestrained guinea-pigs.

1. In a guinea-pig model of allergic asthma, we investigated the involvement of the tachykinin NK2 receptors in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and inflammatory cell influx in the airways, using the selective non-peptide NK2 receptor antagonist SR48968. 2.

Role of tachykinin NK1 and NK2 receptors in allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs.

Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK1 and NK2 receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK2 receptor antagonist SR 48968, but not the NK1 receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR.

Involvement of tachykinin NK1 receptor in the development of allergen-induced airway hyperreactivity and airway inflammation in conscious, unrestrained guinea pigs.

It has been suggested that tachykinin NK1 receptor-mediated neurogenic inflammation, characterized by microvascular leakage, mucus secretion, and infiltration and activation of inflammatory cells in the airways, may be involved in allergic asthma. Therefore, in a guinea pig model of allergic asthma, we investigated the involvement of the NK1 receptor in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and airway inflammation, using the selective nonpeptide NK1 receptor antagonist SR140333. On two different occasions, separated by 1 wk interval, OA-sensitized guinea pigs inhaled either saline (3 min) or SR140333 (100 nM, 3 min) at 30 min before as well as at 5.

Dual action of iNOS-derived nitric oxide in allergen-induced airway hyperreactivity in conscious, unrestrained guinea pigs.

Using a guinea pig model of acute allergic asthma, we recently established that a deficiency of nitric oxide (NO) contributes to airway hyperreactivity (AHR) after the early asthmatic reaction (EAR) and that restoration of NO activity may contribute to the (partial) reversal of AHR after the late asthmatic reaction (LAR). In the present study, we investigated the role of iNOS-derived NO in the regulation of AHR to histamine after the LAR. Inhalation of a selective dose of the specific iNOS inhibitor aminoguanidine (0.

Role of nitric oxide in the development and partial reversal of allergen-induced airway hyperreactivity in conscious, unrestrained guinea-pigs.

1. Using a conscious, unrestrained guinea-pig model of allergic asthma, we investigated the role of endogenous nitric oxide (NO) in the regulation of airway (hyper)reactivity to histamine before and after the allergen-induced early and late asthmatic reactions, by examining the effect of inhalation of the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 12 mM, 15 min) on the histamine-induced airway obstruction of ovalbumin-sensitized guinea-pigs before, and at 5.5 h and 23.

Personal sampling of particles in adults: relation among personal, indoor, and outdoor air concentrations.

To investigate the validity of outdoor particulate matter with a 50% cutoff diameter of 10-microm (PM10) concentrations as a measure of exposure in time series studies, the association between personal and outdoor concentrations, within subjects, over time was investigated. Repeated measurements of personal, indoor, and outdoor PM10 were conducted among 37 nonsmoking, 50- to 70-year-old adults, living in Amsterdam, Netherlands, 1994. Regression analyses were conducted for each subject separately, and the distribution of the individual regression and correlation coefficients was investigated.