bronchial hyperreactivity (BHR)

Somatostatin released from activated capsaicin-sensitive afferents of the lung inhibits inflammation and related bronchial hyperreactivity presumably via somatostatin 4 receptors (sst 4 ). The aim of this study was to examine the effects of TT-232, a heptapeptide sst 4 /sst 1 receptor agonist and J-2156, a high affinity sst 4 receptor-selective peptidomimetic agonist in airway inflammation models. Acute pneumonitis was evoked by intranasal lipopolysaccharide 24 h before measurement. Chronic inflammation was induced by ovalbumin inhalation on days 28, 29 and 30 after i.p. sensitization on days 1 and 14. Semiquantitative histopathological scoring was based on perivascular/peribronchial oedema, neutrophil/macrophage infiltration, goblet cell hyperplasia in the acute model and eosinophil infiltration, mucosal oedema, mucus production and epithelial cell damage in chronic inflammation. Myeloperoxidase activity of the lung was measured spectrophotometrically to quantify granulocyte accumulation and the broncoalveolar lavage fluid was analysed by flow cytometry. Carbachol-induced bronchoconstriction was assessed by unrestrained whole body plethysmography and its calculated indicator, enhanced pause (Penh) was determined. TT-232 and J-2156 induced similar inhibition on granulocyte recruitment and histopathological changes in both models, although macrophage infiltration in LPS-induced inflammation was unaltered by either compounds. Both agonists diminished inflammatory airway hyperresponsiveness. Since their single administration after the development of the inflammatory reactions also inhibited carbachol-induced bronchoconstriction, somatostatin sst 4 receptor activation on bronchial smooth muscle cells is likely to be involved in their anti-hyperreactivity effect. These results suggest that stable, somatostatin sst 4 receptor-selective agonists could be potential candidates for the development of a completely novel group of anti-inflammatory drugs for the treatment of airway inflammation and hyperresponsiveness.

Background: Airway hyperresponsiveness (AHR) to pharmacologic stimuli and sputum eosinophils might be useful in the individual adjustment of long-term asthma management. However, it is not clear whether inhaled glucocorticosteroids (GCSs) provide greater protection against specific surrogate markers of airways inflammation than other means. In addition, detailed longitudinal assessment of changes in airway response with inhaled GCSs has never been carried out. Objectives: We compared changes in AHR to inhaled methacholine and adenosine 5′-monophosphate (AMP) after budesonide treatment in a randomized, double-blind, placebo-controlled, crossover study of patients with mild-to-moderate asthma. Subsequently, we undertook a separate study to examine the time course of the changes in AHR in more detail and the changes in sputum cell counts in relation to budesonide treatment. Methods: In the phase 1 of the study, patients undertook bronchial provocation studies with increasing doubling concentrations of methacholine (0.06 to 16 mg/mL) and AMP (3.125 to 800 mg/mL) before and after budesonide 0.8 mg/daily for 3 weeks. The bronchial responses to the inhaled agonists were expressed as the provocative concentration causing a 20% decline in FEV 1 (PC 20 ). In phase 2 of the study, patients attended the laboratory on 12 separate occasions to investigate changes in PC 20 methacholine, PC 20 AMP, and sputum cell counts before, during, and after withdrawal of therapy with inhaled budesonide 0.8 mg/daily for 6 weeks. Results: Budesonide treatment for 3 weeks significantly attenuated the constrictor response by 0.8 ± 0.3 doubling doses for methacholine and by 2.6 ± 0.5 doubling doses for AMP. These changes were significantly different from each other (P = .003). Significant variation in PC 20 methacholine (P < .05) value, PC 20 AMP (P < .001) value, percentage of sputum eosinophils (P < .001), and percentage of sputum epithelial cells (P < .001) were observed throughout the longitudinal assessment of changes in airway response to budesonide. Compared with the other surrogate markers, PC 20 AMP appears to be useful in promptly detecting early inflammatory changes of the asthmatic airways; a significant change of 1.6 ± 0.3, 2.2 ± 0.3, and 2.8 ± 0.3 doubling doses of PC 20 AMP was observed at 1, 4, and 6 weeks, respectively, in the course of budesonide treatment. Conclusions: The present findings underline the exquisite selectivity of diverse surrogate markers of airway inflammation in response to inhaled budesonide. When compared with that to the other markers, AHR to inhaled AMP is an early and sensitive indicator of the beneficial anti-inflammatory effects of topical GCSs. (J Allergy Clin Immunol 2002;110:855-61.)

Background: Inhalation of diluent is often used in performing methacholine challenge tests, but its elimination has been suggested because marked falls in FEV 1 after diluent inhalation have not been documented and performing this step is time-consuming.

Lieke Schiphof-Godart ([email protected]) Erica van der Wiel ([email protected]) Nick HT ten Hacken ([email protected]) Maarten van den Berge (m. [email protected]) Dirkje S Postma ([email protected]) Thys van der Molen Abstract Background Small airways dysfunction (SAD) contributes to the clinical expression of asthma. The identification of patients who suffer from SAD is important from a clinical perspective, as targeted therapy may improve patients' well-being and treatment efficacy.

Introduction: The purpose of this analysis was to determine if abnormal diffusing capacity of the lung for carbon monoxide (DLco) identified a group of subjects with significantly different characteristics than those with normal lung function or airflow obstruction alone. Methods: Participants were a random sample of adults aged 45-70 years. They completed a detailed respiratory questionnaire, spirometry, methacholine challenge and measurement of single breath DLco. Subjects were categorized into one of three groups: airflow obstruction only, reduced DLco only, or both airflow obstruction and reduced DLco. Results: Individuals with airflow obstruction and reduced DLco in combination reported more symptoms than those with either condition alone. In subjects with a combination of both airflow obstruction and reduced DLco, a significantly higher proportion reported use of medication and laboratory tests. Current smoking was significantly associated with a reduced DLco alone and in combination with airflow obstruction, however, the association was stronger in those with DLco and airflow obstruction. Bronchial hyperreactivity (BHR) was found to be a risk factor while atopy was associated with a reduced risk of DLco and airflow obstruction. Conclusions: Reduced DLco plus airflow obstruction together identifies a group of individuals with significantly more symptoms and worse lung function. Current cigarette smoking, early life serious respiratory infection and BHR were strongly associated with reduced DLco in combination with airflow obstruction.