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Background: About 5-10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1).Methods: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 mug/ml) and dexamethasone (10(-8) and 10(-6) M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts.Results: The inhibition of LPS-induced interleukin (IL)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha release by dexamethasone (10(-6) M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma.Conclusion: Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1. [ABSTRACT FROM AUTHOR]

Background: Bronchiectasis is a suppurative airway disease characterised by persistent cough and sputum production associated with bronchial dilatation. A study was undertaken to determine whether cough sensitivity is increased in bronchiectatic patients.Methods: Twenty two patients with bronchiectasis and 20 healthy non-smoking controls matched for age and sex were recruited into the study. Quality of life (Leicester Cough Questionnaire score), total cough symptom score, and extent of bronchiectasis on HRCT scans were recorded. Cough sensitivity was assessed using incremental inhalation of capsaicin concentrations; the concentration at which 5 or more coughs occurred (C5) was recorded.Results: Patients with bronchiectasis had increased sensitivity to capsaicin compared with controls (mean (SE) log10 C5 1.22 (0.20) v 1.89 (0.21); p<0.03). Capsaicin sensitivity correlated positively with the Leicester Cough Questionnaire score (r = 0.64; p = 0.005) and inversely with the total cough symptom score (r = -0.58; p = 0.004), but not with the extent of the disease. It also correlated with forced expiratory volume in 1 second (FEV1) in litres (r = 0.58; p = 0.005) but not with FEV1 % predicted. Capsaicin sensitivity was not related to the presence of infected sputum or to corticosteroid or bronchodilator use.Conclusions: : Patients with bronchiectasis have a sensitive cough reflex which reflects the severity of cough symptoms. A measure of cough severity could be part of health assessment for patients with bronchiectasis. [ABSTRACT FROM AUTHOR]

Background: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown.Methods: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20.Results: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference -0.5 to -0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI -3.1 to -0.2, p = 0.007), and C5 (median 3.9 v 125 micro M, 95% CI -270.0 to -17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge.Conclusions: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex. [ABSTRACT FROM AUTHOR]

Background: Eotaxin is a chemokine specific for eosinophils and may play an important role in eosinophil recruitment in asthma. The effects of eotaxin inhalation on sputum and blood eosinophils, exhaled nitric oxide (NO), and bronchial responsiveness were determined. Methods: Eotaxin was administered by nebulisation to asthma patients in three studies: (1) an open dose finding study with eotaxin (5, 10 and 20 μg) to two asthmatic subjects; (2) a randomized placebo controlled study with 20 μg eotaxin to five asthmatic subjects and five normal volunteers; and (3) a randomized placebo controlled study with 40 μg eotaxin to nine asthmatics. Forced expiratory volume in 1 second (FEY1), exhaled NO, and blood eosinophils were measured before and hourly for 5 hours after nebulisation and at 24 and 72 hours. Methacholine bronchial challenge and sputum induction were performed before and at 5, 24, and 72 hours after inebriation. Results: In the two placebo controlled studies there was no change in sputum eosinophil count and sputum eosinophilic cationic protein concentration after eotaxin inhalation compared with placebo. FEY1, exhaled NO, and methacholine PC20 did not change. However, high dose eotaxin (40 jig) induced an increase in sputum neutrophil count compared with placebo (pcO.O5). Conclusions: Inhaled eotaxin up to 40 jig induced no changes in sputum eosinophil count but at 40 jig it increased the sputum neutrophil count. The significance of this finding is unknown. [ABSTRACT FROM AUTHOR]

Background: Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations.Methods: Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability.Results: Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p<0.05).Conclusions: NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD [ABSTRACT FROM AUTHOR]

Background: Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment.Methods: Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the beta-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue.Results: PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2.Conclusions: These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics. [ABSTRACT FROM AUTHOR]

Background: Interleukin 5 (IL-5) has an important role in mobilisation of eosinophils from the bone marrow and in their subsequent terminal differentiation. A study was undertaken to determine whether inhaled and intravenous IL-5 could induce pulmonary eosinophilia and bronchial hyperresponsiveness (BHR) independently of these effects.Methods: Nine mild asthmatics received inhaled (15 microg) or intravenous (2 microg) IL-5 or placebo in random order in a double blind, crossover study. Blood samples were taken before and at 0.5, 1, 2, 3, 4, 5, 24, and 72 hours following IL-5 or placebo, and bronchial responsiveness (PC(20) methacholine) and eosinophil counts in induced sputum were determined.Results: Serum IL-5 levels were markedly increased 30 minutes after intravenous IL-5 (p=0.002), and sputum IL-5 levels increased 4 and 24 hours after inhaled IL-5 (p<0.05). Serum eotaxin was raised 24 hours after intravenous IL-5 but not after inhaled IL-5 or placebo. Blood eosinophils were markedly reduced 0.5-2 hours after intravenous IL-5 (p<0.05), followed by an increase at 3, 4, 5, and 72 hours (p<0.05). Sputum eosinophils rose significantly in all three groups at 24 hours but there were no differences between the groups. Bronchial responsiveness was not affected by IL-5.Conclusion: The effects of IL-5 appear to be mainly in the circulation, inducing peripheral mobilisation of eosinophils to the circulation without any effect on eosinophil mobilisation in the lungs or on bronchial responsiveness. [ABSTRACT FROM AUTHOR]

Background: Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma.Methods: In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 microgram beclomethasone dipropionate (BDP) daily and inhaled beta(2) agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 microgram BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 microgram BDP) over a six month period was examined.Results: One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) -2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects.Conclusion: There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects. [ABSTRACT FROM AUTHOR]

Background: Exhaled levels of nitric oxide (NO) are raised in asthma but the relationship between exhaled NO levels and a direct measure of airway inflammation has not been investigated in asthmatic patients treated with inhaled steroids.Methods: The relationship between exhaled NO levels, clinical measures of asthma control, and direct markers of airway inflammation were studied in patients with asthma treated with and without inhaled corticosteroids. Thirty two asthmatic patients (16 not using inhaled steroids and 16 using inhaled beclomethasone dipropionate, 400-1000 microg/day) were monitored with respect to measures of asthma control including lung function, symptom scores, medication usage, and variability of peak expiratory flow (PEF) for one month. Measurements of exhaled NO and fibreoptic bronchoscopy were performed at the end of the monitoring period. Bronchial mucosal biopsy specimens were stained with an anti-MBP antibody for quantification of eosinophils.Results: There was no significant difference in lung function, symptom scores, or medication usage between the two groups, but there was a significant difference in PEF variability (8.7 (1.2)% in steroid naive patients versus 13.6 (1.9)% in steroid treated patients, p<0.05) and exhaled NO levels (9.9 (3.5) ppb in steroid naive patients versus 13.6 (2.0) ppb in steroid treated patients, p<0.05). There was no correlation between exhaled NO and mucosal eosinophils, or between NO and conventional measures of asthma control. There was a significant correlation between mucosal eosinophils and lung function (r = -0.43, p<0.05).Conclusions: Exhaled NO levels do not reflect airway mucosal eosinophilia and these markers reflect different aspects of airway inflammation. The clinical usefulness of exhaled NO needs to be determined in prospective longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of non-asthmatic chronic dry cough remains unclear.Methods: A study was undertaken to determine whether airway inflammation could be a contributing factor by analysing inflammatory cells and cytokines in induced sputum from 19 patients with chronic dry cough of varying aetiology, excluding asthma and bronchiectasis, and from 10 normal controls. The associated causes for the chronic cough were postnasal drip (n = 5), gastro-oesophageal reflux (n = 4), and idiopathic (n = 10). All patients had an enhanced cough reflex to capsaicin.Results: Sputum neutrophilia (median (interquartile range)) was found in the patients with chronic cough (59.4 (27.1)%) compared with the normal controls (28.4 (22.0)%; p < 0.01, 95% CI 11.3 to 42.2). Sputum levels of interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) were also significantly increased compared with normal controls (0.57 (1.08) and 0.25 (0.72) ng/ml; p < 0.05 (95% CI 0.05 to 1.75) for IL-8; 48.3 (34.4) and 12.6 (33.6) pg/ml, p < 0.01 (95% CI 8.8 to 69.8) for TNF-alpha).Conclusion: Neutrophils and cytokines associated with neutrophil chemotaxis and activation may contribute to the pathogenesis of non-asthmatic chronic dry cough. [ABSTRACT FROM AUTHOR]

Background: Patients with difficult asthma suffer chronic moderate to severe persistent asthma symptoms despite high doses of inhaled and oral corticosteroid therapy. These patients suffer a high level of treatment and disease related morbidity but little is known about the degree of airway inflammation in these patients.Methods: Fifty two patients were examined to assess levels of exhaled nitric oxide (NO) as a surrogate marker of inflammatory activity in this condition. From this group, 26 patients were defined with severe symptoms and current physiological evidence of reversible airway obstruction requiring high dose inhaled (> or = 2000 micrograms beclomethasone dipropionate (BDP) equivalent) or oral steroid therapy to maintain disease control.Results: Exhaled NO levels were higher in subjects with difficult asthma (mean 13.9 ppb, 95% CI 9.3 to 18.5) than in normal controls (7.4 ppb, 95% CI 6.9 to 7.8; p < 0.002), but lower than levels in steroid naive mild asthmatics (36.9 ppb, 95% CI 34.6 to 39.3; p < 0.001). Prednisolone treated patients had higher exhaled NO levels than patients only requiring inhaled corticosteroids (17.5 ppb, 95% CI 11.1 to 24.0 versus 7.2 ppb, 95% CI 4.6 to 9.8; p = 0.016), suggesting greater disease severity in this group. Non-compliance with prednisolone treatment was observed in 20% of patients but this did not explain the difference between the treatment groups. Exhaled NO levels were closely correlated with symptom frequency (p = 0.03) and with rescue beta agonist use (p < 0.002), but they did not correlate with lung function.Conclusions: Exhaled NO may serve as a useful complement to lung function and symptomatology in the assessment of patients with chronic severe asthma, and in the control and rationalisation of steroid therapy in these patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the airway and cough responsiveness in non-smoking patients with stable chronic heart failure. Cough and wheeze, features associated with hyper-responsive airways, are not uncommon especially in decompensated chronic heart failure. Bronchial hyperresponsiveness has previously been demonstrated in chronic heart failure but this may have been confounded by smoking and acute decompensation. DESIGN: Case-control study. SETTING: Tertiary specialist hospital. PATIENTS AND INTERVENTIONS: Airway responsiveness to methacholine (a direct stimulant of smooth muscle in the airways), sodium metabisulphite (a putative stimulant of airway sensory nerves), and exercise was examined in 10 non-smoking patients with stable chronic heart failure (age 56.5 (3.2) (SEM) years; 7 men; radionuclide left ventricular ejection fraction 20.8 (2.9)%; radiographic cardiothoracic ratio 0.56 (0.02)). Exhaled nitric oxide, a product of the action of proinflammatory cytokines, was also measured to assess the contribution of local inflammation to airway responsiveness. The cough responses to low-concentration chloride solutions and to capsaicin were studied. Because all patients were receiving angiotensin-converting enzyme inhibitors, which may influence airway responsiveness and cough, 8 asymptomatic non-smoking controls taking angiotensin-converting enzyme inhibitors for essential hypertension were also studied (age 54.3 (2.8) years; 6 men; radiographic cardiothoracic ratio 0.46 (0.01)). RESULTS: The mean provocative concentration that induced a 20% decrease in forced expiratory volume in 1 second (FEV1) was 67.6 v 79.8 mg/ml (P = 0.71) for methacholine and 276.7 v 290.4 mg/ml (P = 0.79) for sodium metabisulphite in chronic heart failure patients and controls respectively. The change in FEV1 after maximal cardiopulmonary exercise testing was +1.44% in patients and +2.53% in controls (P = 0.47), indicating that there was no exercise-induced bronchospasm in either group (peak oxygen consumption was 16.9 (1.3) v 26.5 (2.3) ml/kg/min respectively, P < 0.01). Exhaled nitric oxide concentration was not increased in chronic heart failure (12.3 (1.7) v 16.2 (3.3) ppb, P = 0.32). The median cough counts after nebulised 0 mM and 37.5 mM chloride solutions were 2.5 v 1.0 (P = 0.6) and 5.5 v 5.5 (P = 0.5) respectively and the capsaicin concentration causing two or more coughs was 13.5 v 6.5 microM (P = 0.5). CONCLUSION: Airway hyper-responsiveness is not a predominant feature in non-smoking patients with stable chronic heart failure treated with, and tolerant to, angiotensin-converting enzyme inhibitors. It is unlikely to contribute to the exertional dyspnoea seen in these patients. [ABSTRACT FROM PUBLISHER]

Background: Inhaled frusemide inhibits airway responses to sodium metabisulphite and other indirect bronchial challenges in asthma by undetermined mechanisms which may relate to its ability to stimulate prostaglandin release. Inhalation of sodium metabisulphite provokes indirect bronchoconstriction, possibly by activating sensory nerves. To investigate the role of cyclooxygenase products in the airway actions of frusemide and sodium metabisulphite, the effects of a potent cyclooxygenase inhibitor, flurbiprofen, alone and in combination with frusemide were investigated against airway responsiveness to sodium metabisulphite.Methods: In a double blind double placebo controlled study, 12 mild asthmatic subjects attended on four occasions to undergo three inhalation challenges with sodium metabisulphite. A baseline challenge was performed one hour before oral intake of flurbiprofen 200 mg or matched placebo, and two hours before inhalation of frusemide 40 mg or matched placebo. A second challenge was performed immediately after inhalation of frusemide (two hours after flurbiprofen) with a further challenge three hours later. The log concentration provoking a 20% fall in FEV1 (log PC20) was used to assess airway responsiveness to sodium metabisulphite.Results: Frusemide caused an immediate 1.9 doubling dose protection and a lesser 0.7 doubling dose protection at three hours. This protection was enhanced by flurbiprofen at both time points to 2.7 (early) and 1.9 (late) doubling doses. In addition, flurbiprofen alone significantly reduced airway responsiveness to sodium metabisulphite by 1.1 doubling doses at both two and five hours.Conclusions: The generation of bronchoprotective prostaglandins is unlikely to underlie the inhibitory action of frusemide against airway responsiveness to sodium metabisulphite. Endogenous contractile prostaglandins within the airways may be involved in the bronchoconstrictor response to sodium metabisulphite. [ABSTRACT FROM AUTHOR]

Background: Potassium (K+) channel activators, such as cromakalim, open ATP sensitive K+ channels and relax airway smooth muscle in vitro and inhibit induced bronchoconstriction in vivo in animals. The prolonged half life of cromakalim gives it potential as an oral bronchodilator. The effect of orally administered BRL 38227 (the active enantiomer of cromakalim), at doses of 0.125, 0.25, and 0.5 mg, on airway function and airway responsiveness to histamine and methacholine has been investigated in asthmatic patients.Methods: Seventeen patients with asthma were studied in three separate randomised double blind, placebo controlled studies. In the first study eight patients with moderately severe asthma were given 0.125, 0.25, and 0.5 mg of BRL 38227 or placebo, and responses to histamine were assessed before and five hours after treatment. In the second study responses to methacholine were measured before and five hours after 0.125 and 0.5 mg of BRL 38227 or placebo were given to nine patients with mild asthma. In the third study the effect of 0.5 mg of BRL 38227 or placebo was assessed in eight patients with mild asthma. Responses to histamine were measured before treatment and two and five hours after treatment. To provide a positive control study eight subjects who had taken part in studies 1 and 3 were also given oral salbutamol (8 mg) in a placebo controlled, double blind study. Responses to histamine were assessed before and two hours after treatment.Results: BRL 38227 did not cause significant bronchodilatation or changes in airway responsiveness in any of the studies. Headache was reported in 19 of 25 of patients receiving (in some cases twice) 0.5 mg of BRL 38227. By contrast, oral salbutamol gave significant protection against histamine challenge (geometric mean 2.23 doubling dilutions).Conclusions: After a single oral dose of BRL 38227 no beneficial effect on airway function was detected, despite a high incidence of side effects, which indicates that the orally administered K+ channel activator BRL 38227 may not be useful in the management of asthma. [ABSTRACT FROM AUTHOR]

The effect of inhaled prostaglandin (PG) F2 alpha on the response to the inhaled tussive agent capsaicin was investigated in normal subjects. Seven subjects inhaled three breaths of four doses of capsaicin (0.3, 0.6, 1.2, and 2.4 nmol) before and immediately after inhaling PGF2 alpha (0.1 mumol) or placebo (0.15M NaCl) on separate days. The numbers of capsaicin induced coughs were greater after PGF2 alpha (mean 42.3 coughs) than after 0.15M sodium chloride (30.1). Visual analogue scores (0-10 on a 10 cm continuous scale) showed that capsaicin was more irritant after PGF2 alpha than after saline. Total respiratory resistance (Rrs), measured by the forced oscillation technique, was unaltered throughout the study. A double blind, placebo controlled study of the effects of inhaled salbutamol (200 micrograms, 0.6 mumol) and ipratropium bromide (40 micrograms, 0.1 mumol) on cough induced by capsaicin (2.4 nmol) and by PGF2 alpha (0.1 mumol) and on PGF2 alpha augmented, capsaicin induced coughing was performed in seven subjects. Neither drug had any effect on capsaicin induced coughing. Salbutamol reduced coughing due to PGF2 alpha (mean 7.7 coughs after salbutamol, 9.3 after placebo) but ipratropium bromide did not (mean 6.9 coughs after ipratropium bromide, 6.6 after placebo). Salbutamol also inhibited the augmentation of the capsaicin induced cough that followed inhalation of PGF2 alpha (mean augmentation 1.9 coughs after salbutamol, 4.1 after placebo), whereas ipratropium bromide did not (augmentation 1.7 coughs after ipratropium bromide, 2.7 after placebo). No changes in Rrs were seen after PGF2 alpha or either drug. Thus salbutamol reduces PGF2 alpha induced cough and the augmentation of capsaicin induced cough that follows PGF2 alpha. [ABSTRACT FROM PUBLISHER]

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation. [ABSTRACT FROM PUBLISHER]

The effects of inhaled platelet activating factor were compared with those of inhaled methacholine (control) on airway calibre, airway responsiveness to methacholine and isoprenaline, and circulating cells in eight subjects with mild, stable asthma. Platelet activating factor was given in six doses at 15 minute intervals and airway response measured as change in partial expiratory flow at 30% of vital capacity (Vp30). Platelet activating factor caused a fall in Vp30, the mean (SEM) maximum percentage fall being 28.9 (4.2) five minutes after the first dose (12 micrograms) and 50.9 (8.0) after the second dose (24 micrograms). Tachyphylaxis occurred, however, with the four subsequent doses of inhaled platelet activating factor. There was transient neutropenia after the first dose, from a mean of 3.6 (0.2) x 10(9) to 2.2 (0.5) x 10(9) neutrophils/l; this response also showed tachyphylaxis with subsequent doses. The mean PC40 (the concentration of methacholine needed to cause a 40% fall in Vp30) was unchanged one, three, and seven days after administration of platelet activating factor. There was no significant correlation between baseline PC40 methacholine and the maximal fall in Vp30 after either the first (12 micrograms) or the second dose (24 micrograms) of platelet activating factor. The control challenge with methacholine produced a degree of bronchoconstriction similar to that of platelet activating factor but was not associated with any significant change in bronchial responsiveness or in circulating cells. The bronchodilator response to inhaled isoprenaline measured three days after inhalation of platelet activating factor and of methacholine was similar after the two challenges. Thus asthmatic subjects who are hyperresponsive to methacholine show a similar bronchoconstrictor response to platelet activating factor, as has been observed in normal subjects; overall this did not cause airway hyperresponsiveness to methacholine. [ABSTRACT FROM PUBLISHER]

Platelet activating factor, a potent mediator of inflammation, causes a sustained increase in airway responsiveness to methacholine in man and has been implicated in asthma. The effect of the beta 2 agonist salbutamol (200 micrograms by inhalation) on platelet activating factor induced bronchoconstriction and airway hyperresponsiveness was studied in seven normal subjects in a double blind, crossover study. Salbutamol only partially inhibited the platelet activating factor induced fall in partial flow at 30% of vital capacity (Vp30) (mean percentage fall 47.6 (SEM 7.9); p less than 0.001), whereas it completely blocked a similar degree of bronchoconstriction induced by methacholine. Salbutamol did not prevent the accompanying transient flushing and chest irritation and did not affect the transient neutropenia (mean % fall 69.5 (13.6); p less than 0.01) or the rebound neutrophilia (mean % increase 84.7 (24.7); p less than 0.05) that followed platelet activating factor. There was an increase in the airway responsiveness to methacholine following inhalation of platelet activating factor, the maximum mean change being a three fold increase in PC40 (the provocative concentration of methacholine causing a 40% fall in Vp30) on day 3 (p less than 0.01). Salbutamol caused a significant attenuation of this response on day 3 (p less than 0.02) but had no significant effect on days 1 and 7. Thus a therapeutic dose of salbutamol caused partial inhibition of platelet activating factor induced bronchoconstriction and had a minimal effect on the increased bronchial responsiveness following platelet activating factor. [ABSTRACT FROM PUBLISHER]

We have examined the effect of prior bronchoconstriction on the bronchial responsiveness to inhaled histamine in nine normal subjects. The airway response to increasing concentrations of histamine aerosol was assessed by measurement of specific airways conductance (sGaw) in a body plethysmograph. The threshold provocative dose of histamine needed to cause a 35% fall in starting sGaw (PD35) and the steepest slope of the response were measured from cumulative log dose response curves. Histamine challenges were performed in duplicate after premedication with 0.9% sodium chloride (control) or methacholine aerosol on separate days. The mean starting sGaw did not change significantly after inhalation of 0.9% sodium chloride but methacholine caused a mean reduction in sGaw of 42%. Mean control PD35 values did not differ significantly from mean PD35 values after methacholine. The mean steepest slope of the response after methacoline was 47% lower than the mean control value. There was a significant linear relationship between starting sGaw and the steepest slope for the control and for the methacholine premedicated challenges. The reduction in slope after methacholine was accounted for by the fall in starting sGaw. Because histamine PD35 was not altered by prior bronchoconstriction, it is concluded that the bronchial hyperresponsiveness of asthmatic subjects to non-specific bronchoconstrictor stimuli is unlikely to be a direct consequence of their low starting airway calibre. [ABSTRACT FROM AUTHOR]

Background: Inhalation of lipopolysaccharide (LPS) causes an inflammatory response in the lungs. To explore this response, inflammatory indices were measured in induced sputum from atopic asthmatic patients and compared with atopic and non-atopic subjects after inhalation of LPS.Methods: The effects of inhaled LPS (60 micrograms) or placebo (0.9% saline) were examined in a randomised, double blind, crossover trial in 11 non-atopic normal subjects, seven atopic, non-asthmatic individuals, and eight atopic, asthmatic patients. Sputum was induced by inhalation of 3.5% saline before the test inhalation and again at six hours and 24 hours. Spirometry (forced expiratory volume in one second (FEV1), forced vital capacity (FVC)), heart rate, blood pressure, and temperature were recorded before challenge and at intervals until eight hours, and at 24 hours after challenge.Results: There was no change in cardiovascular parameters or spirometry with either exposure in any group. In the asthmatic patients only, inhalation of LPS caused a rise in temperature, with a peak of 0.6 degree C at seven hours, which was significantly higher than following placebo inhalation (p < 0.05). In normal subjects, LPS caused a significant rise in absolute neutrophil counts at 24 hours compared with placebo (median 1.1 x 10(6) cells/ml after LPS; median 0.2 x 10(6) cells/ml after placebo, p < 0.01), but no change in differential counts. In asthmatic patients, LPS caused a significant rise in differential neutrophil counts at six hours compared with placebo (median 88% after LPS; median 56% after placebo, p < 0.05), but no change in absolute cell counts at any time point. There was no change in neutrophil counts in the atopic subjects. There was a significant rise in sputum interleukin 8 (IL-8) concentrations in normal subjects at six hours compared with placebo (mean placebo 1.1 ng/ml; LPS 3.0 ng/ml, p < 0.05) and in asthmatics at 24 hours (mean placebo 2.0 ng/ml, LPS 6.9 ng/ml, p < 0.05). There were no changes in sputum concentrations of tumour necrosis factor alpha or granulocyte macrophage colony stimulating factor at any time.Conclusions: Inhalation of LPS causes a neutrophilic inflammation with increases in IL-8 in both normal and asthmatic subjects. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide (NO) plays an important part in the regulation of many physiological functions and may also be involved in several pulmonary diseases. Endogenous NO is synthesised by different isoforms of NO synthase (NOS) from L-arginine.Methods: The effect of inhaled L-arginine 0.75 g (six normal and six asthmatic subjects), 1.5 g (six normal and six asthmatic subjects), and 3 g (seven normal and six asthmatic subjects) has been studied in a double blind placebo controlled, randomised, parallel group design study. In addition, the effect of a single dose (3 g) of inhaled L-alanine has been assessed in five normal and five asthmatic subjects.Results: L-arginine increased exhaled NO in a dose-dependent fashion with a maximum at 60 minutes. The cumulative effect of L-arginine (3 g) on NO in asthmatic subjects, expressed as the area under the curve in arbitrary units (au) and compared with the effect of placebo (0.9% NaCl), was significantly higher (mean 0.11 au; 95% confidence interval (CI) 0.03 to 0.19) than in normal subjects (0.012 au; 95% CI 0.002 to 0.022). There was a negative correlation (r = -0.72) between the increase in exhaled NO and the fall in forced expiratory volume in one second (FEV1) (0.034 au, 95% CI 0.030 to 0.038) after 3 g L-arginine in asthmatic subjects. Inhalation of 3 g of L-alanine produced a similar reduction in FEV1 (0.033 au, 95% CI 0.007 to 0.059) but no significantly different changes in exhaled NO (0.017 au, 95% CI 0.001 to 0.039) compared with placebo (0.020 au, 95% CI 0.001 to 0.042).Conclusions: An increase in the amount of substrate for NOS increases the formation of endogenous NO. L-arginine may have therapeutic potential in diseases in which there is defective production of NO, but in asthma it may amplify the inflammatory response in the airways. [ABSTRACT FROM AUTHOR]

Background: Eosinophils in induced sputum and exhaled nitric oxide (NO) are currently used as non-invasive markers in the assessment of airway inflammation in asthma. As both sputum eosinophils (%) and exhaled NO are raised in asthmatic subjects not receiving inhaled steroids and decreased following corticosteroid therapy, a relationship between them is plausible.Methods: Exhaled NO was measured by chemiluminescence analyser, sputum induction by 3.5% saline inhalation, and bronchial responsiveness was measured as PC20FEV1 methacholine in 35 stable asthmatic patients using beta 2 agonist alone and the correlation between these non-invasive markers of airway inflammation was studied.Results: There were significant correlations between exhaled NO and PC20 (r = -0.64), exhaled NO and sputum eosinophils (%) (r = 0.48), and also between sputum eosinophils (%) and PC20 (r = -0.40).Conclusion: The correlation between exhaled NO and PC20 suggests that exhaled NO or the mechanisms leading to its increase may contribute to airway hyperresponsiveness in asthma. Furthermore, the relationship between sputum eosinophils (%), exhaled NO, and PC20 highlight the potential use of eosinophils (%) in induced sputum and exhaled NO to monitor the severity of asthma. [ABSTRACT FROM AUTHOR]

Background: Recruitment of inflammatory cells in the lungs may contribute to tissue injury as a result of mediators released from these cells. Interleukin 1 beta (IL-1 beta) is a potent inducer of neutrophil accumulation, a process that may require local protein biosynthesis. Macrophage inflammatory protein 2 (MIP-2) is a approximately 6 kD heparin binding protein and is a member of the C-X-C superfamily that causes significant neutrophil chemotaxis and activation in vitro. A study was performed to determine whether IL-1 beta could induce the expression of MIP-2 in the lungs of Brown-Norway rats.Methods: rhIL-1 beta (500 U) or 0.9% NaCl was injected intratracheally and bronchoalveolar lavage (BAL) cells and lung tissues were evaluated for MIP-2 mRNA expression after RNA extraction by Northern blot analysis. MIP-2 probe was prepared from cDNA obtained by reverse transcriptase-polymerase chain reaction (RT-PCR) of BAL cells obtained from a rat treated with lipopolysaccharide.Results: There was no detectable MIP-2 mRNA in the lungs of control rats but a marked enhancement of the expression at four hours with no expression at 12 hours and a slight expression at 24 hours. IL-1 beta induced a significant influx of neutrophils into BAL fluid with a transient increase in macrophages. In situ hybridisation of lungs using MIP-2 cDNA probe labelled with digoxigenin showed expression of MIP-2 mRNA in airway mononuclear cells and airway epithelium at four hours after IL-1 beta; at 24 hours the signal had nearly gone.Conclusion: IL-1 beta induces the expression of MIP-2 mRNA in rat lung. MIP-2 may be one chemokine that could contribute to IL-1 beta induced neutrophil influx. [ABSTRACT FROM AUTHOR]

Background: Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined.Methods: Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues.Results: Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P.Conclusions: MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation. [ABSTRACT FROM AUTHOR]

Background: Inhaled frusemide but not bumetanide, another loop diuretic, reduces bronchial responsiveness to sodium metabisulphite (MBS). To investigate whether the effect of frusemide could be mediated through mechanisms other than Na+/K+/Cl- cotransporter inhibition, the effects of amiloride--an inhibitor of sodium channels in the airway epithelium--and of acetazolamide--a specific inhibitor of carbonic anhydrase--against MBS challenge were studied.Methods: In two separate randomised double blind placebo controlled studies, 10 subjects with mild asthma attended on four separate occasions to inhale 7.5 mg amiloride or matched placebo, and 500 mg acetazolamide or placebo, immediately before MBS challenge. The concentration of MBS required to cause a 20% fall in baseline FEV1 (PC20) was measured.Results: Amiloride and acetazolamide had no effect on baseline FEV1. Amiloride had no effect against MBS challenge, but acetazolamide increased -log PC20 from a mean (SE) of 0.75 (0.09) to 0.98 (0.06) representing a 0.77 (0.24) doubling dose increase.Conclusions: These results suggest that carbonic anhydrase activity in the airways, but not sodium flux, modulates bronchial responsiveness to MBS challenge. The action of frusemide is not likely to involve inhibition of carbonic anhydrase activity. [ABSTRACT FROM AUTHOR]

Background: Nebulised frusemide has been shown to be protective against bronchoconstricting stimuli in adult asthmatic subjects and against cold air challenge in children. Animal studies suggest that inhaled frusemide may be more effective in the young.Methods: A double blind placebo, controlled, crossover study on the effect on exercise of pretreatment with frusemide (20 mg) from a metered dose inhaler via a large volume spacer (Volumatic) was performed in 12 asthmatic children. Exercise testing consisted of eight minutes of running on a treadmill in an environmentally controlled laboratory.Results: Deterioration in lung function was less after frusemide than after the placebo exercise tests. The mean (95% CI) maximum percentage falls in forced expiratory volume in one second (FEV1) were 14.4% (7.7 to 21.0) for placebo and 5.7% (2.3 to 9.0) for frusemide.Conclusions: Inhaled frusemide via a metered dose inhaler reduces exercise-induced bronchoconstriction in children. [ABSTRACT FROM AUTHOR]

A 46 year old man with coeliac disease and upper airway obstruction was thought to have undifferentiated carcinoma of the trachea. Subsequent immunohistological examination showed that the neoplasm was a T cell lymphoma. He had combination chemotherapy and is alive and well seven years after diagnosis. [ABSTRACT FROM PUBLISHER]

Presents a response of the author to comments made by A. Morice, C.F. Everett and S.A. Muirennan, on an article related to gastroesophageal disorders.

Presents a letter to the editor on effects of interleukin-5 on asthma patients.