Effect of inhaled glucocorticoids on IL-1 beta and IL-1 receptor antagonist (IL-1 ra) expression in asthmatic bronchial epithelium.

BACKGROUND: Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and the existence of naturally occurring cytokine antagonists has added to this complexity. Upregulation of both interleukin 1 beta (IL-1 beta) and its naturally occurring receptor antagonist, interleukin 1 receptor antagonist (IL-1ra), has previously been observed on asthmatic bronchial epithelium compared with normal airways. METHODS: The effect of inhaled beclomethasone dipropionate (BDP) on asthmatic bronchial epithelial expression of IL-1 beta and IL-1ra was studied. Frozen bronchial biopsy specimens from nine asthmatic subjects receiving 1000 micrograms BDP daily for eight weeks and from six asthmatic subjects receiving matching placebo were stained with anti-IL-1 beta and anti-IL-1ra antibodies. Hue-saturation-intensity (HSI) colour image analysis was used to quantify the brown immunoperoxidase reaction colour present on the bronchial epithelium. RESULTS: There was a significant twofold decrease in the epithelial expression of IL-1 beta after treatment with BDP but no significant change was seen in IL-1ra (P = 0.175). CONCLUSION: The selective inhibition of IL-1 beta, without effect on IL-1ra, provides a novel mechanism for the anti-inflammatory action of glucocorticosteroids.

Regular albuterol, nedocromil sodium, and bronchial inflammation in asthma.

Adult, nonsmoking patients with mild to moderate asthma were randomized to receive 4 mg nedocromil sodium (n = 13), 200 micrograms albuterol (n = 13), or placebo (n = 12) four times daily for 16 wk in a double-blind, double-dummy protocol. Before and after treatment, patients underwent histamine bronchial provocation, followed by fiberoptic bronchoscopy. Bronchial mucosal biopsy tissue and bronchoalveolar lavage fluid were examined in detail. Daily diary cards were kept by each patient. Compared with baseline, the numbers of total (EG1) and activated (EG2) eosinophils, expressed as cells per square millimeter of bronchial biopsy tissue, decreased after treatment with nedocromil sodium (pretreatment: EG1 = 152.2 +/- 42.5 and EG2 = 143.8 +/- 36.8; post-treatment: EG1 = 115.4 +/- 35.1 and EG2 = 104.9 +/- 31.6) and increased after treatment with albuterol (pretreatment: EG1 = 129.3 +/- 28.0 and EG2 = 127.5 +/- 30.2; post-treatment: EG1 = 238.0 +/- 55.0 and EG2 = 211.4 +/- 50.4). Although the changes between the active treatment groups were significantly different (p < 0.05), no such significant differences were found in eosinophil numbers before and after treatment when comparisons were made between either of the active treatment groups and the placebo group. Although not significant, the changes in concentration of eosinophil cationic protein in bronchoalveolar lavage reflected the changes seen in numbers of activated eosinophils. No treatment differences were detected for mast cell or lymphocyte numbers. There were no statistical differences between treatment groups for clinical findings, with the exception of evening peak flow, which was significantly increased (p < 0.05) in the albuterol group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inhaled beclomethasone dipropionate on expression of proinflammatory cytokines and activated eosinophils in the bronchial epithelium of patients with mild asthma.

Increasing evidence suggests that cytokines play a role in airway inflammation by attracting and activating inflammatory cells. This may lead to epithelial cell damage and airway hyperresponsiveness. Bronchial provocative concentration of histamine causing a 20% fall in forced expiratory volume in 1 second was measured in patients with mild asthma, and bronchial biopsy specimens were stained for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, and activated eosinophils (EG2) in the bronchial epithelium. The effect of inhaled beclomethasone dipropionate was also assessed in a placebo-controlled double-blind manner. There was a correlation between GM-CSF expression and EG2-staining cells (r = 0.484 p < 0.05) in the epithelium. Provocative concentration of histamine causing a 20% fall in forced expiratory volume in 1 second was correlated with GM-CSF expression (r = -0.462, p < 0.05). Treatment with inhaled beclomethasone dipropionate 500 micrograms twice a day led to a significant decrease in both the expression of GM-CSF (p < 0.01) and IL-8 (p < 0.02) and the number of EG2-staining cells (p < 0.01) in the epithelium. The changes in GM-CSF (r = 0.798, p < 0.01) and IL-8 (r = 0.653, p < 0.02) expression were correlated with the changes in EG2-staining cells after treatment. These results suggest that GM-CSF may influence eosinophil activation in the epithelium in vivo and participate in the etiology of bronchial hyperresponsiveness in mild asthma. Also, beclomethasone dipropionate may inhibit eosinophil activation partly by downregulating the expression of GM-CSF and IL-8 in the bronchial epithelium.

Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma.

The effect of prolonged inhaled corticosteroid treatment on bronchial immunopathology was assessed in 25 nonsmoking mildly asthmatic subjects previously receiving intermittent inhaled beta 2-agonist alone. Inhaled beclomethasone dipropionate (BDP), 500 micrograms twice per day or placebo was administered for 4 mo in a double-blind parallel group study. Histamine bronchial provocation, fiberoptic bronchoscopic biopsy, and bronchoalveolar lavage (BAL) were performed before and after treatment. There was no difference in bronchial responsiveness or lung function between groups. In patients treated with BDP compared with placebo, there was a significant reduction in toluidine blue-staining mast cells (p = 0.028) and total (p = 0.005) and activated eosinophils (p = 0.05) in biopsies but no difference in eosinophils or eosinophil cationic protein in BAL. Granulocyte-macrophage colony-stimulating factor expression was significantly reduced in the bronchial epithelium, and the thickness of Type III collagen deposition in the bronchial lamina reticularis reduced from 29.7 +/- 4.4 to 19.8 +/- 3.4 microns (mean +/- 95% confidence interval) (p = 0.04). No change in helper or activated helper T cells occurred. Prolonged BDP treatment reduces inflammatory infiltration, proinflammatory cytokine expression, and subepithelial collagen deposition, a recognized abnormality in asthma.

Lymphocyte infiltration and thickness of the nasal mucous membrane in perennial and seasonal allergic rhinitis.

We have used immunocytochemical techniques to study infiltration by lymphocytes in biopsy specimens of the nasal mucosal membrane in 24 atopic patients and 10 normal volunteers. Twelve patients had perennial rhinitis and 12 had seasonal allergic rhinitis (SR) to grass pollen. Biopsy specimens were taken both in and out of the pollen season in patients with SR. Biopsy specimens were strained with the indirect immunoperoxidase technique and monoclonal antibodies to CD3, CD4, CD8, CD22, and CD25. T helper cells (CD4+) and CD24+ cells were significantly more numerous in patients exposed to allergen (those with perennial rhinitis and SR in season) compared with normal volunteers, whereas values for SR out of season were intermediate. The thickness of the nasal epithelium was significantly (p < 0.05) greater in biopsy specimens from patients with perennial rhinitis (mean, 51.43 microns) than in those from patients with SR in season (median, 32.44 microns). These results suggest that in allergic rhinitis, natural exposure to allergen is accompanied by increased infiltration of the nasal mucous membrane by T-helper and CD25+ cells.

Factors relating to the development of respiratory symptoms in coffee process workers.

After several cases of occupational asthma had been reported in a coffee processing factory in England, 197 coffee workers representing 80% of the production workforce were studied to determine the factors affecting the development of work related respiratory symptoms of wheeze, cough, and dyspnoea. Two computer administered questionnaires concerning the presence of respiratory symptoms and the occurrence of work related respiratory symptoms were used. Workers underwent skin prick testing to green coffee bean extract (GCB) and 11 common inhalant allergen extracts and bronchial provocation testing with methacholine. The presence of specific immunoglobulin E (IgE) antibodies to GCB and castor bean extract (CAB) were determined by a radioallergosorbent test (RAST). The prevalence of work related respiratory symptoms was 12.7%, bronchial hyperresponsiveness 30%, atopy 54%, positive GCB skin prick test 14.7%, positive GCB RAST 14%, and positive CAB RAST 14.7%. None of the workers was sensitised to fungi present in the factory and the numbers of certain species of fungi, despite being greater than may be found out of doors or in an uncontaminated indoor environment, were fewer than are generally associated with the presence of work related respiratory symptoms among agricultural workers. Storage mites were not isolated. Green coffee bean extract and CAB RAST were significantly correlated using the McNemar test but there was limited allergenic cross reactivity in RAST inhibition studies of the two extracts. The only factors that were significantly and independently associated with work related symptoms were CAB RAST and duration of employment. Bronchial hyperresponsiveness was not independently associated with work related respiratory symptoms. The significant independent associations of bronchial hyperresponsiveness included GCB RAST, duration of employment, and resting forced expiratory volume in one second. Exposure to CAB, a highly potent antigen, may be overriding the effects of other factors such a GCB, atopy, bronchial hyperresponsiveness, and smoking. This study suggests that CAB contamination remains a potential problem in the coffee processing industry and all efforts to eliminate it from the working environment should continue.

A general practice based survey of bronchial hyperresponsiveness and its relation to symptoms, sex, age, atopy, and smoking.

The prevalence and associations of bronchial hyperresponsiveness were investigated in a general practice population. The sample was obtained by using every 12th patient on the practice age-sex register, replacing non-responders with corresponding age and sex matched individuals from up to two further 1 in 12 samples. The response rate was 43%; 366 patients were studied. Doubling concentrations of methacholine were given to a maximum of 32 mg/ml or until a 20% fall in forced expiratory volume in one second (FEV1) occurred (provocation concentration, PC20FEV1). Bronchial hyperresponsiveness was defined arbitrarily as a PC20FEV1 of 2 mg/ml or less (or 11 mumol cumulative dose, PD20FEV1). The prevalence of bronchial hyperresponsiveness was 23%. Bronchial hyperresponsiveness was not associated with age but was more prevalent in women than men (31%:13%). It was also more common in those who had ever wheezed (39%) and in those who had had an attack of rhinitis in the preceding month (45%, p less than 0.1), in atopic individuals (30%), and in smokers (32%), but it was not associated with cough or dyspnoea. There was a positive correlation between PC20FEV1 and resting FEV1 (r = 0.288) and a negative correlation between PC20FEV1 and mean daily peak flow variability (r = -0.356). Stepwise binary logistic regression analysis showed significant independent effects on PC20FEV1 for mean daily peak flow variability, gender, number of positive skin test responses, resting FEV1, and mean histamine skin weal area, but no relation with smoking or mean allergen weal area. The prevalence of bronchial hyperresponsiveness was much higher than the prevalence of diagnosed asthma in the practice in 1984 (4.9%). Analysis of case notes of 169 individuals showed that those with bronchial hyperresponsiveness had not attended the practice more frequently for respiratory complaints during the previous five years.