Effect of allergen challenge on airway responsiveness to histamine and sodium metabisulphite in mild asthma.

BACKGROUND: Airway responsiveness to histamine and methacholine, direct smooth muscle spasmogens, is increased following inhalation of allergen. Although the aetiology of this phenomenon is unclear, increased cellular or neural activity may be involved since allergen also induces increases in airway responsiveness to the mast cell stimulus adenosine-5'-monophosphate (AMP) and the neural stimulus bradykinin. METHODS: To explore this further, the airway responsiveness to sodium metabisulphite (MBS), an indirect neural stimulus with similar characteristics to bradykinin, was compared in 18 mild steroid-naive asthmatic subjects with the airway responsiveness to histamine before and after allergen challenge with extracts of house dust mite, grass pollen, or cat. All subjects inhaled doubling increments of histamine and MBS until the concentration provoking a 20% fall in forced expiratory volume in one second (PC20) was reached before and three hours after allergen challenge. Twelve of the subjects had additional challenges at 24 hours after the allergen. RESULTS: Following allergen challenge all subjects showed an early response and 14 also had a late asthmatic response. For histamine there was a significant increase in airway responsiveness at both three and 24 hours compared with values before the allergen (0.89 (0.25) and 1.53 (0.52) doubling dose changes, respectively). In contrast, airway responsiveness to MBS was unaltered by allergen challenge (0.29 (0.27) and -0.33 (0.28) doubling dose changes compared with pre-allergen values at three and 24 hours, respectively). CONCLUSION: These data suggest that activation of airway sensory nerves is unlikely to contribute to the increase in airway responsiveness following inhalation of allergen. The previously observed allergen induced increase in airway responsiveness to bradykinin and AMP may involve non-neural pathways.     

Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma

BACKGROUND—Nitric oxide (NO) may bebronchoprotective in asthma, possibly due to a direct action on airwaysmooth muscle or through mast cell stabilisation. To investigate thisthe effects of two doses of nebulisedN^G-nitro-L-arginine methyl ester(L-NAME), a non-selective NO synthase (NOS) inhibitor, onexhaled NO levels and airway responsiveness to histamine, a directsmooth muscle spasmogen, and adenosine-5'-monophosphate (AMP), anindirect spasmogen which activates mast cells, were evaluated inpatients with mild asthma.
METHODS—The study consisted of two phaseseach with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either L-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studiedin a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaledL-NAME in a dose of 170 mg or 0.9% saline before beingchallenged with histamine and AMP.
RESULTS—The mean (95% CI) reduction in exhaled NOlevels after L-NAME 54 mg was 78% (66 to 90) but this didnot alter airway responsiveness; the geometric mean (SE) concentrationprovoking a fall of 20% or more in forced expiratory volume in onesecond (PC₂₀) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast,L-NAME 170 mg reduced NO levels to a similar extent (81%(95% CI 76 to 87)) but increased airway responsiveness byapproximately one doubling dose to both spasmogens; the geometric mean(SE) PC₂₀ for histamine after L-NAME 170 mg andsaline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p<0.001),and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively(p<0.001).
CONCLUSIONS—These results suggest thatL-NAME increases airway responsiveness in asthma. This mayoccur through mechanisms separate from NO inhibition or throughpathways independent of those responsible for production of NO measuredin exhaled air.

     

Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

BACKGROUND: Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship. METHODS: Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate. RESULTS: At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r2 = 0.20, p<0.001) and ventilation heterogeneity (partial r2 = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r2 = 0.64, p<0.001). CONCLUSIONS: Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti-inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long-term outcomes.     

Effect of an oral gold compound, auranofin, on non-specific bronchial hyperresponsiveness in mild asthma.

BACKGROUND--A recent double blind clinical trial in Japan has shown that auranofin (6 mg/day) is a useful treatment for patients with moderate to severe asthma. To investigate the mechanism of action of auranofin the bronchial responsiveness to inhaled methacholine has been studied in well controlled asthmatic subjects. METHODS--Nineteen adult asymptomatic asthmatic subjects received auranofin (3 mg orally twice a day) or inactive placebo in random order for 12 weeks in a double blind fashion. Bronchial responsiveness to inhaled methacholine and pulmonary function tests were measured at the same time on different days before, and six and 12 weeks after, each treatment. RESULTS--Non-specific bronchial hyperresponsiveness 12 weeks after treatment with auranofin was decreased compared with that before treatment with auranofin and 12 weeks after treatment with inactive placebo, although the treatment did not improve pulmonary function tests. CONCLUSIONS--Non-specific bronchial hyperresponsiveness 12 weeks after treatment with auranofin is decreased in a group of mild asymptomatic asthmatic patients with normal lung function.     

Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5'-monophosphate in non-atopic asthma.

Inhaled adenosine 5'-monophosphate (AMP) causes bronchoconstriction in atopic asthma, probably after in vivo conversion to adenosine. It has been suggested that adenosine potentiates preformed mediator release from mast cells on the mucosal surface of the airways by interacting with specific purinoceptors, without affecting the release of newly generated mediators. The airway response of nine non-atopic subjects with "intrinsic" asthma to inhaled AMP and the influence of the oral, selective H1 histamine receptor antagonist terfenadine on this response was investigated. The geometric mean provocation concentrations of histamine and AMP required to produce a 20% fall in FEV1 (PC20) were 1.82 and 13 mmol/l. In subsequent placebo controlled time course studies the FEV1 response to a single inhalation of the PC20 histamine was ablated after pretreatment with oral terfenadine 180 mg. This dose of terfenadine caused an 80% inhibition of the bronchoconstrictor response to the PC20 AMP when measured as the area under the time course-response curve and compared with the response to PC20 AMP preceded by placebo. Terfenadine 600 mg failed to increase protection against AMP further, but both doses of terfenadine delayed the time at which the mean maximum fall in FEV1 after AMP was achieved. Terfenadine 180 mg had no effect on methacholine induced bronchoconstriction in the same subjects. These data suggest that inhaled AMP may potentiate the release of preformed mediators from preactivated mast cells in the bronchial mucosa of patients with intrinsic asthma.     

Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma

BACKGROUND: Airway hyperresponsiveness, induced sputum eosinophils, and exhaled nitric oxide (NO) levels have all been proposed as non-invasive markers for monitoring airway inflammation in patients with asthma. The aim of this study was to compare the changes in each of these markers following treatment with inhaled glucocorticosteroids in a single study. METHODS: In a randomised, double blind, placebo controlled, parallel study 25 patients with mild asthma (19-34 years, forced expiratory volume in one second (FEV1) >75% predicted, concentration of histamine provoking a fall in FEV1 of 20% or more (PC20) <4 mg/ml) inhaled fluticasone propionate (500 microg twice daily) for four weeks. PC20 to histamine, sputum eosinophil numbers, and exhaled NO levels were determined at weeks 0, 2, and 4, and two weeks after completing treatment. Sputum was induced by inhalation of hypertonic (4.5%) saline and eosinophil counts were expressed as percentage non-squamous cells. Exhaled NO levels (ppb) were measured by chemiluminescence. RESULTS: In the steroid treated group there was a significant increase in PC20, decrease in sputum eosinophils, and decrease in exhaled NO levels compared with baseline at weeks 2 and 4 of treatment. Subsequently, each of these variables showed significant worsening during the two week washout period compared with week 4. These changes were significantly different from those in the placebo group, except for the changes in sputum eosinophils and exhaled NO levels during the washout period. There were no significant correlations between the changes in the three markers in either group at any time. CONCLUSIONS: Treatment of asthmatic subjects with inhaled steroids for four weeks leads to improvements in airway hyperresponsiveness to histamine, eosinophil counts in induced sputum, and exhaled nitric oxide levels. The results suggest that these markers may provide different information when monitoring anti-inflammatory treatment in asthma.     

Effect of caffeine on histamine bronchoprovocation in asthma.

It was recently reported that caffeine may reduce the clinical symptoms of asthma and may prevent the clinical manifestations of this disease. The effect of caffeine on histamine responsiveness is unknown. The effect of caffeine (5 mg/kg) and placebo on histamine responsiveness (the provocation concentration causing a 20% fall in FEV1, PC20) was studied in 10 subjects with mild asthma (prechallenge FEV1 84% of predicted value). The PC20 for histamine bronchoprovocation after caffeine ingestion was 2.65 (95% confidence limits 0.99, 7.10) mg/ml. After placebo the PC20 was 1.89 (0.96, 3.71) mg/ml. It is concluded that caffeine in a dose equivalent to about three cups of coffee has a very small effect, if any, on histamine bronchoprovocation in those with mild asthma. Specific instructions about not having drinks containing caffeine before histamine challenge are therefore not necessary.     

Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness

BACKGROUND: A study was undertaken to assess whether the recent increases in prevalence of both asthma and obesity are linked and to determine if obesity is a risk factor for diagnosed asthma, symptoms, use of asthma medication, or airway hyperresponsiveness. METHODS: Data from 1971 white adults aged 17-73 years from three large epidemiological studies performed in NSW were pooled. Doctor diagnosis of asthma ever, history of wheeze, and medication use in the previous 12 months were obtained by questionnaire. Body mass index (BMI) in kg/m(2) was used as a measure of obesity. Airway hyperresponsiveness (AHR) was defined as dose of <3.9 micromol histamine required to provoke a fall in forced expiratory volume in one second (FEV(1)) of 20% or more (PD(20)FEV(1)). Adjusted odds ratios (OR) were obtained by logistic regression. RESULTS: After adjusting for atopy, age, sex, smoking history, and family history, severe obesity was a significant risk factor for recent asthma (OR 2. 04, p=0.048), wheeze in the previous 12 months (OR 2.6, p=0.001), and medication use in the previous 12 months (OR 2.83, p=0.005), but not for AHR (OR 0.87, p=0.78). FEV(1) and forced vital capacity (FVC) were significantly reduced in the group with severe obesity, but FEV(1)/FVC ratio, peak expiratory flow (PEF), and mid forced expiratory flow (FEF(25-75)) were not different from the group with normal BMI. The underweight group (BMI <18.5 kg/m(2)) had increased symptoms of shortness of breath, increased airway responsiveness, and reduced FEV(1), FVC, PEF, and FEF(25-75) with similar use of asthma medication as subjects in the normal weight range. CONCLUSIONS: Although subjects with severe obesity reported more wheeze and shortness of breath which may suggest a diagnosis of asthma, their levels of atopy, airway hyperresponsiveness, and airway obstruction did not support the suggestion of a higher prevalence of asthma in this group. The underweight group appears to have more significant respiratory problems with a higher prevalence of symptoms, reduced lung function, and increased airway responsiveness without an increase in medication usage. This group needs further investigation.     

Effect of changing dietary sodium on the airway response to histamine.

The airway response to histamine has been shown to be related to the 24 hour urinary excretion of sodium. To assess whether this relation is likely to represent a direct causal association a randomised double blind crossover trial of slow sodium (80 mmol/day) was compared with placebo in 36 subjects having a low sodium diet. The dose of histamine causing a 20% fall in FEV1 (PD20) was 1.51 doubling doses lower when the men were taking sodium than when they were taking placebo (p less than 0.05). On the basis of PD10 values, the difference in men was 1.66 doubling doses of histamine (p less than 0.05). There was no corresponding effect in women. Regressing PD10 against urinary excretion of electrolytes with data from the two occasions during the trial and the measurements made before the trial showed a significant association with sodium excretion after allowance had been made for any effect associated with potassium or creatinine excretion, the latter being a marker of the completeness of the urine collection. Again there was no corresponding effect among women. These findings are compatible with the differences in regional mortality data for England and Wales, which show a relation between asthma mortality and regional per person purchases of table salt for men but not for women.     

Effect of prior bronchoconstriction on the airway response to histamine in normal subjects.

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.     

Enhancement of goblet cell hyperplasia and airway hyperresponsiveness by salbutamol in a rat model of atopic asthma

BACKGROUND: Goblet cell hyperplasia (GCH) is a prominent feature in animal models of atopic asthma produced by immunisation and following multiple challenges with antigens. The aim of this study was to examine the effect of a beta(2) agonist on the development of GCH induced by the immune response. METHODS: Brown Norway rats were immunised and challenged with an aerosol of ovalbumin for four weeks. Salbutamol (0.5 mg/kg/day) or vehicle was continuously delivered for the four weeks using a subcutaneously implanted osmotic minipump. The density of goblet cells, other morphological changes, and airway responsiveness to methacholine were evaluated 24 hours after the final challenge. RESULTS: Treatment with salbutamol induced a more than twofold increase in the mean (SE) number of goblet cells (53.7 (7.3) vs 114.5 (11.8) cells/10(3) epithelial cells, p<0.01) while it did not significantly influence airway wall thickening and eosinophilic infiltration. Airway responsiveness to methacholine expressed as the logarithmic value of the concentration of methacholine required to generate a 50% increase in airway pressure (logPC(150)Mch) was also enhanced by the beta(2) agonist (-0.56 (0. 21) vs -0.95 (0.05), p<0.05). Additional experiments revealed that the same dose of the beta(2) agonist alone did not cause GCH in non-immunised rats and that the enhancement of GCH by salbutamol was completely abolished by simultaneous treatment with methylprednisolone (0.5 mg/kg/day). CONCLUSIONS: These data suggest that salbutamol enhances goblet cell hyperplasia and airway hyperresponsiveness in this rat model of atopic asthma.     

异丙酚对哮喘小鼠气道高反应性和气道炎症的调节作用

目的 评价腹腔注射不同剂量异丙酚对哮喘小鼠气道高反应性、肺部炎症以及Th1/Th2平衡的调节作用.方法 健康雌性BALB/c小鼠100只,6～8周龄,体重18 ～ 20 g,采用随机数字表法,将小鼠分为5组(n=20)∶对照组(C组)、哮喘组(A组)、低剂量异丙酚组(50 mg/kg i.p.,LP组)、中等剂量异丙酚组(100 mg/kg i.p.,MP组)和高剂量异丙酚组(150 mg/kg i.p.,HP组).使用卵清蛋白(OVA)构建过敏性哮喘模型小鼠,腹腔注射-诱导过敏性哮喘模型.各组随机取10只于模型构建成功后24 h即高剂量麻醉处死,行心脏取血及支气管肺泡灌洗,以ELISA法检测血清OVA特异性IgE和支气管肺泡灌洗液中特征性细胞因子IL-4、IL-5、IFN-γ浓度,并行细胞计数/分类计数.各组剩余的10只于模型构建成功后24h行肺功能检测和取肺进行HE染色,比较各组小鼠气道反应性和肺组织的病理组织学评分.结果 腹腔注射异丙酚(LP组和MP组)可明显地抑制哮喘小鼠的气道高反应性.不同剂量异丙酚干预组(LP组、MP组和HP组)均可明显抑制哮喘小鼠肺组织中嗜酸性粒细胞浸润,降低IL-4、IL-5和血清OVA特异性IgE水平,上调IFN-γ/IL-4比值.结论 异丙酚能够有效抑制哮喘小鼠肺部炎症,上调Th1/Th2比值,改善肺功能,发挥气道保护作用.     

Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma

BACKGROUND: Sputum eosinophil counts and exhaled nitric oxide (NO) levels are increased in asthma and both measurements fall in response to corticosteroids. METHODS: Exhaled NO levels and sputum eosinophil counts were assessed as non-invasive markers of the response to an oral steroid in 37 patients (19 women) with stable chronic asthma (mean (SD) age 48.6 (12.2) years, asthma duration 25. 9 (17.3) years, and baseline forced expiratory volume in one second (FEV(1)) 76.3 (21.9)% predicted). Spirometric tests, with reversibility to a beta agonist (2.5 mg nebulised salbutamol), and induced sputum (using nebulised 3% saline) were performed at recruitment and following treatment with 30 mg prednisolone/day for 14 days. RESULTS: Baseline NO levels correlated with the percentage improvement in FEV(1) from baseline to the post-steroid, post-bronchodilator value (r(s) = 0.47, p = 0.003), with an NO level of >10 ppb at baseline having a positive predictive value of 83% for an improvement in FEV(1) of > or =15% (sensitivity 59%, specificity 90%). Sputum eosinophilia (> or =4%) had a positive predictive value of 68% (sensitivity 54%, specificity 76%) for an increase in FEV(1) of > or =15%. A combination of sputum eosinophilia and increased NO levels resulted in a positive predictive value of 72% and a negative predictive value of 79% (sensitivity 76%, specificity 75%). CONCLUSION: Exhaled NO levels and sputum eosinophilia may be useful in predicting the response to a trial of oral steroid in asthma.