Suppression of gastric H2-receptor mediated function in patients with bronchial asthma and ragweed allergy

We have previously demonstrated a depression of airway, vascular, and cutaneous H2-histamine receptor function in sheep with experimental allergic asthma. In the present investigation, we wished to determine if there is a depression of gastric H2-receptor function in subjects with allergic bronchial asthma. In eight normal subjects and seven subjects with allergic bronchial asthma and bronchial reactivity to ragweed antigen, gastric H2-receptor function was assessed by measuring basal and maximal stimulated acid output following pretreatment with a placebo or the H2-antagonist, cimetidine. Maximal stimulated acid output was defined as the peak acid output (PAW mEq/hr) of hydrochloric acid following a subcutaneous injection of histalog (1.5 mg/kg), and selective H2-stimulation as delta PAO = PAOplacebo-PAOcimetidine. While basal acid output was not different between the two groups, mean (+/- SD) PAO was significantly lower in the asthmatic group (14.0 +/- 8.2 mEq/hr) than the normal group (27.9 +/- 9.4 mEq/hr) (p less than 0.01). Mean PAO expressed as percent of predicted maximum was 112 +/- 36 percent in the normal group and 61 +/- 34 percent in the asthmatic group (p less than 0.01). Mean delta PAO was significantly higher in the normal group (17.1 +/- 4.8 mEq/hr) than in the asthmatic group (7.0 +/- 5.3 mEq/hr) (p less than 0.005) indicating suppressed selective H2-receptor stimulation in the latter. We conclude that in subjects with bronchial asthma and marked bronchial hyperreactivity to ragweed antigen, there is a depression of gastric H2-histamine receptor function.     

Assessment of bronchial wall thickening on posteroanterior chest radiographs in acute asthma.

A central bronchus that is readily visible end-on in approximately 50% of normal frontal chest radiographs is the bronchus to the anterior segment of either upper lobe. Bronchial wall thickening, or "cuffing," is considered to be a radiographic sign of an asthmatic exacerbation and is cited as a useful sign in a number of leading textbooks; however, to the authors' knowledge, no prior chest radiographic study has quantitatively assessed this specific sign in a population of asthmatics suffering an acute exacerbation. Posterior chest radiographs were reviewed retrospectively for 51 nonasthmatic, nonsmoking control subjects and for 45 adult asthmatic subjects during an acute exacerbation of moderate to severe asthma. Readers were blinded as to whether the radiograph was from an asthmatic or control subject. If visible end-on, the bronchus to the anterior segment of either upper lobe was assessed by measuring the diameter of the lumen and the thickness of the bronchial wall. At least one clearly defined bronchus to the anterior segment of an upper lobe was visible end-on in 22 patients (43%) in the control group and in 21 patients (47%) in the asthma group (p = NS). Mean wall thickness was 0.7 +/- 0.1 mm in the control group and 0.8 +/- 0.1 mm in the asthma group (p = 0.04). Lumen/wall thickness was 3.1 +/- 0.2 (SEM) in the control group and 2.5 +/- 0.2 in the asthma group (p = 0.055). The presence of bronchial wall thickness does not reliably distinguish radiographs of acutely asthmatic from normal individuals.     

Magnesium levels in plasma and erythrocytes before and after histamine challenge.

Previous studies have assessed the protective effect of nebulized magnesium sulphate on bronchial hyperreactivity. This study investigated the effect of histamine challenge on intracellular (erythrocytes) and extracellular (plasma) levels of magnesium and the possible relationship between degree of bronchial hyperreactivity and levels of Mg in plasma and erythrocytes. The authors studied 42 mildly asthmatic patients (10 on inhaled steroids) and 20 healthy subjects. Histamine challenge was performed by the dosimeter method and provocative dose causing a 20% fall in forced expiratory volume in one second (PD20) (FEV1) was calculated. Mg levels were measured with a calmagite colourimetric assay, both at baseline and when FEV1 had fallen by 20%. The results showed that Mg levels in plasma did not significantly change after histamine challenge (from 2.06+/-0.02 mg x dL(-1) to 2.08+/-0.02 mg x dL(-1) respectively, p=0.14). Conversely there was a statistically significant decrease in Mg levels in erythrocytes between these two time points (from 1.84+/-0.02 fmmol x cell to 1.78+/-0.02 fmmol x cell p<0.0001). Similar results were observed when the subgroups were studied separately. There was no significant correlation between PD20, the difference in both magnesium concentrations (baseline-PD20 time) or the initial values of Mg levels in erythrocytes and plasma. To conclude, histamine challenge reduces magnesium levels in erythrocytes while plasma levels remain unchanged. This histamine-induced decrease in magnesium levels occurs regardless of the diagnosis of asthma, and it is not correlated with the degree of bronchial hyperreactivity.     

Low magnesium concentration in erythrocytes of children with acute asthma

Magnesium (Mg) is the second most abundant intracellular cation and is involved in numerous physiological functions, including protein folding, intracellular signaling and enzyme catalysis. It has been shown that magnesium deficiency exacerbates pulmonary airways hyper reactivity. Several studies suggest that magnesium level has no effect on asthma but others had shown a contributory effect. Because of its intracellular abundance the aim of this study was to determine if there was any difference in plasma and intracellular Mg concentrations of children with acute asthma compared to non asthmatic children. Twenty nine patients with acute asthma aged 2 to11 years admitted to the emergency department of hospital and 37 non asthmatic children with the same age were included in our study. 0.5 mL of heparinized whole blood samples of patients who were meeting inclusion criteria at the onset of admission with bronchoconstriction and before using any medication was drawn and it was immediately sent to the laboratory. Plasma and erythrocytes were separated and stored at -20C and later their Mg levels were quantified with atomic absorption spectrophotometry method. The average plasma and intracellular magnesium levels in patients were (0.79 +/- 0.098 mmol/L) and (1.17 +/- 0.27 mmol/L) respectively. Results of 37 non asthmatic persons [plasma (0.85 +/- 0.1 mmol/L ) and erythrocytes (1.33 +/- 0.21 mmol/L)] showed that there was no significant difference between plasma Mg levels in two groups (p 0.06) but intracellular magnesium level was significantly lower (p 0.03) in patients group. These results indicate that intracellular Mg level may be a more accurate method to assess Mg level in patients with asthma. Hence, determination of Mg concentration in erythrocytes may be used in evaluation of asthma pathophysiology. There are recommendations for using intravenous Mg sulfate in acute asthma, and this study supports the rational for using it in emergency departments for acute severe asthma.     

Mast cells in bronchoalveolar lumen of patients with bronchial asthma

Bronchoalveolar lavage was performed on patients with stable bronchial asthma to elucidate the existence and significance of mast cells in human bronchoalveolar lumen. The percentage of total mast cell population, in which 2 different types of mast cells could be identified morphologically in lavage fluids, was 0.25 +/- 0.19% (mean +/- SD) in asthmatic patients and 0.08 +/- 0.02% in control subjects. The number of mast cells in asthmatic patients was greater than in control subjects (p less than 0.05). The histamine content per mast cell in bronchoalveolar lumen was calculated to be 8.2 +/- 6.0 pg/cell in asthmatic patients and 15.3 +/- 10.8 pg/cell in control subjects, which suggests that the " releasability " of histamine is greater in asthmatic patients during asymptomatic periods than it is in control subjects, although the differences were not statistically significant. Our results suggest that an increase in the mast cell population of bronchoalveolar lumen is significant in the pathogenesis of bronchial asthma.     

Effect of cold air exposure and exercise on nonspecific bronchial reactivity

Exercise and eucapnic hyperventilation with cold air can produce bronchoconstriction in asthmatic subjects, but their enhancement of nonspecific bronchial reactivity remains unclear. We studied the effect of submaximal exercise and cold air exposure on bronchial reactivity to methacholine in a normal control group (n = 10) and in subjects with bronchial asthma (n = 17). Bronchial provocation testing was performed to determine the provoking dose (PD35) of methacholine that caused a 35 percent decrease in specific airway conductance (Gaw/VL) in the two groups. Each subject was studied on three different occasions to determine the PD35 to methacholine on a control day, after ten minutes of submaximal exercise, and after a 30-minute exposure to cold air. Methacholine challenge was performed after the Gaw/VL had returned to the baseline values. In the normal group, neither cold air exposure nor exercise challenge had any significant effect on baseline Gaw/VL, whereas in the asthmatic group, both stimuli caused 20 percent and 15 percent decreases in Gaw/VL, respectively (p less than .05). Mean +/- SD control PD35 was 6.1 +/- 11.6 breath units in the asthmatic group, which decreased to 2.2 +/- 2.8 after exercise and 3.0 +/- 5.0 breath units after cold air exposure (p less than .05). In the normal group, control PD35 was 73 +/- 32 breath units, which was not different from PD35 values of 64 +/- 75 and 52 +/- 64 breath units after exercise and cold air exposure, respectively (p = NS). These data suggest that submaximal exercise and cold air exposure enhance nonspecific bronchial reactivity in asthmatic but not in normal subjects.     

Status of intracellular and extracellular magnesium concentration in patients with cardiac syndrome X

OBJECTIVES: This study sought to clarify the differences of intracellular and extracellular magnesium levels in patients with cardiac syndrome X. METHODS: We evaluated the intracellular and extracellular magnesium status of 22 patients with cardiac syndrome X (group A) and 22 age--and gender--matched disorder-free control subjects (group B). Levels of magnesium were determined in serum, urine, erythrocytes, and the 24-h magnesium retention rate was calculated by a magnesium loading test. RESULTS: Group A showed a higher 24-h magnesium retention rate (49.8 +/- 1.3% vs. 32.6 +/- 7.5%, p < 0.05) and a lower intracellular concentration of magnesium in erythrocytes than group B (3.7 +/- 1.4 vs. 5.6 +/- 1.3 fg/cell, p < 0.05), demonstrating the presence of magnesium deficiency in group A.There were no significant differences in the serum concentration of magnesium between groups A and B (0.87 +/- 0.23 vs. 0.83 +/- 0.15 mmol/l). CONCLUSIONS: This study demonstrated that the intracellular magnesium level decreased in patients with cardiac syndrome X.     

Childhood asthma: exhaled nitric oxide in relation to clinical symptoms.

Bronchial asthma is associated with increased levels of exhaled nitric oxide which are suppressible by glucocorticosteroid inhalation. Children with bronchial asthma were studied to elucidate the relation between endogenous NO release and recent symptoms of bronchial obstruction. Twenty-five children with atopic asthma and 11 healthy control subjects were enrolled and exhaled NO was studied using chemiluminescence analysis. The subjects breathed purified air (<0.5 parts per billion (ppb) NO) exclusively through their mouths. Orally expired NO was measured during continuous nasal aspiration (1.3 L x min(-1)) to remove nasally produced NO. Nasal NO concentration was determined within the aspirated gas. Orally expired NO concentration was 2.5+/-0.3 ppb (mean +/-SEM) in healthy control subjects, 3.19+/-0.88 ppb (NS) in symptom-free children, and 8.28+/-0.81 ppb (p< or =0.01) in children with bronchial asthma who had had recent symptoms of bronchial obstruction. Similarly, in the subgroup of children treated regularly with inhaled glucocorticosteroids those with recent symptoms had significantly higher orally exhaled NO concentrations than healthy control subjects (9.5+/-1.5 ppb, p<0.05). The nasal NO concentration was 152.8+/-12.7 ppb in healthy control subjects and not significantly different in asthmatic children. In this group of asthmatic children, recent symptoms of bronchial obstruction were linked to significantly higher concentrations of NO in orally exhaled gas and to increased oral NO excretion rates. If substantiated by further studies, measurement of orally exhaled NO during nasal aspiration may become useful to monitor disease control in asthmatic children.     

Evaluation of serum interleukin-8 as a marker of disease activity in acute asthma in children.

Cytokine-mediated interactions among the inflammatory cells may play a role in the pathogenesis of bronchial asthma. Interleukin-8 (IL-8) is a major cytokine in the recruitment of neutrophils to the area of inflammation. Serum IL-8 is a marker of disease activity and treatment efficacy in bronchial asthma. To understand the role of IL-8 in disease activity in acute asthma, changes in serum concentrations of IL-8 elaborated by activated eosinophil before and after prednisolone therapy with clinical improvement were determined in the present study. Circulating levels of IL-8 in 15 normal control subjects and in sera from 20 allergic asthmatic children with acute exacerbation and in stable condition were determined by using commercially available assay kits. The mean concentration of serum IL-8 was statistically significantly higher in asthmatic children with acute exacerbation (63.62 +/- 11.41 pg/mL) and in stable asthmatics (64.22 +/- 10.31 pg/mL) compared to the control group subjects (50.40 +/- 30.70 pg/mL; p < 0.01). However, the difference was not statistically significant between the acute exacerbation and stable asthmatics groups (p > 0.05). Serum IL-8 is a poor indicator of disease activity in acute asthma; therefore, monitoring by serum IL-8 concentration is of limited value. The clinical value of serum IL-8 as a marker of disease activity remains to be established.     

Extended exhaled NO measurement differentiates between alveolar and bronchial inflammation

Lower respiratory tract inflammation can be detected by measuring exhaled nitric oxide (NO) concentration at a single exhalation flow rate, but this does not differentiate between alveolar and bronchial NO production. We assessed alveolar NO concentration and bronchial NO flux with an extended method of measuring exhaled NO at several exhalation flow rates in 40 patients with asthma, 17 patients with alveolitis, and 57 healthy control subjects. Bronchial NO flux was higher in asthma (2.5 +/- 0.3 nl/s, p < 0.001) than in alveolitis (0.7 +/- 0.1 nl/s) and healthy control subjects (0.7 +/- 0.1 nl/s). Alveolar NO concentration was higher in alveolitis (4.1 +/- 0.3 ppb, p < 0.001) than in asthma (1.1 +/- 0.2 ppb) and healthy control subjects (1.1 +/- 0.1 ppb). In asthma, bronchial NO flux correlated with serum level of eosinophil protein X (EPX) (r = 0.60, p < 0.001) and bronchial hyperresponsiveness (r = 0.55, p < 0.001). In alveolitis, alveolar NO concentration correlated inversely with pulmonary diffusing capacity (r = -0.55, p = 0.022) and pulmonary restriction. Glucocorticoid treatment or allergen avoidance normalized bronchial NO flux in asthma and decreased alveolar NO concentration toward normal in alveolitis. In conclusion, extended exhaled NO measurement can be used to separately assess alveolar and bronchial inflammation and to assess disease activity/severity in asthma and alveolitis.     

Relationship between bronchial response to respiratory heat exchange and nonspecific airways reactivity in asthmatic patients

In this study we have examined the relationship between the bronchial response to inhaled histamine and the bronchial response to breathing cold air at rest in nine control subjects and nine patients with asthma. Dried warm air (mean temp: +/- 1SD: 25.4 +/- 1.6 degrees C) and cold air (-19.7 +/- 2.6 degrees C) were breathed for 10 minutes each during quiet breathing at rest prior to as well as during both measurements of forced expired spirograms and the phase 3 slope of the single-breath oxygen test (delta N2/L). Subjects were also challenged with inhaled aerosolized histamine to determine the concentration required to reduce the forced expired volume in one second (FEV1) by 20 percent (PC20). Both asthmatic and control subjects had significantly greater respiratory heat exchange breathing cold as compared to warm air (p less than 0.01 in both cases). Control subjects did not change FEV1 or delta N2/L breathing cold air. Asthmatic patients increased delta N2/L from a mean warm air value of 2.41 +/- 1.31% N2/L to a mean cold air value of 5.39 +/- 4.55% N2/L (p less than 0.05). There was a significant linear correlation between the percent increase in delta N2/L from warm to cold air and 1/log10PC20 (r = -0.97, p less than 0.001) and also the percent decrease in FEV1 and log PC20 (r = -0.76, p less than 0.03) in the asthmatic patients. We conclude that cold air-induced alterations in ventilation/distribution and expired flow rates in asthmatic patients are related to pre-existing nonspecific airways reactivity.     

Bronchial dilatation in asthma: relation to clinical and sputum indices

BACKGROUND: Investigations using high-resolution CT (HRCT) show that bronchial dilatation (BD) is found in many patients with asthma. However, the pathogenesis and pathophysiologic relevance of BD in asthma are poorly understood. A balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may control the remodeling of extracellular matrix, and excess MMPs have been associated with destruction or dilatation of airways in patients with bronchiectasis. OBJECTIVES: To study the prevalence of BD as assessed by HRCT according to standard subjective criteria in 37 patients with stable asthma and 10 healthy control subjects, and to examine the relation of BD in asthmatic patients to clinical characteristics and sputum indices, including MMP-9 and TIMP-1 levels. DESIGN: A prospective cohort study. RESULTS: At least one dilated bronchus was present in 23 asthmatic subjects (62%) and 2 control subjects (20%) [p = 0.030]. The ratio of dilated bronchi to all eligible bronchi in each subject (individual BD%) was higher in the asthmatic patients than in the control subjects (11.4 +/- 16.1% vs 1.3 +/- 3.0%, p = 0.011) [mean +/- SD]. Asthmatic patients with (n = 23) and those without BD (n = 14) were similar with regard to age, duration and severity of asthma, atopy, pulmonary function, sputum eosinophil or neutrophil count, and sputum levels of MMP-9 or TIMP-1 and their molar ratio. Individual BD% of asthmatic patients was also unrelated to these clinical and sputum variables. When analysis was confined to the 23 patients with BD, however, individual BD% correlated with the severity score of asthma (r = 0.49, p = 0.023). The results of follow-up HRCT obtained from 19 patients suggested that BD was a fixed rather than transient phenomenon. CONCLUSION: BD is more prevalent in asthmatic patients than in normal subjects and might be associated with the severity of asthma. Cellular inflammation or possible imbalance between MMP-9 and TIMP-1 was not demonstrated in this study to be related to BD in asthma.     

Serum leukotriene B4 levels in patients with obstructive pulmonary disease.

Leukotriene B4 has been found to be increased in the serum of cigarette smokers and some patients with bronchial asthma, as well as in the sputum of patients with cystic fibrosis and COPD. Corticosteroids supposedly may block the formation of LTB4. To determine if the effect of CS on airway disease is by reduction in LTB4, we studied serum LTB4 levels in clinically stable patients with asthma or COPD who were treated with or without CS. The LTB4 was extracted from serum and assayed by radioimmunoassay. Serum LTB4 concentrations, expressed as the mean +/- SD, were 0.36 +/- 0.15 ng/ml in ten normal controls, 0.56 +/- 0.18 ng/ml in nine asthmatic subjects, 0.67 +/- 0.2 ng/ml in eight asthmatic subjects receiving CS, 0.81 +/- 0.19 ng/ml in seven patients with COPD, and 0.97 +/- 0.29 ng/ml in eight patients with COPD receiving CS. Serum LTB4 levels in normal controls differed significantly from all groups with COPD or asthma (p less than 0.01). Levels of LTB4 in asthmatic subjects differed from levels in patients with COPD (p less than 0.03), and levels in asthmatic subjects receiving CS differed from subjects with COPD receiving CS (p less than 0.03). Concentrations of LTB4 within either the COPD or the asthmatic groups were not lower in the patients treated with CS. We conclude that serum LTB4 concentrations are higher in COPD than in asthma or normal controls and that administration of CS is not associated with low LTB4 levels. The beneficial effects of CS in obstructive airway disease appear to be mediated by mechanisms other than reduction of LTB4.     

Comparison between bronchial and alveolar samples of bronchoalveolar lavage fluid in asthma.

BACKGROUND: Cell content of BALF may vary according to the segment of the lung washed. It was proposed to separate BALF into several aliquots, the first sample being more related to bronchi. The present study compared bronchial and alveolar samples by fractionating aliquots of BALF in normal and asthmatic subjects. METHODS: One hundred asthmatic subjects (mean +/- SEM: 37 +/- 1.5 yr in age) were compared with 31 normal subjects (mean +/- SEM: 32 +/- 2.2 yr in age). None of the subjects was a smoker and none was taking drugs that might interfere with the results. The severity of asthma was defined by the clinical score of Aas examining the chronic severity of asthma and ranging from 1 to 5 (range: 1 to 4; mean +/- SEM: 2.2 +/- 0.1) and FEV1 (range: 45 to 130 percent; mean +/- SEM: 82 +/- 1.8 percent of predicted values). Bronchoscopy was done in a standardized manner. A first aliquot of 50 ml of saline each were instilled and the BALF recovered was pooled (alveolar sample). After centrifugation, total and differential cell counts (May Grünwald-Giemsa) were carried out on bronchial and alveolar samples. RESULTS: The alveolar sample contained significantly more cells per milliliter of BALF than the bronchial sample in normal (p less than 0.0077, Wilcoxon test) and in asthmatic subjects (p = 0.0001, Wilcoxon test). Both in normal and asthmatic subjects, bronchial samples contained significantly more neutrophils and epithelial cells and fewer macrophages and lymphocytes than alveolar samples. In asthmatic subjects, the bronchial sample contained a significantly greater percentage of eosinophils than the alveolar sample. Eosinophils were significantly increased in asthmatic subjects for both the bronchial and alveolar samples. Bronchial and alveolar eosinophilia both were correlated with the Aas score (r = 0.25, p = 0.024 and r = 0.38, p = 0.0006, respectively, by Spearman Rank test). CONCLUSIONS: This study shows in a large number of subjects that the cell content of bronchial and more distal segments of the lung is not comparable, indicating that studies should not give pooled data in asthmatic subjects. Moreover, it confirms the presence of BALF eosinophilia in asthmatic subjects.     

Reduced intracellular magnesium concentrations in asthmatic patients.

Magnesium is important in the regulation of bronchomotor tone, and low dietary intake of magnesium has been associated with airway hyperresponsiveness in epidemiological studies. The concentration of magnesium in serum, erythrocytes and urine in 49 patients with asthma (29 males, aged 15-65 yrs) and in 25 normal subjects (15 males, aged 17-36 yrs) was studied by atomic absorption. Magnesium concentrations were significantly lower in erythrocytes and urine in both atopic (n = 26) and nonatopic (n = 23) asthmatic patients as compared with the control group, whereas serum concentrations did not differ. The concentration of magnesium in erythrocytes was not related to the degree of airway obstruction as measured by forced expiratory volume in one second (FEV1) but was significantly correlated with airway hyperresponsiveness measured as the provocative concentration causing a 20% fall in FEV1 to inhaled acetylcholine (r = 0.64; p<0.05). In addition, a magnesium tolerance test showed increased retention of magnesium (58.9% of administered dose in asthmatic patients compared with 8.9% in normal subjects, p<0.05). In conclusion, the low cellular concentration of magnesium may be associated with airway hyperresponsiveness in asthmatic patients.     

Serum interleukin-5 measurements for monitoring acute asthma in children.

Cytokine-mediated interactions among the inflammatory cells may play a role in the pathogenesis of bronchial asthma. Interleukin-5 (IL-5) is a major cytokine in the recruitment of neutrophils to the area of inflammation. Serum IL-5 is a marker of disease activity and treatment efficacy in bronchial asthma. To understand the role of IL-5 in disease activity in acute asthma, changes in serum concentrations of IL-5 elaborated by activated eosinophil before and after prednisolone therapy with clinical improvement were determined in the present study. Circulating levels of IL-5 in 16 normal control subjects and in sera from 22 allergic asthmatic children with acute exacerbation and in stable condition were determined by using commercially available assay kits. The mean concentration of serum IL-5 was higher in patients with acute exacerbation (6.30 +/- 2.21 pg/mL) and in stable asthmatics (5.55 +/- 2.23 pg/mL) compared to control group subjects (4.81 +/- 0.54 pg/mL; p > 0.05). However, the difference was not statistically significant between the acute exacerbation and stable asthmatics groups (p > 0.05). Serum IL-5 is a poor indicator of disease activity in acute asthma; therefore, monitoring serum IL-5 concentration is of limited value. The clinical value of serum IL-5 as a marker of disease activity remains to be established.     

Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene

OBJECTIVES: Cytotoxic T-lymphocyte antigen (CTLA)-4 is a homolog of CD28, which is expressed only on activated T cells. It binds to accessory molecule B7 and mediates T-cell-dependent immune response. Signaling through CTLA-4 may down-regulate type 1 T-helper cell proliferation; moreover, some studies suggest that CTLA-4 might also deliver a positive signal to type 2 T-helper cell activation. Disruption of this delicate balance of immune regulation may lead to autoimmune diseases or atopic diseases. To evaluate the possible role of CTLA-4 polymorphisms in bronchial asthma, we investigated the association between polymorphisms (exon 1 +49 A/G, promoter -318 C/T) and atopy, asthma severity, and bronchial hyperresponsiveness in bronchial asthma patients and a group of healthy control subjects. PATIENTS: Eighty-eight asthmatic patients and 88 healthy control subjects were studied. MEASUREMENTS AND RESULTS: Asthma severity assessment, methacholine challenge, allergy skinprick test, and serum total IgE measurements were performed. The genotypes of the CTLA-4 promoter (-318 C/T) and exon 1 (+49 A/G) in all subjects were determined using the polymerase chain reaction and restriction fragment length polymorphism. The CTLA-4 promoter (-318 C/T) polymorphism was shown to be associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association was found between severe asthma and the T allele (p = 0.037). The CTLA-4 exon 1 (+49 A/G) polymorphism was shown to be associated with bronchial hyperresponsiveness, but not with asthma, atopy, or asthma severity. Asthmatic patients of the GG genotype had more hyperresponsive airways than those with the AG or AA genotype (p = 0.019). CONCLUSIONS: The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. The CTLA-4 exon 1 (+49 A/G) polymorphism may have a disease-modifying effect in asthmatic airways.     

尿紧张素Ⅱ在支气管哮喘气道重塑中的作用

目的观察支气管哮喘(简称哮喘)大鼠及哮喘患者支气管管壁尿紧张素Ⅱ(UⅡ)的变化,探讨UⅡ在哮喘发病及气道重塑中的作用。方法将20只一级雄性Wistar大鼠分为对照组和哮喘组,每组10只。哮喘组大鼠采用卵白蛋白10mg腹腔内注射及雾化吸入(5mg)处理建立大鼠哮喘模型;肺组织切片经苏木精伊红(HE)染色,采用图像分析技术测量大鼠支气管管腔的内周长(Pi)、管壁面积(WA)、平滑肌面积(WAm),以WA/Pi和WAm/Pi反映其气道重塑情况;对哮喘大鼠和5例哮喘患者肺组织切片采用链亲和素蛋白过氧化物酶(SP)免疫组织化学法染色检测支气管UⅡ的表达变化,以灰度扫描和计数UⅡ阳性染色细胞数判断其表达强度。结果哮喘组大鼠WA/Pi、WAm/Pi分别为(24.1±2.4)μm2/μm、(5.3±1.9)μm2/μm,与对照组[(16.5±1.7)μm2/μm、(3.8±1.2)μm2/μm]比较差异有统计学意义(t分别=3.892、3.785,P均<0.01);哮喘大鼠支气管UⅡ的表达强度为2.46±0.15,与对照组(1.26±0.11)比较差异有统计学意义(t=6.236,P<0.01);UⅡ的表达强度与WAm/Pi呈正相关(r=0.712,P<0.01);UⅡ阳性染色细胞百分数为(82±8)%,与对照组[(22±8)%]比较差异也有统计学意义(t=19.102,P<0.01);哮喘患者支气管UⅡ的表达强度为2.61±0.19,与对照组(1.36±0.12)比较差异有统计学意义(t=7.374,P<0.01);UⅡ阳性染色细胞百分数为(75±9)%,与对照组[(27±7)%]比较差异有统计学意义(t=16.236,P<0.01)。结论哮喘气道UⅡ的表达和合成明显增加,其可能与哮喘发病及其气道重塑具有密切的关系。     

Exhaled nitric oxide and thermally induced asthma

The purpose of the present study was to determine if nitric oxide (NO) is involved in the pathogenesis of thermally induced asthma. To provide data on this issue, 10 normal and 13 asthmatic subjects performed isocapnic hyperventilation with frigid air while the fractional concentration of NO in the expirate air (FENO) was serially monitored with a chemiluminescence analyzer. FEV1 was measured before and after hyperpnea. Prior to and throughout the challenge, the asthmatics had significantly larger values for FENO (baseline FENO normal, 11 +/- 2 ppb; asthma, 16 +/- 1; p = 0.03). Posthyperpnea, the normal subjects had little change in bronchial caliber (deltaFEV1 baseline to 5 min posthyperpnea, -3.5 +/- 1.5%; p = 0.06), whereas the patients with asthma developed significant airway obstruction (deltaFEV1, -27.7 +/- 2.9%; p = 0.0001). During hyperventilation, the volume of NO rose in both groups. The asthmatic subjects, however, generated approximately 55% more NO/min than did the normal control subjects even though their level of ventilation was approximately 66% less. In contrast to the normal subjects, NO production in the asthmatics continued into the recovery period after the challenge stopped and FENO rose temporally as the airflow limitation developed. These results suggest that NO plays an intimate role in the development of airway obstruction that follows hyperpnea.     

Cellular events in the bronchi in mild asthma and after bronchial provocation

We have undertaken detailed cellular and ultrastructural examination of bronchial biopsies and bronchial lavage fluid from allergic asthmatic patients in order to determine the nature and degree of the inflammatory processes in mild allergic asthma. Eight atopic asthmatic patients (mean PC20 histamine, 0.90 mg/ml) and four nonasthmatic control subjects underwent fiberoptic bronchoscopy. All asthmatic subjects were clinically stable for 2 wk prior to bronchoscopy and required either no treatment or inhaled albuterol alone. A single 50-ml bronchial wash was undertaken, followed by endobronchial biopsy of subcarinae. These procedures were repeated in the asthmatic subjects 18 h after bronchial provocation with allergen or methacholine. Subsequently, all subjects underwent bronchial reactivity testing with inhaled histamine. The clinical and physiologic data were not revealed to the pathologist interpreting the specimens. The asthmatic subjects shed a significantly greater number of epithelial cells into the lavage fluid than did the nonasthmatic subjects (7.23 versus 1.48 x 10(4)/ml, p = 0.048). There was a statistically significant inverse correlation between the lavage epithelial cell count and bronchial reactivity (rho = -0.64, p = 0.03). In the asthmatic subjects, but not in the control subjects, there was extensive deposition of collagen beneath the epithelial basement membrane, mast cell degranulation, and mucosal infiltration by eosinophils, which exhibited morphologic evidence of activation. Eosinophils, monocytes, and platelets were found in contact with the vascular endothelium, with emigration of eosinophils and monocytes in the asthmatic subjects. These changes were found irrespective of bronchial challenge with allergen. We conclude that allergic asthma is accompanied by extensive inflammatory changes in the airways, even in mild clinical and subclinical disease.