Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma

Airway wall thickening has been assumed to cause airway hyperresponsiveness, but a protective effect against airway narrowing has also been suggested. We investigated the relationship between airway wall thickness as assessed by helical computed tomography and two components of airway responsiveness, airway sensitivity and reactivity, in patients with stable asthma with (n = 23) and without (n = 22) inhaled steroid treatment. A cross-section of the apical bronchus of the right upper lobe was obtained. Airway wall area corrected by body surface area was measured as an index of wall thickness. Airway sensitivity and reactivity were measured by continuous inhalation of methacholine, on the basis of the methacholine respiratory resistance dose-response curve. The eosinophil count in sputum was determined in 16 patients [steroid (+) group] and 14 patients [steroid (-) group]. In both groups of patients, airway sensitivity was not related to airway reactivity. Airway sensitivity was related to eosinophil count [r = 0.57 in the steroid (+) group and r = 0.49 in the steroid (-) group], but not to airway wall thickness. In contrast, airway reactivity negatively correlated with airway wall thickness [r = -0.56 in the steroid (+) group and r = -0.55 in the steroid (-) group] but not with eosinophil count. Our results suggest that airway wall thickening attenuates airway reactivity in patients with asthma. These findings may have important implications in pathophysiology and in the treatment of airway remodeling.     

Study of IgE-dependent basophil releasability in allergic patients.

For this study, venous blood from 160 patients with a diagnosis of asthma and/or rhinitis was used. Histamine release test (H.R.T.) with anti-IgE at 1/5 and 1/25 dilutions and with causal antigen in the case of atopic patients (144) was carried out on all patients. Basophils from atopic patients released more histamine than those from nonatopic patients (p < 0.001). Basophils of atopic patients released more histamine with 1/5 anti-IgE dilution (p < 0.01), while non-atopic patients did so with the 1/25 dilution (p < 0.05). On grouping atopic patients according to positive or negative results in Ag-specific histamine release, 14% of patients presented negative Ag-specific H.R.T. and 85.7% of the cases did not respond to anti-IgE stimulus; this was 12% of the total number of atopics. On the other hand, 17% of the patients studied did not show positive histamine release against anti-IgE and 70.6% of them had negative Ag-specific release. As for the effect of age on IgE-dependent histamine release, the group of patients who presented greater releasability corresponded to those older than 6 years of age. The discrepancies observed between the clinical history, skin tests, serum IgE and antigen-dependent histamine release in some patients could be related to the individual basophil ability to release histamine. Therefore, this basophil releasability evaluation has an important practical application in discerning false negatives in antigen-specific H.R.T.     

Effect of dietary caffeine on airway reactivity in asthma

The potential influence of dietary caffeine on bronchoprovocation challenges with carbachol was examined in 7 patients with asymptomatic asthma. In a double-blind fashion placebo or caffeine (6 mg/kg body weight; equivalent to approximately 4 cups of coffee) solved in orange juice was administered, and carbachol challenges were performed. The average peak serum concentration achieved 60 min after dosing was 7.6 +/- SD 2.1 mg/l. These caffeine levels did not produce any appreciable attenuation of the bronchoconstrictor response to carbachol inhalations. It thus appears that dietary caffeine is barely a cause of erroneous interpretations of bronchoprovocation challenges with carbachol.     

A comparison of in vivo and in vitro human airway reactivity to histamine

To examine for a relationship between in vivo nonspecific bronchial reactivity to histamine and in vitro smooth muscle response to histamine, we performed inhalation dose-response curves prior to lung surgery in 12 patients and compared this with their bronchial smooth muscle response in vitro. In vivo reactivity was assessed by the provocative concentration of histamine resulting in a 20% fall in forced expiratory volume in one second (PC20), and in vitro reactivity was measured by the negative log of the molar concentration of histamine producing 50% maximal contraction (pD2) as well as maximal tension generated (Tmax). In addition, morphometric analysis was performed on the in vitro tissue to quantitate the amount of smooth muscle present. A wide range of in vivo responses was found in the 12 subjects (PC20-0.065 lead to 16). There was less in vitro variability and no correlation between PC20 and in vitro reactivity assessed by pD20 or Tmax or between PC20 and the percent of smooth muscle.     

Both inhaled histamine and hypertonic saline increase airway reactivity in non-sensitised rabbits.

BACKGROUND: Asthmatics react with bronchoconstriction upon a variety of stimuli, i.e. exercise and hypertonic aerosol challenge. We have previously shown that hyperventilation with dry gas in a rabbit model resulted in a change of the ion content of the tracheal wall. This was followed by a hyperreactive response to histamine. OBJECTIVE: We hypothesised that nebulisation with 3.6% hypertonic saline will be accompanied by a hyperreactive response to histamine in a rabbit model. METHODS: Anaesthetised rabbits were given histamine after nebulisation with hypertonic saline. In addition, repeat nebulisation with hypertonic saline was given with or without histamine between these nebulisations. RESULTS: There was a different response to histamine 10 mg x ml(-1) whether hypertonic saline had been given or not (p < 0.001). Histamine nebulisation, given after hypertonic saline, caused an increase from baseline in resistance of 65 +/- 12 cm H(2)O.litre(-1) x s (mean +/- SEM, p < 0. 001) and a decrease in compliance of 2.3 +/- 0.4 ml x cm H(2)O(-1) (p < 0.001). The corresponding values for the control animals were 10 +/- 4 cm H(2)O.litre(-1) x s (n.s.) and 1.7 +/- 0.2 ml x cm H(2)O(-1) (p < 0.001). At a second nebulisation with hypertonic saline, with a histamine challenge 30 min before, the resistance increased from baseline by 35 +/- 10 cm H(2)O x litre(-1) x s (p < 0.01). This was not observed when no histamine had been given between the hypertonic saline nebulisations. CONCLUSIONS: This study in rabbits shows that hypertonic solutions cause an increase in the responsiveness to histamine and that histamine causes an increase in responsiveness to hypertonic saline. This is similar to the response of asthmatics to hypertonic saline.     

支气管哮喘、咳嗽变异性哮喘及急性支气管炎气道反应性特点及意义

目的探讨支气管哮喘、咳嗽变异性哮喘及急性支气管炎气道反应性特点,以便为临床诊断提供依据。方法采用日本产ＡＳＴＯＧＡＰＨＴＣＫ６０００ＣＶ气道反应测定仪,以乙酰甲胆碱为气道激发剂,观察６０例支气管哮喘、５８例咳嗽变异性哮喘及３７例急性支气管炎患者气道反应性变化。结果支气管哮喘和咳嗽变异性哮喘病人气道激发试验均为阳性,哮喘病人的气道反应阈值（Ｄｍｉｎ）低于咳嗽变异性哮喘病人（Ｐ＜００５）。急性支气管炎病人中,气道激发试验３３例阴性,占８９％,４例阳性,占１１％。４例阳性急性支气管炎患者的气道反应性曲线与哮喘组及咳嗽变异性哮喘组明显不同,其Ｄｍｉｎ也显著高于哮喘组（Ｐ＜００１）及咳嗽变异性哮喘组（Ｐ＜００５）。结论气道反应性测定对于不同类型哮喘及急性支气管炎的鉴别和指导治疗具有很好的临床应用价值。     

Acute canine adenovirus 2 infection increases histamine airway reactivity in beagle puppies

Acute infection with canine adenovirus was studied in 23 specific pathogen-free outbred beagle puppies (median age = 78 days, range = 67 to 86 days) to determine its effects on pulmonary function and airway responsiveness to aerosolized histamine. The following groups were studied: uninoculated (n = 6, Control); inoculated with canine adenovirus type 2 (CAV2) (n = 11, Infected); and subclinical spontaneous infection with CAV2 (n = 6, Subclinical). While anesthetized with chloralose and mechanically ventilated, lung function and responsiveness to aerosolized histamine were measured 3 days before inoculation (Day -3), the day of inoculation (Day 0), and 3 to 4 (Day 3-4), 6 (Day 6), 8 to 10 (Day 8-10), and 12 to 14 (Day 12-14) days after inoculation. Histamine responsiveness was assessed by calculating the provocation concentration of histamine diphosphate to increase lung resistance (RL) to 150% (PC 150% RL), or decrease dynamic lung compliance (Cdyn) to 75% (PC 75% Cdyn) of the response to saline [RL(sal) and Cdyn(sal), respectively]. Arterial blood gases, functional residual capacity (FRC), specific static lung compliance (spCst), RL, Cdyn, and histamine responsiveness were not significantly different on Day 0 among the groups (p greater than 0.05). Control and Subclinical puppies remained healthy, had a mean weight gain of 0.7 kg, and did not change their histamine responsiveness during the study period. Infected puppies developed moderate to severe clinical illnesses, had poor weight gain, and were histamine hyperresponsive on Days 3-4 and 6. One infected puppy died on Day 3-4, and two died on Day 6 of their illness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma.

Short-acting beta2-agonists provide greater protection against bronchoconstriction induced by adenosine 5'-monophosphate (AMP) than by direct-acting bronchoconstrictors such as histamine and methacholine. AMP is thought to cause bronchoconstriction via release of mediators from mast cells, which suggests that these drugs stabilize mast cells in vivo. This in vivo property has not yet been demonstrated for long-acting beta2-agonists. We undertook a double-blind, randomized, placebo-controlled, cross-over study to investigate the effects of a single dose of formoterol inhaled via Turbuhaler (12 micrograms) and of albuterol inhaled via Turbuhaler (200 micrograms) on airway responsiveness to AMP and histamine in 16 subjects with mild atopic asthma. Albuterol reduced airway responsiveness to AMP and histamine by 4.1 +/- 0.5 and 3.5 +/- 0.4 doubling doses, respectively. In contrast, formoterol caused a greater protective effect against AMP than against histamine challenge, decreasing airway responsiveness by 6.0 +/- 0.8 and 4.2 +/- 0.4 doubling doses, respectively (p < 0.05). Thus, the long-acting beta2-agonist formoterol appears to have a mast cell-stabilizing effect in vivo in mild asthma.     

Damage of the airway epithelium and bronchial reactivity in patients with asthma

We measured bronchial reactivity to inhaled histamine and prepared electron micrographs from bronchial biopsies from 8 asthmatic patients who never smoked (2 females, 6 males, 18 to 62 yr of age). Judging from their clinical histories and the need for medication and long-term follow-up of PEF values, 2 of them had mild asthma, 3 moderately severe, and 3 severe asthma. They had not experienced respiratory infections for at least 2 months prior to the study. The result, obtained from the cumulative dose-response curve, was expressed as the provocative dose (PD20) of histamine producing a 20% fall in forced expiratory volume in one second (FEV1). In 5 patients, the PD20 varied from 0.049 mg to 2.234 mg. In the sixth patient, only PD15 could be measured (5.187 mg). In 2 patients, the low initial FEV1 values, because of severe, partly irreversible obstruction, prevented the measurement of bronchial reactivity. Bronchial biopsies were taken with rigid tube bronchoscopy from 3 levels: (1) at the carina of the right upper lobe, (2) at the opening of the right middle or lower lobe, and (3) inside the right lower lobe. The specimens were prepared for both light and electron microscopy. Fresh biopsies showed that asthma patients can have epithelial destruction at all levels of the airways. The ciliated cells appeared to be the most destroyed cell type in the epithelium. Intraepithelial nerves and mast cells were seen. Epithelial destruction in the respiratory tract of the asthma patients with mild to severe bronchial hyperresponsiveness was prominent enough to expose the epithelial nerves for specific or nonspecific stimuli.     

Bronchial reactivity in asthma to inhaled histamine during treatment with ketotifen.

A 12-week open trial using varying dosages of ketotifen, an oral drug with a prophylactic anti-asthmatic effect, was carried out in 20 patients with stable chronic bronchial asthma (age 20--50 years, no steroid treatment) to determine whether the frequency of asthma attacks and bronchodilator consumption could be reduced, and whether pulmonary function would improve. The protective action of ketoifen against a histamine inhalation test was measured at the beginning of the trial and at regular intervals during the trial. The patients experienced a significant improvement in their asthma and a significant decrease in the number of asthma attacks during the trial. Concomitantly, the need for other anti-asthma agents was reduced. Pulmonary function tests improved before and following histamine inhalation after 4, 8 and 12 weeks of treatment. In some patients cromoglycate was successfully replaced by ketotifen. Efficacy was rated as very good or good in 17 patients and moderate in 3 patients. Tolerance was good in all patients, no serious side-effects were observed. Summing up, it may be stated that ketotifen is a compound which by virtue of its activity profile and route of administration offers a new approach to the prophylactic treatment of bronchial asthma.     

The presence of airway reactivity before the development of asthma

Exaggerated airway reactivity is an essential component of the current asthmatic. It is not clear, however, if airway reactivity is genetically determined or acquired. To examine the possibility that increased bronchial reactivity exists prior to the development of asthma, we report on 20 subjects who were studied before and after the onset of clinical asthma. Subjects were part of a larger on-going study of the Natural History of Asthma. Thirteen subjects indicated by their answers to the National Heart, Lung, and Blood Institute respiratory questionnaire that they were not asthmatic at their initial visit. Seven subjects had pulmonary symptoms on their initial visit, but had not been diagnosed as asthmatic. Bronchial reactivity was assessed using a standardized methacholine challenge. For the 20 subjects, there was a mean interval of 3.5 yr between the initial visit and the diagnosis of asthma. Ten of 13 nonasthmatic subjects had moderate or strongly positive responses (208 breath units or less) to methacholine prior to onset of asthma. These 13 subjects were compared to age- and sex-matched controls, from both asthmatic and nonasthmatic families, who had not become asthmatic. There was a difference in bronchial responses at the initial visit between the 13 study subjects and their control subjects from nonasthmatic families, but not between the subjects and their controls from asthmatic families. Five of 7 subjects with pulmonary symptoms had responses of 100 breath units or less. Overall, 19 of 20 subjects had strongly positive responses to methacholine after the diagnosis of asthma was established. The results show that enhanced airway reactivity usually precedes the development of asthma, which could support a genetic basis for it.     

Difference in airway reactivity in children with atopic vs nonatopic asthma.

STUDY OBJECTIVE: To examine the difference in the mechanisms of bronchial hyperresponsiveness (BHR) in nonatopic asthma and in atopic asthma, we studied bronchial reactivity against nonspecific stimuli in children with atopic asthma and nonatopic asthma. DESIGN AND PARTICIPANTS: Fourteen children with nonatopic asthma, 24 children with atopic asthma, and 20 age-matched controls participated in this study. MEASUREMENTS: Inhalation challenge was performed by administering progressively doubling doses of methacholine with a continuous inhalation provocation method. The speed of bronchoconstriction to methacholine (Sm) and the speed of reversal of bronchoconstriction to methacholine after inhalation of a beta2-agonist (r-Sm), which was considered to represent the effect of the beta2-agonist, were calculated from the dose-response curve. RESULTS: The value of Sm was higher in the nonatopic asthma group than in the atopic asthma group and the control group. The value of r-Sm was also higher in the nonatopic asthma group than in the atopic asthma group, but did not differ from that in the control group. CONCLUSION: These results indicate that bronchial reactivity against methacholine and the beta2-agonist was greater in nonatopic asthma than in atopic asthma, and that the mechanism of BHR in children with nonatopic asthma may differ from that in children with atopic asthma.     

Effects of nedocromil and salbutamol on airway reactivity in children with asthma.

Nedocromil and salbutamol are effective drugs in preventing exercise-induced asthma (EIA). The aim of this study was to compare the protective effects of both drugs and a combination of both drugs against cold dry air-induced bronchoconstriction, using cold dry air challenges (CACh) as a surrogate for exercise. Twenty-five atopic children (mean age 13.7, range 8-18 yrs) with EIA participated in the study. Lung function tests were performed before medication, 30 min after medication and just before CACh, and 3 and 15 min after the challenge on four consecutive days. CACh consisted of a 4-min isocapnic hyperpnoea of -10 degrees C, absolutely dry air. Treatment consisted of nedocromil (two puffs of 2 mg) plus placebo, salbutamol (two puffs of 100 microg) plus placebo, the combination of both drugs, and placebo alone, in a random order. Both active drugs were significantly more protective than placebo and the combination showed an additive effect. Mean maximum postchallenge decrease in forced expiratory volume in one second after placebo was 27+/-8.1%, 12+/-9.5% after nedocromil, 8+/-10.4% after salbutamol, and 4.5+/-6.71% after the combination of both drugs, respectively. These results suggest that both drugs protect against exercise-induced asthma. Although not as effective as salbutamol and combined medication, nedocromil can give sufficient protection for many patients.     

A simplified method for measuring basophil histamine release and blocking antibodies in hay fever patients. Basophil histamine content and cell preservation.

A simplified method for measuring basophil histamine release in grass pollen hay fever patients has been developed. Leukocytes were challenged in vitro with extracts of Phleum pratense (timothy) and the release of histamine was determined indirectly as the residual histamine in the cell sediment. Several steps to purify histamine thus became superfluous and histamine was directly conjugated with o-phthaldialdehyde to form a fluorophore. The simplified method showed a basophil histamine content which was in accordance with results obtained by more specific methods. No difference in basophil histamine content was found between normal and allergic persons. For the histamine liberation assay blood could be adequately preserved for transport for 48 h at room temperature by adding cell culture medium. Basophil histamine release technique allows evaluation of cell sensitivity for determination of the degree of allergy as well as the level of blocking antibodies.     

Decreased intracellular histamine concentration and basophil activation in anaphylaxis

BackgroundHistamine is a crucial mediator in the development of anaphylaxis. Although histamine is promptly degraded because of its short half-life in plasma, basophils, which release histamine, remain in the blood for days. To explore basophils as a potential marker and their involvement in the pathogenesis of anaphylaxis, we evaluated the intracellular histamine concentration and the degree of basophil activation in anaphylaxis patients.MethodsWe conducted a case–control study enrolling anaphylaxis patients and healthy controls. Basophil activation was evaluated by flow cytometry using up-regulation of CD203c expression.ResultsWe enrolled 23 patients and measured their blood histamine concentration. Basophil activation was analyzed in seven of 23 patients. The median intracellular histamine concentrations at admission were significantly lower in patients compared with controls (16.4 ng/mL [interquartile range {IQR}, 2.70 to 34.0] vs. 62.3 ng/mL [IQR, 46.0 to 85.1]; p < 0.0001). The median basophil number at admission was also significantly lower in patients compared with controls (2.21 cell/μL [IQR, 0.75 to 12.3] vs. 21.0 cell/μL [IQR, 19.5 to 28.9]; p = 0.027). CD203c expression was not up-regulated in any of the seven patients in vitro, but it was up-regulated in response to anti-IgE stimulation in vitro in two patients at admission and four patients at follow-up.ConclusionsAnaphylaxis is associated with a decrease in intracellular histamine, and a reduced number and reactivity of peripheral basophils. Impaired basophil function and a decrease in their number and intracellular histamine levels in the circulation may reflect the underlying mechanism, suggesting that basophils may be a marker of anaphylaxis.     

The effect of parainfluenza 3 infection on guinea pig basophil and lung mast cell histamine release

The guinea pig infected with parainfluenza 3 (P-3) has provided an animal model to study mechanisms of virus-induced asthma and airway hyperreactivity. Evidence to identify the mechanisms by which P-3 infection enhances airway hyperreactivity, however, has not been established. The present study evaluated the effect of P-3 infection on histamine release (HR) from isolated peripheral blood guinea pig basophils and lung mast cells. Basophil HR was determined in animals made basophilic with 13 daily intraperitoneal injections of sheep blood. On Day 10 of the sensitization, blood was obtained from all animals, and leukocyte HR was determined to sheep gammaglobulin (SG), which served as the secretagogue. After these baseline studies, the animals were separated into two groups; one was insufflated with P-3 virus and the other with growth medium that did not contain virus. Four days later, animals were killed, basophils and lung mast cells were isolated, HR was determined, and lung tissue was cultured for the presence of virus. In basophils isolated from animals proven to be infected with P-3 virus, we found significantly more histamine released in response to the lower doses of SG and a significant shift in the -log EC50 dose of this antigen causing HR in these cells. Experiments conducted with the calcium ionophore A23187 as the basophil secretagogue in the same experimental design did not demonstrate similar HR findings. Furthermore, a defect in calcium disposition did not account for the enhanced HR from basophils isolated from infected animals. HR from pulmonary mast cells was similar in cells isolated from P-3-infected and control insufflated animals.(ABSTRACT TRUNCATED AT 250 WORDS)