Action of Budesonide on Asthmatic Bronchial Hyperresponsiveness: Effects on Directly and Indirectly Acting Bronchoconstrictors

doi:10.1378/chest.100.3.670

Chest

Volume 100, Issue 3, September 1991, Pages 670-674

https://doi.org/10.1378/chest.100.3.670 Get rights and content

We have investigated the effects of inhaled budesonide on the bronchial responsiveness to both directly and indirectly acting spasmogens in man. Following treatment with budesonide or placebo for three weeks in a double-blind, crossover trial with a three-week washout, the response to histamine and bradykinin was determined in ten patients with mild asthma. After treatment with budesonide, the response to both inhaled histamine and bradykinin was decreased when compared with placebo. The PD₃₅ histamine was increased by 1.95 doubling doses and PD₃₅ bradykinin by 2.1 doubling doses. Daily (PEF) recordings were significantly increased during budesonide therapy, the morning PEF by 34.8 ± 14.1 L/min and evening by 50.3 ± 23.1 L/min. Baseline laboratory lung function on the study days was not altered by budesonide nor were symptom records altered significantly. Inhaled budesonide therefore inhibits to the same extent the exaggerated response to both directly acting histamine and bradykinin which acts through airway nerves.

(Chest 1991; 100:670-74)

Section snippets

Subjects

Ten atopic subjects with mild asthma requiring only irregular therapy with inhaled β₂ agonists (Table 1) took part in this study which had the permission of the Royal Postgraduate Medical School and Hammersmith Special Health Authority Ethics Committee.

Challenges

Histamine challenge: Baseline lung function was taken as the mean of six consecutive measurements of (SGaw) measured using a computer-assisted body Plethysmograph.¹² The subjects then inhaled five breaths of 0.9 percent saline solution from a

Lung Function

There were no differences between the baseline FEV₁ and SGaw on all the study days, the mean ± SE FEV₁ being 3.16 ±0.14 L before and 3.14 ±0.24 L after placebo and 3.34 ± 0.14 L before and 3.41 ± 0.15 L after budesonide. The mean ± SE SGaw was 0.77 ± 0.11 kPa^–1•s^–1 before and 0.76±0.12 kPa^–1•s^–1 after placebo and 0.91 ± 0.12 kPa^–1•s^–1 before and 0.87±0.1 kPa^–1•s^–1 after budesonide (Table 2).

Challenge

Analysis of the four histamine and bradykinin challenges show no difference between the two pre-drug

DISCUSSION

Inhaled budesonide (1.2 mg/24 h) for three weeks reduced the BHR to both the direct stimulus histamine and the indirect stimulus bradykinin to the same degree (1.95 and 2.1 doubling doses, respectively). In this group of patients with mild asthma, budesonide had little effect on symptoms or clinic lung function, although there was a small but significant increase in daily PEF.

The magnitude of decrease in BHR to histamine is consistent with that previously reported.2, 3, 4, 5, 6 We are unaware

ACKNOWLEDGMENTS

The writers thank the Medical Research Council and the Chest, Heart and Stroke Association for their support of this work.

REFERENCES (26)

RyanG et al.
Effects of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled nonstroid-dependent asthma.
J Allergy Clin Immunol
(1985)
KraanJ et al.
Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline.
J Allergy Clin Immunol
(1985)
KerrebijnKF et al.
Effect of long-term treatment with inhaled corticosteroids and beta-agonists on bronchial responsiveness in children with asthma.
J Allergy Clin Immunol
(1987)
AndersonS et al.
An evaluation of pharmacotherapy for exercise-induced asthma.
J Allergy Clin Immunol
(1979)
NewballHH et al.
Bradykinin and human airways.
Respir Physiol
(1975)
RossoniG et al.
Bronchoconstriction by histamine and bradykinin in guinea-pigs: relationship to thromboxane A₂ generation and the effect of aspirin.
Prostaglandins
(1980)
KraanJ et al.
Dosage and time effects of inhaled budesonide on bronchial hyperreactivity.
Am Rev Respir Dis
(1988)
JuniperEF et al.
Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics.
Am Rev Respir Dis
(1990)
VathenenAS et al.
Effect of inhaled budesonide on bronchial reactivity in asthma.
Thorax
(1989)
BrittonJ et al.
Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.
Thorax
(1988)

AllistoneA et al.

The effect of intravenous sodium cromoglycate on the bronchoconstriction induced by sulphur dioxide inhalation in man.

Clin Sci

(1985)

FullerRW et al.

Bradykinin-induced bronchoconstriction in humans.

Am Rev Respir Dis

(1987)

MannJS et al.

Adenosine-induced bronchoconstriction in asthma.

Am Rev Respir Dis

(1985)

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The exact mechanism of action of AMP on airway wall is not well-defined, but the role of mast cells is crucial based on a variety of inflammatory mediators, such as histamine, prostaglandins, leukotrienes, and IL-8 release, from human mast cells enhanced by adenosine in vitro.156–159 Although there are studies that have shown differential BHR response to antiinflammatories such as ICSs, there are also those that show concordant effects of these medications on bronchial responsiveness to direct and indirect stimuli.143,160–163 Perhaps the variability in bronchial response to direct and indirect stimuli from ICS therapy depends not only on the specific drug or stimulant but also on the duration of treatment, dosage, and delivery (see Table 1).
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The exact effects of AMP on airway wall are not well-defined, but the role of mast cells is crucial based on a variety of inflammatory mediators such as histamine, prostaglandins, leukotrienes, and IL-8 release from human mast cells enhanced by adenosine in vitro.117–120 Although there are studies that have shown differential BHR response to anti-inflammatories such as inhaled corticosteroids, there are also those that show concordant effects of these medications on bronchial responsiveness to direct and indirect stimuli.104,121–124 Although most of the indirect stimuli that invoke an inflammatory response share a common pathway in the kinetics, the extent to which the initial insult affects the influx of inflammatory cells and release of mediators is what the differential responses between challenges.
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The exact effects of AMP on airway wall are not well-defined, but the role of mast cells is crucial based on a variety of inflammatory mediators such as histamine, prostaglandins, leukotrienes, and IL-8 release from human mast cells enhanced by adenosine in vitro [89–92]. Although there are studies that have shown differential BHR response to anti-inflammatories such as inhaled corticosteroids, there are also those that show concordant effects of these medications on bronchial responsiveness to direct and indirect stimuli [93–97]. Although most of the indirect stimuli that invoke an inflammatory response share a common pathway in the kinetics or the extent to which the initial insult affects the mobilization and influx of inflammatory cells and release of mediators creates the differential responses between challenges.
Bronchial hyperresponsiveness (BHR) is an important feature of asthma and is useful in diagnosis, monitoring, and prognostication. It probably represents inherent elements of the disease process such as genetic predisposition, airway inflammation, and airway remodeling. Airway inflammation likely accounts for the variable component of BHR, whereas the persistent component of BHR correlates significantly with structural changes in the airway, such as basement membrane thickness and epithelial damage. It might be this component that is resistant or refractory to the effects of available interventions. A few trials of immunomodulatory therapy have shown considerable improvements in markers of airway inflammation, without significantly modifying airway reactivity. Interventions to impact the more permanent feature of BHR are needed.
Beclomethasone dipropionate attenuates airways hyperresponsiveness to neurokinin A and histamine in asthma
2006, Respiratory Medicine
Inhaled corticosteroids (ICS) are the most effective anti-inflammatory agents available for the treatment of asthma but they produce only modest effects on airway inflammation and non-specific bronchial hyperresponsiveness (BHR). However, little is known about the possibility that treatment with ICS might cause additional protection on BHR to inhaled tachykinins such as neurokinin A (NKA).
Therefore, we compared the effects of beclomethasone dipropionate (BDP) on the degree of BHR to inhaled histamine and NKA in a double-blind, controlled, cross-over study of asthmatic patients.
Patients attended the laboratory before and after each 6 weeks treatment period to undertake concentration–response studies with histamine and NKA. Bronchial responsiveness to both funs was expressed as the provocative concentration producing a 20% decrease in FEV₁ from baseline (PC₂₀).
BDP therapy attenuated the constrictor response to both agonists to a similar degree, their geometric mean (range) PC₂₀ values increasing from 0.47 (0.21–1.41) mg/ml to 2.43 (0.51–4.50) mg/ml (P<0.01, post-salb vs. post-BDP treatment) and from 101.7 (27.3–356.1) μg/ml to 666.7 (151.5–1000) μg/ml (P<0.01, post-salb vs. post-BDP treatment) for histamine and NKA, respectively.
Airway responsiveness to histamine and NKA is reduced by BDP to the same extent. As a result of these findings, provocation with NKA is unlikely to provide additional useful information in the assessment of airway inflammation in asthma.
The role of endogenous and exogenous AMP in asthma and chronic obstructive pulmonary disease
2004, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Furthermore, when different direct and indirect stimuli are compared head to head, it seems that responsiveness to AMP always improves more than responsiveness to the direct stimulus methacholine.52,56-60 By contrast, when bradykinin, exercise, or ultrasonically nebulized distilled water is assessed, responsiveness is frequently similar with the indirect and direct stimuli (Table I).58,61-66 This would suggest that AMP better reflects airway inflammation than these indirect stimuli.
Bronchial hyperresponsiveness is present in virtually all patients with asthma and in more than two thirds of patients with chronic obstructive pulmonary disease. Thus far, methacholine and histamine are usually used to measure bronchial hyperresponsiveness. Both are direct stimuli, because they act directly on airway smooth muscle. Another possible stimulus to measure bronchial hyperresponsiveness is AMP. AMP is an indirect stimulus, because it acts via the release of histamine and other mediators from immunologically primed mast cells. There is increasing interest in the role of AMP as a bronchoconstrictor stimulus because it has been suggested that the concentration of AMP causing the FEV₁ to decrease by 20% (PC₂₀ AMP) may be used as a noninvasive marker of airway inflammation. The aim of this article was to review the literature assessing AMP's value in asthma and chronic obstructive pulmonary disease.
Sensitivity and Validity of Three Bronchial Provocation Tests to Demonstrate the Effect of Inhaled Corticosteroids in Asthma
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The length of the study was considered important given the chronic nature of asthma. To our knowledge, our study is the longest comparison of bronchial provocation tests during treatment with ICS.567891011121314 The present study can also be criticized due to the lack of objective measurement of drug compliance; however, we asked the compliance during every visit and always encouraged the patients to take their medication regularly.
To compare the sensitivity and validity of mannitol, histamine, and cold air challenges to demonstrate the effect of inhaled corticosteroids (ICS) in asthma.
A prospective study.
Seventeen patients with recently diagnosed, steroid-naive asthma who fulfilled the diagnostic criteria of Finnish Social Insurance Institution and were hyperresponsive to both mannitol and histamine.
The following procedures were carried out at baseline and after 3 months and 6 months of treatment with inhaled budesonide, 800 μg/d: symptom assessment with a questionnaire, ambulatory peak expiratory flow (PEF) measurements twice daily for 2 weeks, and bronchial challenges with mannitol, histamine, and cold air.
Budesonide decreased the sum symptom score, daily use of bronchodilating drugs, and diurnal PEF variation, but did not change FEV₁ percentage of predicted significantly. In addition, budesonide significantly decreased mannitol (p = 0.005) and histamine (p = 0.002) response dose ratios. The magnitude of the budesonide-induced change in responsiveness to these two challenges did not differ significantly. The effect of budesonide on cold air responsiveness did not reach statistical significance (p = 0.064). Change in mannitol responsiveness correlated significantly with the changes in sum symptom score and in FEV₁. Change in cold air responsiveness correlated with the changes in sum symptom score and in diurnal PEF variation. Change in histamine responsiveness correlated only with change in FEV₁.
Mannitol challenge is both a sensitive and valid test to demonstrate the effects of ICS in asthma. Histamine challenge is equally sensitive for this purpose, but its validity may be lower than that of mannitol challenge. Cold air challenge seems to be a valid test to demonstrate the effects of ICS, but its sensitivity may be lower than that of mannitol and histamine challenges.

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: Manuscript received November 5; revision accepted January 22.

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Chest

Clinical InvestigationsAction of Budesonide on Asthmatic Bronchial Hyperresponsiveness: Effects on Directly and Indirectly Acting Bronchoconstrictors

Section snippets

Subjects

Challenges

Lung Function

Challenge

DISCUSSION

ACKNOWLEDGMENTS

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Physiol

Prostaglandins

Dosage and time effects of inhaled budesonide on bronchial hyperreactivity.

Am Rev Respir Dis

Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics.

Am Rev Respir Dis

Effect of inhaled budesonide on bronchial reactivity in asthma.

Thorax

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

Thorax

The effect of intravenous sodium cromoglycate on the bronchoconstriction induced by sulphur dioxide inhalation in man.

Clin Sci

Bradykinin-induced bronchoconstriction in humans.

Am Rev Respir Dis

Adenosine-induced bronchoconstriction in asthma.

Am Rev Respir Dis

Clinical Investigations
Action of Budesonide on Asthmatic Bronchial Hyperresponsiveness: Effects on Directly and Indirectly Acting Bronchoconstrictors