ANNUAL REVIEWS
Annu. Rev. Med. 1991. 42:139-50 Copyright © 1991 by Annual Reviews Inc. All rights reserved
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ASTHMA AND AIRWAY
Annu. Rev. Med. 1991.42:139-150. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/16/15. For personal use only.
HYPERRESPONSIVENESS Roland H. Ingram, Jr., M.D.
Departments of Medicine, University of Minnesota Medical School; and Hennepin County Medical Center, Minneapolis, Minnesota 55415 KEY
WORDS:
inflammation, mechanical interdependence
ABSTRACT
Airway hyperresponsiveness to a large number of stimuli is a characteristic of asthma in humans. Various components of the tracheobronchial tree might contribute to this characteristic, such as smooth muscle, the bron chial epithelium, various neurohumoral mechanisms, and the mechanical linkages between the lung parenchyma and the airways. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics, making them more prone to overt attacks in response to minor stimuli that would ordinarily be well tolerated. Depending upon the inciting stimulus, different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness. INTRODUCTION
Airways respond to noxious, particulate, thermal, or pharmacologic stim uli in a number of ways. Both the type and the degree of response can vary depending upon the kind and magnitude of the stimulus and upon the prestimulation state of the airways. The latter source of variability indi cates that the degree of airway responsiveness is a mutable attribute that d iffers among persons and over time within a given person. Although the degree of responsiveness is variable, some people maintain a relatively 139 0066-4219/91/0401-0139$02.00
Annu. Rev. Med. 1991.42:139-150. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/16/15. For personal use only.
140
INGRAM
high level of responsiveness, and they comprise the majority of asthmatic subjects. Indeed, airway hyperresponsiveness is an integral part of the definition of asthma (1). This review first considers the kinds of airway responses before focussing on the acute and transient obstructive episodes that are provoked in a controlled laboratory setting, where such acute provocations are used to assess the levels of responsiveness for diagnostic purposes, for assessments of changes in status, and for epidemiologic studies. The current views of the mechanisms of hyperresponsiveness are presented, including the role of alterations in prechallenge lung function, the role of inflammation and its varying components, and the role of several endogenous factors that moderate or amplify the obstructive response to a variety of stimuli. KINDS OF AIRWAY RESPONSES
Responses to provocative stimuli include cough, increased production of tracheobronchial secretions, alterations in ciliary activity, and inflam mation involving the airway epithelium and the submucosa, along with constriction of smooth muscle in the airway wall. Coughing is an obvious means of ridding the airways of irritants and excessive secretions. A persistent and unproductive cough, however, becomes a futile and annoying symptom that may precede and/or follow severe exacerbations of asthma (2) and is a major correlate of cold-air induced asthma in some subjects (3). When persistent cough is productive, it represents a reasonable process for eliminating excess secretions. In the latter instance the primary response is hypersecretion and the secondary one is the cough itself. A minimally or nonproductive cough in the presence of retained secretions indicates some combination of inflammation, altered mucociliary function, and obstruction. Undoubtedly these alterations are extremely important in the development and perpetuation of severe and prolonged asthmatic attacks. However, current assessments of airway responsiveness focus on those stimuli (e. g. methacholine) that produce a response both rapid in onset and relatively brief in duration. Therefore constriction of smooth muscle in the airway wall is thought to be the major cause of the decrease in airway caliber in response to these stimuli. ASSESSMENT OF RESPONSIVENESS
Most commonly, the response to increasing concentrations of aerosolized methacholine, a muscarinic agonist, or histamine is assessed as the log provocative dose (PD) leading to a 20% fall in the forced expiratory volume in one second (FEVl.o) or a 35% decrease in specific conductance
Annu. Rev. Med. 1991.42:139-150. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/16/15. For personal use only.
ASTHMA AND HYPERRESPONSIVENESS
141
(PD20 and PD35, respectively). Under baseline conditions with equivalent prechallenge lung function between challenges, the PDs are reproducible within a half log concentration. Although histamine and methacholine are most commonly used, the nonspecific nature of airway responses is demonstrated by similar distributions of responsiveness to isocapnic hypernea with cold air, ultrasonic nebulization of water, and to several spasmogenic mediators, including the sulfidopeptide leukotrienes. Such data from the general population resemble a log normal distribution of responsiveness (4), with asthmatics representing the more responsive mem bers, i.e. asthmatics appear to demonstrate quantitative rather than quali tative differences (Figure 1). Measures of responsiveness are used mainly as research tools, although provocations can be useful clinically when the patient's history suggests recurrent attacks of airway obstruction and the pulmonary function is normal. Under such circumstances, an increased level of responsiveness to
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Annu. Rev. Med. 1991. 42:139-50 Copyright © 1991 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
ASTHMA AND AIRWAY
Annu. Rev. Med. 1991.42:139-150. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/16/15. For personal use only.
HYPERRESPONSIVENESS Roland H. Ingram, Jr., M.D.
Departments of Medicine, University of Minnesota Medical School; and Hennepin County Medical Center, Minneapolis, Minnesota 55415 KEY
WORDS:
inflammation, mechanical interdependence
ABSTRACT
Airway hyperresponsiveness to a large number of stimuli is a characteristic of asthma in humans. Various components of the tracheobronchial tree might contribute to this characteristic, such as smooth muscle, the bron chial epithelium, various neurohumoral mechanisms, and the mechanical linkages between the lung parenchyma and the airways. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics, making them more prone to overt attacks in response to minor stimuli that would ordinarily be well tolerated. Depending upon the inciting stimulus, different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness. INTRODUCTION
Airways respond to noxious, particulate, thermal, or pharmacologic stim uli in a number of ways. Both the type and the degree of response can vary depending upon the kind and magnitude of the stimulus and upon the prestimulation state of the airways. The latter source of variability indi cates that the degree of airway responsiveness is a mutable attribute that d iffers among persons and over time within a given person. Although the degree of responsiveness is variable, some people maintain a relatively 139 0066-4219/91/0401-0139$02.00
Annu. Rev. Med. 1991.42:139-150. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/16/15. For personal use only.
140
INGRAM
high level of responsiveness, and they comprise the majority of asthmatic subjects. Indeed, airway hyperresponsiveness is an integral part of the definition of asthma (1). This review first considers the kinds of airway responses before focussing on the acute and transient obstructive episodes that are provoked in a controlled laboratory setting, where such acute provocations are used to assess the levels of responsiveness for diagnostic purposes, for assessments of changes in status, and for epidemiologic studies. The current views of the mechanisms of hyperresponsiveness are presented, including the role of alterations in prechallenge lung function, the role of inflammation and its varying components, and the role of several endogenous factors that moderate or amplify the obstructive response to a variety of stimuli. KINDS OF AIRWAY RESPONSES
Responses to provocative stimuli include cough, increased production of tracheobronchial secretions, alterations in ciliary activity, and inflam mation involving the airway epithelium and the submucosa, along with constriction of smooth muscle in the airway wall. Coughing is an obvious means of ridding the airways of irritants and excessive secretions. A persistent and unproductive cough, however, becomes a futile and annoying symptom that may precede and/or follow severe exacerbations of asthma (2) and is a major correlate of cold-air induced asthma in some subjects (3). When persistent cough is productive, it represents a reasonable process for eliminating excess secretions. In the latter instance the primary response is hypersecretion and the secondary one is the cough itself. A minimally or nonproductive cough in the presence of retained secretions indicates some combination of inflammation, altered mucociliary function, and obstruction. Undoubtedly these alterations are extremely important in the development and perpetuation of severe and prolonged asthmatic attacks. However, current assessments of airway responsiveness focus on those stimuli (e. g. methacholine) that produce a response both rapid in onset and relatively brief in duration. Therefore constriction of smooth muscle in the airway wall is thought to be the major cause of the decrease in airway caliber in response to these stimuli. ASSESSMENT OF RESPONSIVENESS
Most commonly, the response to increasing concentrations of aerosolized methacholine, a muscarinic agonist, or histamine is assessed as the log provocative dose (PD) leading to a 20% fall in the forced expiratory volume in one second (FEVl.o) or a 35% decrease in specific conductance
Annu. Rev. Med. 1991.42:139-150. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/16/15. For personal use only.
ASTHMA AND HYPERRESPONSIVENESS
141
(PD20 and PD35, respectively). Under baseline conditions with equivalent prechallenge lung function between challenges, the PDs are reproducible within a half log concentration. Although histamine and methacholine are most commonly used, the nonspecific nature of airway responses is demonstrated by similar distributions of responsiveness to isocapnic hypernea with cold air, ultrasonic nebulization of water, and to several spasmogenic mediators, including the sulfidopeptide leukotrienes. Such data from the general population resemble a log normal distribution of responsiveness (4), with asthmatics representing the more responsive mem bers, i.e. asthmatics appear to demonstrate quantitative rather than quali tative differences (Figure 1). Measures of responsiveness are used mainly as research tools, although provocations can be useful clinically when the patient's history suggests recurrent attacks of airway obstruction and the pulmonary function is normal. Under such circumstances, an increased level of responsiveness to
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Z ..... o z o
NON ASTHMATICS
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