Title: Airway Smooth Muscle in Asthma: Flirting with Disaster
Author: Fredberg, J. J.; (Date: Dec, 1998)
Journal: Eur Respir J; V. 12; Issue: 6; Pages: 1252-6
Notes: Journal Article
Author Address: Dept of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
Title: Frozen Objects: Small Airways, Big Breaths, and Asthma
Author: Fredberg, J. J.; (Date: Oct, 2000)
Journal: J Allergy Clin Immunol; V. 106; Issue: 4; Pages: 615-24
Abstract: Airway hyperresponsiveness is one of the cardinal features of asthma but remains largely unexplained. The new concept of perturbed myosin binding within airway smooth muscle sheds light on the question of why airway narrowing is limited in the healthy lung and not in the asthmatic lung and points to unanticipated mechanisms through which lung development and allergic status may be major modulators of airway hyperresponsiveness.
Notes: Journal Article
Review
Review, Tutorial
URL: http://www1.mosby.com/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=abs&id=a109429&target=
Author Address: Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
Title: Airway Smooth Muscle in Asthma. Perturbed Equilibria of Myosin Binding
Author: Fredberg, J. J.; (Date: Mar, 2000)
Journal: Am J Respir Crit Care Med; V. 161; Issue: 3 Pt 2; Pages: S158-60
Notes: Journal Article
Review
Review, Tutorial
Author Address: Harvard School of Public Health, Boston, Massachusetts, USA.
Title: Perturbed Equilibrium of Myosin Binding in Airway Smooth Muscle and Its Implications in Bronchospasm
Author: Fredberg, J. J.; Inouye, D. S.; Mijailovich, S. M.; Butler, J. P.; (Date: Mar, 1999)
Journal: Am J Respir Crit Care Med; V. 159; Issue: 3; Pages: 959-67
Abstract: In asthma, the mechanisms relating airway obstruction, hyperresponsiveness, and inflammation remain rather mysterious. We show here that regulation of airway smooth muscle length corresponds to a dynamically equilibrated steady state, not the static mechanical equilibrium that had been previously assumed. This dynamic steady state requires as an essential feature a continuous supply of external mechanical energy (derived from tidal lung inflations) that acts to perturb the interactions of myosin with actin, drive the molecular state of the system far away from thermodynamic equilibrium, and bias the muscle toward lengthening. This mechanism leads naturally to the suggestion that excessive airway narrowing in asthma may be associated with the destabilization of that dynamic process and its resulting collapse back to static equilibrium. With this collapse the muscle undergoes a phase transition and virtually freezes at its static equilibrium length. This mechanism may help to elucidate several unexplained phenomena including the multifactorial origins of airway hyperresponsiveness, how allergen sensitization leads to airway hyperresponsiveness, how hyperresponsiveness can persist long after airway inflammation is resolved, and the inability in asthma of deep inspirations to relax airway smooth muscle.
Notes: Journal Article
Author Address: Physiology Program, Harvard School of Public Health, Boston, Massachusetts, USA.
Title: The Unbearable Lightness of Breathing
Author: Fredberg, J. J.; Shore, S. A.; (Date: Jan, 1999)
Journal: J Appl Physiol; V. 86; Issue: 1; Pages: 3-4
Notes: Comment
Editorial
URL: http://jap.physiology.org/cgi/content/full/86/1/3
Title: Potent Bronchoprotective Effect of Deep Inspiration and Its Absence in Asthma
Author: Kapsali, T.; Permutt, S.; Laube, B.; Scichilone, N.; Togias, A.; (Date: Aug, 2000)
Journal: J Appl Physiol; V. 89; Issue: 2; Pages: 711-20
Abstract: In the absence of deep inspirations, healthy individuals develop bronchoconstriction with methacholine inhalation. One hypothesis is that deep inspiration results in bronchodilation. In this study, we tested an alternative hypothesis, that deep inspiration acts as a bronchoprotector. Single-dose methacholine bronchoprovocations were performed after 20 min of deep breath inhibition, in nine healthy subjects and in eight asthmatics, to establish the dose that reduces forced expiratory volume in 1 s by >15%. The provocation was repeated with two and five deep inspirations preceding methacholine. Additional studies were carried out to assess optimization and reproducibility of the protocol and to rule out the possibility that bronchoprotection may result from changes in airway geometry or from differential spasmogen deposition. In healthy subjects, five deep inspirations conferred 85% bronchoprotection. The bronchoprotective effect was reproducible and was not attributable to increased airway caliber or to differential deposition of methacholine. Deep inspirations did not protect the bronchi of asthmatics. We demonstrated that bronchoprotection is a potent physiologic function of lung inflation and established its absence, even in mild asthma. This observation deepens our understanding of airway dysfunction in asthma.
Notes: Clinical Trial
Journal Article
URL: http://jap.physiology.org/cgi/content/full/89/2/711
http://jap.physiology.org/cgi/content/abstract/89/2/711
Author Address: Division of Clinical Immunology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21224, USA.
Title: Analysis of Time Course and Magnitude of Lung Inflation Effects on Airway Tone: Relation to Airway Reactivity
Author: Parham, W. M.; Shepard, R. H.; Norman, P. S.; Fish, J. E.; (Date: Aug, 1983)
Journal: Am Rev Respir Dis; V. 128; Issue: 2; Pages: 240-5
Notes: Journal Article
Title: Deep Inspiration-Induced Bronchoprotection Is Stronger Than Bronchodilation
Author: Scichilone, N.; Kapsali, T.; Permutt, S.; Togias, A.; (Date: Sep, 2000)
Journal: Am J Respir Crit Care Med; V. 162; Issue: 3 Pt 1; Pages: 910-6
Abstract: We have previously shown that in healthy subjects, deep inspiration (DI) has not only a bronchodilatory but also a bronchoprotective effect that is absent in asthmatic subjects. We conducted the study reported here to test the hypothesis that the bronchoprotective effect is stronger than the bronchodilatory effect, and to determine the extent to which these two effects are related. Ten healthy subjects underwent provocations in which single doses of methacholine, previously shown to reduce FEV(1) by 10% to 20% (Dose 1) and by 20% to 40% (Dose 2) were administered after a 20-min period devoid of DI. To measure the bronchodilator effect, DIs were performed immediately after the first spirometry after methacholine, and were followed by another lung function test. To measure their bronchoprotective effect, DIs were performed before administration of a single dose of methacholine, and the FEV(1) after methacholine was compared with that of another single-dose challenge in which DIs were not included. From these outcomes, bronchodilation and bronchoprotection indices were constructed and compared with each other. At Dose 1 (mild obstruction), the ability of DIs to reverse methacholine-induced obstruction was equal to their ability to prevent it (bronchodilation index [BDI] versus bronchoprotection index [BPI]: 1.62 +/- 0.21 versus 2.02 +/- 0.40 [mean +/- SEM], p = 0.26). At Dose 2, the relative potency of both the bronchodilating and bronchoprotective effects of DIs increased, but bronchoprotection was significantly stronger (BDI versus BPI: 3.40 +/- 0.43 versus 6.98 +/- 1.42, p = 0.02). Correlation analysis of the two indices indicated that as the BPI increased, the BDI reached a plateau. We conclude that in healthy humans, the bronchoprotective effect of lung inflation is stronger than the bronchodilatory effect.
Notes: Journal Article
Author Address: Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Title: The Lack of the Bronchoprotective and Not the Bronchodilatory Ability of Deep Inspiration Is Associated with Airway Hyperresponsiveness
Author: Scichilone, N.; Permutt, S.; Togias, A.; (Date: Feb, 2001)
Journal: Am J Respir Crit Care Med; V. 163; Issue: 2; Pages: 413-9
Abstract: In healthy subjects, deep inspiration (DI) acts both as a bronchodilator and a bronchoprotector. The latter is impaired in asthmatics. We have now evaluated whether the lack of bronchoprotection is related to bronchial hyperresponsiveness (BHR), and whether the bronchodilatory effect is also lost in asthmatics. Ten healthy subjects (PC20 > 75 mg/ml), 12 asthmatics with moderate to severe BHR (PC20 < 1 mg/ml), 14 asthmatics with mild to borderline BHR (1 < PC20 < 25 mg/ml), and 10 rhinitics with mild to borderline BHR (1 < PC20 < 25 mg/ml) underwent single-dose methacholine provocations inducing at least 20% reduction in FEV1 after 20 min of DI inhibition. To measure the bronchodilatory effect, DIs were taken immediately after the postmethacholine spirometry, and lung function was again tested. To measure the bronchoprotective effect, DIs were taken before the administration of spasmogen. All four groups achieved the same reductions in FEV1 and FVC, in the absence of deep breaths (analysis of variance [ANOVA], p = 0.49). Only healthy subjects showed bronchoprotection (percent bronchoprotection, mean +/- SEM; healthy: 79 +/- 4.0; asthmatics with moderate to severe BHR: 12 +/- 14.5; asthmatics with mild to borderline BHR: -7 +/- 19.7; rhinitics with mild to borderline BHR: 2 +/- 14.0). In contrast, DIs were able to partially reverse bronchial obstruction in all four groups, albeit percent bronchodilation in healthy subjects was somewhat stronger. The dissociation between bronchoprotection and bronchodilation suggests that the two effects involve different mechanisms.
Notes: Journal Article
Author Address: Division of Clinical Immunology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Title: Airways Hyperresponsiveness and the Effects of Lung Inflation
Author: Scichilone, N.; Pyrgos, G.; Kapsali, T.; Anderlind, C.; Brown, R.; Permutt, S.; Togias, A.; (Date: Jan-Mar, 2001)
Journal: Int Arch Allergy Immunol; V. 124; Issue: 1-3; Pages: 262-6
Abstract: Lung inflation has a beneficial effect on the airways of healthy subjects. It acts as a bronchoprotector, that is to prevent bronchoconstriction, and as a bronchodilator, in that it reverses bronchial obstruction. The bronchoprotective effect of deep inspiration is more potent than the bronchodilatory one, and the two phenomena appear to advocate different mechanisms. Asthmatics and rhinitics with airways hyperresponsiveness show an impairment in bronchoprotection induced by deep breaths, whereas the bronchodilatory effect, although reduced, is still effective. The lack of the bronchoprotective effect of deep inspiration may contribute to the development of airways hyperresponsiveness. The mechanisms through which lung inflation exerts its beneficial role in healthy subjects, and the factors impairing such an effect in those with airways hyperresponsiveness, are currently under investigation. Copyright 2001 S. Karger AG, Basel
Notes: Journal Article
Review
Review, Tutorial
URL: http://www.online.karger.com/library/karger/renderer/dataset.exe?jcode=IAA&action=render&rendertype=fulltext&uid=IAA.iaa24262
http://www.karger.com/journals/iaa/iaa_jh.htm
Author Address: Division of Clinical Immunology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21224, USA.
Title: Airway Hyperresponsiveness in Asthma: A Problem of Limited Smooth Muscle Relaxation with Inspiration
Author: Skloot, G.; Permutt, S.; Togias, A.; (Date: Nov, 1995)
Journal: J Clin Invest; V. 96; Issue: 5; Pages: 2393-403
Abstract: We hypothesized that hyperresponsiveness in asthma is caused by an impairment in the ability of inspiration to stretch airway smooth muscle. If the hypothesis was correct, we reasoned that the sensitivity to inhaled methacholine in normal and asthmatic subjects should be the same if the challenge was carried out under conditions where deep inspirations were prohibited. 10 asthmatic and 10 normal subjects received increasing concentrations of inhaled methacholine under conditions where forced expirations from a normal end-tidal inspiration were performed. When no deep inspirations were allowed, the response to methacholine was similar in the normal and asthmatic subjects, compatible with the hypothesis we propose. Completely contrary to our expectations, however, was the marked responsivity to methacholine that remained in the normal subjects after deep breaths were initiated. 6 of the 10 normal subjects had > 20% reduction in forced expiratory volume in one second (FEV 1) at doses of methacholine < 8 mg/ml, whereas there was < 15% reduction with 75 mg/ml during routine challenge. The ability of normal subjects to develop asthmatic responses when the modulating effects of increases in lung volume was voluntarily suppressed suggests that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma.
Notes: Clinical Trial
Journal Article
Randomized Controlled Trial
Author Address: Department of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland 21224-6801, USA.
Title: Prevalence of Dysfunctional Breathing in Patients Treated for Asthma in Primary Care: Cross Sectional Survey
Author: Thomas, M.; McKinley, R. K.; Freeman, E.; Foy, C.; (Date: May 5, 2001)
Journal: Bmj; V. 322; Issue: 7294; Pages: 1098-100
Abstract: OBJECTIVES: To estimate the prevalence of dysfunctional breathing in adults with asthma treated in the community. DESIGN: Postal questionnaire survey using Nijmegen questionnaire. SETTING: One general practice with 7033 patients. PARTICIPANTS: All adult patients aged 17-65 with diagnosed asthma who were receiving treatment. MAIN OUTCOME MEASURE: Score >/=23 on Nijmegen questionnaire. RESULTS: 227/307 patients returned completed questionnaires; 219 (71.3%) questionnaires were suitable for analysis. 63 participants scored >/=23. Those scoring >/=23 were more likely to be female than male (46/132 (35%) v 17/87 (20%), P=0.016) and were younger (mean (SD) age 44.8 (14.7) v 49.0 (13.8, (P=0.05). Patients at different treatment steps of the British Thoracic Society asthma guidelines were affected equally. CONCLUSIONS: About a third of women and a fifth of men had scores suggestive of dysfunctional breathing. Although further studies are needed to confirm the validity of this screening tool and these findings, these prevalences suggest scope for therapeutic intervention and may explain the anecdotal success of the Buteyko method of treating asthma.
Notes: Journal Article
URL: http://bmj.com/cgi/content/full/322/7294/1098
Author Address: Surgery, Minchinhampton, Stroud, Gloucestershire GL6 9JF.