Mechanism of Methacholine Dose-Response Plateaus in Normal Subjects

Moore, Barbara; King, Gregory G.; D’yachkova, Yulia; Ahmad, Hayat; Paré, Peter D.

doi:10.1164/ajrccm.158.2.9709048

Cited by 15 publications

(11 citation statements)

References 15 publications

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“…Our results provide new experimental validation of this conceptual framework. We demonstrate that breathing-induced reversal of bronchoconstriction in individual intraparenchymal airways depends on the degree to which each breath actually stretches the airway tidally, which in turn depends on both the depth of breathing (tidal volume) (38,(45)(46)(47)(48)(49)(50) and the severity of bronchoconstriction (51,52).…”

Section: Discussionmentioning

confidence: 88%

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Lavoie¹,

Krishnan

Siegel³

et al. 2012

Am J Respir Crit Care Med

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Rationale: In the normal lung, breathing and deep inspirations potently antagonize bronchoconstriction, but in the asthmatic lung this salutary effect is substantially attenuated or even reversed. To explain these findings, the prevailing hypothesis focuses on contracting airway smooth muscle and posits a nonlinear dynamic interaction between actomyosin binding and the tethering forces imposed by tidally expanding lung parenchyma. Objective: This hypothesis has never been tested directly in bronchial smooth muscle embedded within intraparenchymal airways. Our objective here is to fill that gap. Methods: We designed a novel system to image contracting intraparenchymal human airways situated within near-normal lung architecture and subjected to dynamic parenchymal expansion that simulates breathing. Measurements and Main Results: Reversal of bronchoconstriction depended on the degree to which breathing actually stretched the airway, which in turn depended negatively on severity of constriction and positively on the depth of breathing. Such behavior implies positive feedbacks that engender airway instability. Overall conclusions: These findings help to explain heterogeneity of airflow obstruction as well as why, in people with asthma, deep inspirations are less effective in reversing bronchoconstriction.Keywords: airway; smooth muscle; bronchoconstriction; stretch; asthma Among all factors known to antagonize bronchoconstriction in a healthy lung, a deep breath is among the most effective (1-5). In the asthmatic lung, however, this protective phenomenon is substantially attenuated, and during a spontaneous asthmatic attack it is sometimes even reversed (1, 6, 7). Some have suggested that the inability of a deep breath to dilate the constricted asthmatic airway might be an important cause of excessive airway narrowing (1,6,8).To explain these observations, a new conceptual framework has called attention to the role of airway smooth muscle (ASM) and the dynamic load against which it must contract (9). With each breath (10), lung parenchyma exerts a distending force on intrapulmonary airways and stretches the bands of ASM that they contain. In this conceptual framework, these tidal stretches perturb the binding of myosin to actin, causing the myosin molecule to detach from actin much sooner than it would have otherwise and thus reducing the myosin duty cycle (11-13). As a result, the contracted ASM band within a bronchoconstricted airway relengthens and thus partially relieves the bronchoconstriction. Importantly, such force fluctuation-induced muscle relengthening has molecular determinants that differ from those that determine isometric force (9, 14-17). As such, the length of contracting ASM becomes equilibrated dynamically, not statically as assumed in earlier models (18,19), and the force generated by the muscle at any instant can be dramatically less than the force predicted by the isometric force length curve (11,20).This mechanistic framework provides a plausible basis to explain how the effects of deep breath...

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Section: Discussionmentioning

confidence: 88%

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Lavoie¹,

Krishnan

Siegel³

et al. 2012

Am J Respir Crit Care Med

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“…In the healthy intact dog, airway smooth muscle possesses sufficient force generating capacity to close all airways (Brown and Mitzner, 1998;Warner and Gunst, 1992). This fact may at first seem to be unremarkable, but it is not easily reconciled with the observation that when healthy animals or humans are challenged with inhaled contractile agonists in concentrations thought to be sufficient to activate the muscle maximally, resulting airway narrowing is limited in extent, and that limit falls far short of airway closure (Moore et al, 1997;Moore et al, 1998). Breathing remains unaccountably easy.…”

Section: Classical Behavior Of Airway Smooth Muscle and The Balance Omentioning

confidence: 99%

Biophysical basis for airway hyperresponsivenessThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

Fredberg

2007

Can. J. Physiol. Pharmacol.

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Airway hyperresponsiveness is the excessive narrowing of the airway lumen caused by stimuli that would cause little or no narrowing in the normal individual. It is one of the cardinal features of asthma, but its mechanisms remain unexplained. In asthma, the key end-effector of acute airway narrowing is contraction of the airway smooth muscle cell that is driven by myosin motors exerting their mechanical effects within an integrated cytoskeletal scaffolding. In just the past few years, however, our understanding of the rules that govern muscle biophysics has dramatically changed, as has their classical relationship to airway mechanics. It has become well established, for example, that muscle length is equilibrated dynamically rather than statically, and that in a dynamic setting nonclassical features of muscle biophysics come to the forefront, including unanticipated interactions between the muscle and its time-varying load, as well as the ability of the muscle cell to adapt (remodel) its internal microstructure rapidly in response to its ever-changing mechanical environment. Here, we consider some of these emerging concepts and, in particular, focus on structural remodeling of the airway smooth muscle cell as it relates to excessive airway narrowing in asthma.

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“…Other potential explanations for the difference in slopes after censoring might be 1) methacholine has a cumulative effect and the curves are not drawn on cumulative scale; 18 2) borderline responsive subjects have a methacholine concentration-response curve that is intermediate between that of hyper-responsive and nonresponsive subjects; 29,30 3) these subjects may experience bronchodilatation when they perform a forced expiratory flow-volume curve and some of them (with greater dilator effect of a deep inhalation) may have greater methacholine responsiveness. [27][28][29][30][31][32] The current ATS statement recommends that one not extrapolate beyond the maximum administered methacholine concentration. 3 Our results further imply that one should not calculate the slope or extrapolate the PC 20 based on MCT data in the (unobserved) plateau portion of the curve.…”

Section: Discussionmentioning

confidence: 99%

Truncating the Dose Range for Methacholine Challenge Tests: Three Occupational Studies

Agalliu

Eisen

Hauser

et al. 2003

Journal of Occupational and Environmental Medicine

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The methacholine challenge test protocol was assessed in the reanalysis of three occupational studies. We evaluated the impact of truncating the range of methacholine on responsiveness, as defined by slope and PC(20). In original analysis, reactivity was similar for apprentices and auto body shop workers, whereas boilermakers were more responsive. Truncating high concentrations did not change the classification of subjects with PC(20) <8 or 16 in any population. However, when responsiveness was measured by slope, the mean responsiveness increased, from -7.9 to -15.3 for apprentices and -7.2 to -10.0 for auto-body shop workers. Results support the American Thoracic Society's recommended maximum of 16 mg/ml and provide evidence that extending the dose range beyond that does not increase sensitivity, whereas stopping before 16 may exaggerate response. Furthermore, to ensure validity, neither slope nor PC(20) should be extrapolated beyond data.

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Mechanism of Methacholine Dose-Response Plateaus in Normal Subjects

Cited by 15 publications

References 15 publications

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Dilatation of the Constricted Human Airway by Tidal Expansion of Lung Parenchyma

Biophysical basis for airway hyperresponsivenessThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

Truncating the Dose Range for Methacholine Challenge Tests: Three Occupational Studies

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