Characteristics of airway tone during exercise in patients with asthma

Stirling, David R.; Cotton, David; Graham, Brian L.; Hodgson, Wayne C.; Cockcroft, D. W.; Dosman, James A.

doi:10.1152/jappl.1983.54.4.934

Cited by 52 publications

(48 citation statements)

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“…Airway resistance rose considerably in response to methacholine administration when tidal volume was zero, whereas the bronchoconstrictor response was progressively attenuated when the same methacholine dose was given during mechanical ventilation with higher and higher tidal volumes; indeed, bronchoconstriction was prevented essentially completely by mechanical ventilation with large (20 ml/kg) tidal volumes. Hyperpnea similarly suppresses bronchoconstriction in other animals and in humans (7)(8)(9)(10), and accounts for the delayed onset of bronchoconstriction induced in subjects with asthma by exercise (which provokes hyperpnea) or by eucapnic voluntary hyperventilation of dry air, until after cessation of exercise or hyperpnea. Thus, even in asthma, deep breathing functionally antagonizes bronchoconstriction, though studies (11)(12)(13)(14)(15) suggest that the degree to which breathing antagonizes bronchoconstriction may be abnormally reduced in subjects with asthma.…”

Section: Smooth Muscle Contraction and Airway Constrictionmentioning

confidence: 96%

Disrupting Actin-Myosin-Actin Connectivity in Airway Smooth Muscle as a Treatment for Asthma?

Lavoie¹,

Dowell²,

Lakser³

et al. 2009

Proceedings of the American Thoracic Society

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Breathing is known to functionally antagonize bronchoconstriction caused by airway muscle contraction. During breathing, tidal lung inflation generates force fluctuations that are transmitted to the contracted airway muscle. In vitro, experimental application of force fluctuations to contracted airway smooth muscle strips causes them to relengthen. Such force fluctuation-induced relengthening (FFIR) likely represents the mechanism by which breathing antagonizes bronchoconstriction. Thus, understanding the mechanisms that regulate FFIR of contracted airway muscle could suggest novel therapeutic interventions to increase FFIR, and so to enhance the beneficial effects of breathing in suppressing bronchoconstriction. Here we propose that the connectivity between actin filaments in contracting airway myocytes is a key determinant of FFIR, and suggest that disrupting actin-myosin-actin connectivity by interfering with actin polymerization or with myosin polymerization merits further evaluation as a potential novel approach for preventing prolonged bronchoconstriction in asthma.

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Section: Smooth Muscle Contraction and Airway Constrictionmentioning

confidence: 96%

Disrupting Actin-Myosin-Actin Connectivity in Airway Smooth Muscle as a Treatment for Asthma?

Lavoie¹,

Dowell²,

Lakser³

et al. 2009

Proceedings of the American Thoracic Society

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“…Shen and coworkers demonstrated in ventilated rabbits that breathing reduced methacholine-elicited airway resistance in a tidal volume-dependent manner (5). In normal individuals who demonstrated increased airway resistance to inhaled methacholine, the degree of bronchoconstriction could be reversed again by normal, tidal breathing (6,7) or by taking a single deep inspiration (8)(9)(10). This airway dilation with deep inspiration also was demonstrated directly by looking at computed tomography (CT) scans of normal volunteers (8).…”

mentioning

confidence: 95%

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

Mitchell¹,

Dowell²,

Solway³

et al. 2008

Proceedings of the American Thoracic Society

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Superimposition of force fluctuations on contracted tracheal smooth muscle (TSM) has been used to simulate normal breathing. Breathing has been shown to reverse lung resistance of individuals without asthma and animals given methacholine to contract their airways; computed tomography scans also demonstrated bronchial dilation after a deep inhalation in normal volunteers. This reversal of airway resistance and bronchial constriction are absent (or much diminished) in individuals with asthma. Many studies have demonstrated that superimposition of force oscillations on contracted airway smooth muscle results in substantial smooth muscle lengthening. Subsequent studies have shown that this force fluctuation-induced relengthening (FFIR) is a physiologically regulated phenomenon. We hypothesized that actin filament length in the smooth muscle of the airways regulates FFIR of contracted tissues. We based this hypothesis on the observations that bovine TSM strips contracted using acetylcholine (ACh) demonstrated amplitude-dependent FFIR that was sensitive to mitogen-activated protein kinase (p38 MAPK) inhibition-an upstream regulator of actin filament assembly. We demonstrated latrunculin B (sequesters actin monomers thus preventing their assimilation into filaments resulting in shorter filaments) greatly increases FFIR and jasplakinolide (an actin filament stabilizer) prevents the effects of latrunculin B incubation on strips of contracted canine TSM. We suspect that p38 MAPK inhibition and latrunculin B predispose to shorter actin filaments. These studies suggest that actin filament length may be a key determinant of airway smooth muscle relengthening and perhaps breathing-induced reversal of agonist-induced airway constriction. Keywords: actin filament length; latrunculin B; jasplakinolideMany studies have demonstrated that superimposition of force oscillations on contracted airway smooth muscle results in substantial smooth muscle lengthening in vitro (1-4), a phenomenon we refer to as force fluctuation-induced relengthening (FFIR). It has been proposed that imposition of these force oscillations simulate the effect of breathing on airway responsiveness and caliber. Shen and coworkers demonstrated in ventilated rabbits that breathing reduced methacholine-elicited airway resistance in a tidal volume-dependent manner (5). In normal individuals who demonstrated increased airway resistance to inhaled methacholine, the degree of bronchoconstriction could be reversed again by normal, tidal breathing (6, 7) or by taking a single deep inspiration (8-10). This airway dilation with deep inspiration also was demonstrated directly by looking at computed tomography (CT) scans of normal volunteers (8). Lung tethering forces on the conducting airways probably contributed to this dilation by loading the smooth muscle in the bronchiolar walls (8-10). However, this reversal of bronchoconstriction with breathing or deep inspiration is absent or minimal in individuals with asthma (9, 10); their airways remain constricted to methacholin...

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“…actin filament dynamics; force oscillations; isotonic contractions; hysteresivity A NUMBER OF PREVIOUS STUDIES in animals (22,24,25,27) and humans (7,29) have demonstrated that tidal breathing per se reduces airway constriction during contractile stimulation, and deep breathing does so more effectively. Even a single deep inspiration can substantially reverse experimentally induced bronchoconstriction in normal individuals (1, 4, 11).…”

mentioning

confidence: 99%

Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle

Dowell

Lakser²,

Gerthoffer

et al. 2005

Journal of Applied Physiology

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-We hypothesized that differences in actin filament length could influence force fluctuationinduced relengthening (FFIR) of contracted airway smooth muscle and tested this hypothesis as follows. One-hundred micromolar AChstimulated canine tracheal smooth muscle (TSM) strips set at optimal reference length (L ref) were allowed to shorten against 32% maximal isometric force (F max) steady preload, after which force oscillations of Ϯ16% F max were superimposed. Strips relengthened during force oscillations. We measured hysteresivity and calculated FFIR as the difference between muscle length before and after 20-min imposed force oscillations. Strips were relaxed by ACh removal and treated for 1 h with 30 nM latrunculin B (sequesters G-actin and promotes depolymerization) or 500 nM jasplakinolide (stabilizes actin filaments and opposes depolymerization). A second isotonic contraction protocol was then performed; FFIR and hysteresivity were again measured. Latrunculin B increased FFIR by 92.2 Ϯ 27.6% L ref and hysteresivity by 31.8 Ϯ 13.5% vs. pretreatment values. In contrast, jasplakinolide had little influence on relengthening by itself; neither FFIR nor hysteresivity was significantly affected. However, when jasplakinolide-treated tissues were then incubated with latrunculin B in the continued presence of jasplakinolide for 1 more h and a third contraction protocol performed, latrunculin B no longer substantially enhanced TSM relengthening. In TSM treated with latrunculin B ϩ jasplakinolide, FFIR increased by only 3.03 Ϯ 5.2% L ref and hysteresivity by 4.14 Ϯ 4.9% compared with its first (pre-jasplakinolide or latrunculin B) value. These results suggest that actin filament length, in part, determines the relengthening of contracted airway smooth muscle.actin filament dynamics; force oscillations; isotonic contractions; hysteresivity A NUMBER OF PREVIOUS STUDIES in animals (22,24,25,27) and humans (7,29) have demonstrated that tidal breathing per se reduces airway constriction during contractile stimulation, and deep breathing does so more effectively. Even a single deep inspiration can substantially reverse experimentally induced bronchoconstriction in normal individuals (1, 4, 11). However, the ability of deep breathing to dilate the airways is absent in asthmatic subjects (4, 11). Understanding why this protective mechanism fails in asthma is the focus of ongoing investigation in several laboratories and is the ultimate goal of the present study.Fredberg and coworkers (13, 14) studied the influence on airway smooth muscle shortening of the load fluctuations imposed by breathing. They stimulated bovine trachealis strips with ACh and allowed them to shorten isotonically against a constant load to a steady-state length and then superimposed sinusoidal force oscillations of increasing amplitudes (to simulate tidal breathing) on the constant mean load (5). These increasing force oscillations caused substantial smooth muscle relengthening, despite continued contractile stimulation. They showed that relengthening coul...

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Characteristics of airway tone during exercise in patients with asthma

Cited by 52 publications

References 0 publications

Disrupting Actin-Myosin-Actin Connectivity in Airway Smooth Muscle as a Treatment for Asthma?

Disrupting Actin-Myosin-Actin Connectivity in Airway Smooth Muscle as a Treatment for Asthma?

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle

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