Passive sensitization of human bronchi augments smooth muscle shortening velocity and capacity

Mitchell, Robert W.; Rühlmann, E.; Magnussen, H; Leff, Alan R.; Rabe, Klaus F.

doi:10.1152/ajplung.1994.267.2.l218

Cited by 78 publications

(98 citation statements)

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“…Fredberg has suggested, however, that an increased intrinsic rate of crossbridge cycling would make it more difficult for the force fluctuations to disrupt the reaction. This suggestion would be consistent with studies demonstrating increased intrinsic crossbridge cycling rates (shortening velocity) in allergen-sensitized muscle (16)(17)(18)(19). Thus asthmatic airway smooth muscle may have a greater actomyosin crossbridge cycling rate that may be intrinsic to the muscle and/or enhanced by the surrounding inflammatory environment.…”

Section: Discussionsupporting

confidence: 86%

“…Airway smooth muscle from these individuals with asthma and from sensitized dogs concomitantly demonstrated increased shortening velocity and capacity (17,18). Furthermore, seventh-generation human bronchi passively sensitized using human sera with high titers to house dust mite antigen showed, in addition to increased shortening velocity and capacity (19), robust myogenic responsiveness to quick stretch compared with sham-sensitized control airways (20). These in vitro findings paralleled the increased airway sensitivity and responsiveness observed in individuals with asthma.…”

Section: Mechanistic Explanations From In Vitro Studiesmentioning

confidence: 53%

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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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Section: Discussionsupporting

confidence: 86%

Section: Mechanistic Explanations From In Vitro Studiesmentioning

confidence: 53%

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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“…The increased relengthening observed for latrunculin B was not associated with any decrease in phosphorylation of MLC 20 . In fact, relative to vehicle-treated control TSM strips (1.024 Ϯ 0.084, n ϭ 3), latrunculin B-treated muscles demonstrated a significant increase in relative MLC 20 phosphorylation (2.196 Ϯ 0.314, n ϭ 3; P ϭ 0.023).…”

Section: Resultsmentioning

confidence: 68%

“…TSM from immune-sensitized dogs demonstrate increased isotonic shortening velocity and capacity compared with muscle strips from littermate control animals, yet no differences in F max could be found between these two tissues when isometric, tetanic parameters were analyzed (12). Similar differences between isometric and isotonic responses were observed in passively and sham-sensitized human seventh-generation airways (20), and abnormal contraction dynamics have been established in single smooth muscle cells from lung biopsies of asthmatic vs. nonasthmatic subjects (15).…”

Section: Fig 6 Protocolmentioning

confidence: 96%

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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“…The anti-CD23 antibody blocked the increase in maximal isometric contractility to acetylcholine induced by serum-treated tracheal smooth muscle strips. Passive sensitization of human bronchial smooth muscle also increases both shortening velocity and capacity, and myogenic contractions to quick stretch, an effect that was related to IgE concentrations in sensitizing sera [77,78]. Receptors for various cytokines have been found in airway smooth muscle cells passivelysensitized with atopic serum, such as receptors for IL-5, GM-CSF, IL-2, IL-12 and IFNc.…”

Section: Effects Of Inflammatory Factors On Airway Smooth Muscle Contmentioning

confidence: 97%

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Chung

2000

Eur Respir J

131

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In addition to its contractile properties, airway smooth muscle may contribute to the pathogenesis of asthma by increased proliferation, and by the expression and secretion of pro‐inflammatory cytokines and mediators. Studies of airway smooth muscle cells in culture have shown that many mitogenic mediators can induce proliferation, and that these may therefore, contribute to the increase in airway smooth muscle mass observed in asthma. Other mechanisms for airway smooth muscle proliferation include the interaction with inflammatory cells such as T‐cells and eosinophils. Airway smooth muscle cells may also be a source of inflammatory mediators and cytokines, in particular chemokines, thus implicating airway smooth muscle cells as contributors to the inflammatory mechanisms of asthma. The pro‐activating signals for converting airway smooth muscle cells into a proliferative and secretory cell in asthma are unknown, but may include viruses and immunoglobulin E. Airway smooth muscle contractility may also be altered in response to inflammation. Airway smooth muscle cells may play an important interactive role with inflammatory and other structural cells, contributing to inflammation, injury and repair of the airways. Such a recognition makes it imperative to consider the airway smooth muscle as a target of therapeutic drugs for suppressing not only the contractile but also the proliferative and secretory effects of asthma.

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Passive sensitization of human bronchi augments smooth muscle shortening velocity and capacity

Cited by 78 publications

References 0 publications

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

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

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

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