Invited Review: Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma?

Fernandes, Darren; Mitchell, Richard W.; Lakser, Oren; Dowell, Maria; Stewart, Alastair G.; Solway, Julian

doi:10.1152/japplphysiol.00192.2003

Cited by 69 publications

(48 citation statements)

References 96 publications

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“…Longer actin filaments in people with asthma are not that hard to hypothesize, since the environment in asthmatic, inflamed airways is rife with cytokines and mediators that promote hypertrophy and hyperplasia in most of the tissues in the bronchiolar wall (28,29). Furthermore, it is well established that stress, stretch, and cytokines can directly activate p38 MAPK, an upstream regulator of HSP27 and actin filament length (23,24,31).…”

Section: Actin Filament Length As a Regulator Of Ffirmentioning

confidence: 99%

“…Herrera and colleagues have demonstrated that associated actin (32) and myosin (25)(26)(27) filaments in TSM increase in length with contraction, and dynamically shorten and lengthen with airway smooth muscle cell migration (23,24). This dynamic nature of actin filament assembly and evanescence cannot be accounted for by the actin filamentstabilizing effects of such proteins as tropomyosin (29)(30)(31) or caldesmon (33,34). Therefore, we used pharmacologic tools to test the hypothesis that altering actin dynamics and therefore actin filament length would indeed modify FFIR of contracted airway smooth muscle.…”

Section: Actin Filament Length As a Regulator Of Ffirmentioning

confidence: 99%

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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: Actin Filament Length As a Regulator Of Ffirmentioning

confidence: 99%

Section: Actin Filament Length As a Regulator Of Ffirmentioning

confidence: 99%

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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“…As noted above, actin filament length is regulated through multiple pathways, many of which respond to external stimuli, including inflammatory stressors such as cytokines and growth factors known to be present in asthmatic airways (3). Perhaps the inflammatory environment of the asthmatic airway leads to abnormally long actin filaments in asthmatic airway myocytes that impart a reduced ability to relengthen with deep inspiration.…”

Section: Fig 6 Protocolmentioning

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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“…These drugs also have lower incidence of side effects and seem to be more suitable for clinical use [53]. Application of roflumilast was more effective in subjects with asthma [54], whereas cilomilast was more effective in COPD patients [55]. Lipworth et al [56] published the hypothesis that roflumilast could be as effective as beclometasone dipropionate in the treatment of moderate asthma; therefore it can be an alternative treatment and can replace the inhalative corticosteroids.…”

Section: Selective Phosphodiesterase Inhibitors (Pde)mentioning

confidence: 99%

Bronchial hyperreactivity: pathogenesis and treatment options

Antošová¹,

Strapková²,

Plevková³

2011

OJMIP

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This review is written to summarize and critically analyze pathogenesis of bronchial hyperreactivity (BHR) as an underlying outcome for suitable treatment options. It describes and discusses the role of genetic predisposition, inflammatory mediators and other endogenous factors (growth factors, nuclear transcription factors), neural regulation and proinflammatory neurotransmitter in the pathogenesis of BHR. Based on these data it provides brief insight into the treatment options, which could be applied to minimize symptoms of respiratory diseases characterized by BHR and successfully diminish the pathogenesis pathways involved.

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Invited Review: Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma?

Cited by 69 publications

References 96 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

Bronchial hyperreactivity: pathogenesis and treatment options

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