Passive sensitization of human airways induces  myogenic contractile responses in vitro

Mitchell, Richard W.; Rabe, Klaus F.; Magnussen, H; Leff, Alan R.

doi:10.1152/jappl.1997.83.4.1276

Cited by 42 publications

(40 citation statements)

References 11 publications

(21 reference statements)

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“…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 Studiessupporting

confidence: 52%

“…We also found that the phosphorylation level of the regulatory myosin light chain 20 (rMLC 20 ) was not different between control and latrunculin B-treated tissues that had been flash-frozen near the end of the 20-minute oscillation protocol (1). These data indicated that the increased FFIR in the presence of latrunculin B could not be accounted for by a reduction of crossbridge activation in these TSM preparations.…”

Section: Actin Filament Length As a Regulator Of Ffirmentioning

confidence: 67%

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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: Mechanistic Explanations From In Vitro Studiessupporting

confidence: 52%

Section: Actin Filament Length As a Regulator Of Ffirmentioning

confidence: 67%

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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“…More significantly, the force-generating ability of ASM is potentiated by stretch in infant guinea pigs but not in adult animals [215], and appears to be related to maturational changes in the release of prostanoids [216]. These findings may have relevance to the observations of WEIST et al [206], who showed that airway reactivity in healthy infants is not only greater than that in healthy adults, but is also insensitive to deep inspiration, similar to the situation in asthmatic adults [18] and in passively sensitised human bronchi [217]. Thus, there is reason to suspect that immature and asthmatic ASM may adapt differently to chronic length change.…”

Section: Effects Of Chronic Lung-volume Alteration and Smooth Muscle mentioning

confidence: 78%

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

An¹,

Bai²,

Bates³

et al. 2007

European Respiratory Journal

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342

298

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Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

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“…In some asthmatic patients, a sustained bronchoconstriction may develop after taking one or more full inflations (13,18), an effect that has been attributed to a myogenic response triggered by the stretching of airway smooth muscle (22,23). In vitro, this behavior was observed after passive sensitization with allergic serum (14) or chemical agents able to convert airway smooth muscle from multiunit to single-unit conditions (23). In vivo, this phenomenon seems to occur only in a minority of subjects with rather severe asthma.…”

Section: Discussionmentioning

confidence: 99%

Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects

Crimi

Pellegrino

Milanese

et al. 2002

Journal of Applied Physiology

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Crimi, Emanuele, Riccardo Pellegrino, Manlio Milanese, and Vito Brusasco. Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects. J Appl Physiol 93: 1384-1390, 2002. First published June 21, 2002 10.1152/japplphysiol.00209.2002Deep breaths taken before inhalation of methacholine attenuate the decrease in forced expiratory volume in 1 s and forced vital capacity in healthy but not in asthmatic subjects. We investigated whether this difference also exists by using measurements not preceded by full inflation, i.e., airway conductance, functional residual capacity, as well as flow and residual volume from partial forced expiration. We found that five deep breaths preceding a single dose of methacholine 1) transiently attenuated the decrements in forced expiratory volume in 1 s and forced vital capacity in healthy (n ϭ 8) but not in mild asthmatic (n ϭ 10) subjects and 2) increased the areas under the curve of changes in parameters not preceded by a full inflation over 40 min, during which further deep breaths were prohibited, without significant difference between healthy (n ϭ 6) and mild asthmatic (n ϭ 16) subjects. In conclusion, a series of deep breaths preceding methacholine inhalation significantly enhances bronchoconstrictor response similarly in mild asthmatic and healthy subjects but facilitates bronchodilatation on further full inflation in the latter.forced expiratory volume in 1 s; specific airway conductance; partial flow-volume curve; functional residual capacity; residual volume RECENT STUDIES HAVE SHOWN that deep breaths taken immediately before inhalation of methacholine (MCh) greatly modulate the bronchoconstrictor response in normal (10, 12, 21) but not in asthmatic (10) subjects. This would suggest that the shortening capacity of airway smooth muscle is reduced by previous lung stretching in healthy subjects, and the lack of such a bronchoprotective mechanism may be responsible for airway hyperresponsiveness in asthma. A mechanistic interpretation of the above studies is, however, limited by the use of forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC), measurements that are highly and variably affected by the full lung inflation preceding the forced expiratory maneuver. During induced bronchoconstriction, a full inflation transiently increases airway caliber, and the magnitude of this increase depends on the relative magnitude of the distending force of lung parenchyma and the constrictor force of airway smooth muscle (17). Therefore, any parameter derived from a full forced expiratory maneuver, including FEV 1 and FVC, will depend on both airway smooth muscle shortening capacity and airway wall response to a deep breath.It is reasonable to postulate that, if the lack of a bronchoprotective effect by multiple deep breaths taken before inhaling a constrictor agent in asthma is due to the inability to reduce the shortening capacity of airway smooth muscle, then the different effects of the deep breaths on airway response to MCh between asthmati...

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Passive sensitization of human airways induces myogenic contractile responses in vitro

Cited by 42 publications

References 11 publications

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects

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