A theoretical study of the effect of airway smooth muscle orientation on bronchoconstriction

If airway smooth muscle shortened in vivo to the extent that it does in vitro, then maximal bronchoconstriction would result in complete closure of virtually all airways. The fact that this does not happen indicates the existence of inhibitory mechanisms preventing maximal muscle shortening. There are many factors potentially limiting shortening in vivo. In this study we investigated one of these factors, the orientation of the smooth muscle around the airway wall. The airway was modeled as a cylinder of given wall thickness around which the muscle was wound as a spiral. The longitudinal and circumferential elasticities of the airway were embodied in a 2 x 2 matrix of elastic coefficients. We investigated smooth muscle shortening under three conditions: 1) a longitudinally stiff airway, 2) a circumferentially stiff airway, and 3) a longitudinally and circumferentially compressible airway. In case 1, for a given degree of smooth muscle shortening, airway resistance increased markedly with increasing pitch of the smooth muscle spiral. On the other hand, the muscle tension required to elicit a given change in resistance also increased markedly with pitch. In case 2, the effect with increasing pitch was reversed. In case 3, resistance first increased and then decreased as spiral pitch increased. Similarly, the muscle tension required to elicit a given change in resistance first increased and then decreased with pitch. These results suggest that the orientation of the smooth muscle about the airway may be very important in determining airway responsiveness.

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In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss

European Respiratory Journal ◽

10.1183/13993003.01680-2017 ◽

2018 ◽

Vol 51 (5) ◽

pp. 1701680 ◽

Cited By ~ 15

Author(s):

Igor L. Chernyavsky ◽

Richard J. Russell ◽

Ruth M. Saunders ◽

Gavin E. Morris ◽

Rachid Berair ◽

...

Keyword(s):

Smooth Muscle ◽

Asthma Control ◽

Muscle Mass ◽

Airway Smooth Muscle ◽

In Silico ◽

Heat Distribution ◽

Airway Wall ◽

Epithelial Integrity

Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37–70°C) for 10 s to mimic thermoplasty. In silico we developed a mathematical model of airway heat distribution post-thermoplasty. In vivo we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.In vitro airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C. In silico simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm. In vivo at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured via Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1–1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0–10; p=0.03) and epithelial integrity increased (14%, IQR 6–29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated in vitro and in silico modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.

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In vivo loads on airway smooth muscle: the role of noncontractile airway structures

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y92-077 ◽

1992 ◽

Vol 70 (4) ◽

pp. 602-606 ◽

Cited By ~ 5

Author(s):

Philip Robinson ◽

Mitsushi Okazawa ◽

Tony Bai ◽

Peter Paré

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Muscle Activation ◽

Muscle Length ◽

Tracheal Cartilage ◽

Elastic Load ◽

Muscle Shortening ◽

Trachealis Muscle

The degree of airway smooth muscle contraction and shortening that occurs in vivo is modified by many factors, including those that influence the degree of muscle activation, the resting muscle length, and the loads against which the muscle contracts. Canine trachealis muscle will shorten up to 70% of starting length from optimal length in vitro but will only shorten by around 30% in vivo. This limitation of shortening may be a result of the muscle shortening against an elastic load such as could be applied by tracheal cartilage. Limitation of airway smooth muscle shortening in smaller airways may be the result of contraction against an elastic load, such as could be applied by lung parenchymal recoil. Measurement of the elastic loads applied by the tracheal cartilage to the trachealis muscle and by lung parenchymal recoil to smooth muscle of smaller airways were performed in canine preparations. In both experiments the calculated elastic loads applied by the cartilage and the parenchymal recoil explained in part the limitation of maximal active shortening and airway narrowing observed. We conclude that the elastic loads provided by surrounding structures are important in determining the degree of airway smooth muscle shortening and the resultant airway narrowing.Key words: elastic loads, tracheal cartilage, airway smooth muscle shortening.

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Limitation of airway smooth muscle shortening by cartilage stiffness and lung elastic recoil in rabbits

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.2.738 ◽

1993 ◽

Vol 75 (2) ◽

pp. 738-744 ◽

Cited By ~ 9

Author(s):

R. H. Moreno ◽

C. Lisboa ◽

J. C. Hogg ◽

P. D. Pare

Keyword(s):

Smooth Muscle ◽

Effective Dose ◽

Airway Smooth Muscle ◽

Maximal Response ◽

Positive End Expiratory Pressure ◽

Elastic Recoil ◽

Pulmonary Resistance ◽

Muscle Shortening

Airway smooth muscle can contract to 20% of its starting length when stimulated maximally and allowed to contract isotonically in vitro. In vivo airway smooth muscle contraction of this degree would result in widespread airway closure. We hypothesized that elastic loads related to cartilage stiffness and lung parenchyma-airway interdependence limit in vivo airway smooth muscle shortening. We measured pulmonary resistance in anesthetized tracheostomized New Zealand White rabbits before and after intravenous treatment with papain in a concentration that produced generalized cartilage softening. Papain treatment caused a significant increase in pulmonary resistance that was completely reversed by application of 4 cmH2O positive end-expiratory pressure and that was partially reversed by vagotomy. Papain pretreatment also resulted in a substantial alteration in the pulmonary resistance-dose relationship to intravenously administered acetylcholine. In addition, maximal resistance after the highest concentration of acetylcholine was greater in papain-treated animals than in the control animals, but the position of the dose-response relationship was not shifted (i.e., there was no change in the effective dose causing 50% maximal response). Application of 4 cmH2O positive end-expiratory pressure in untreated animals resulted in a marked decrease in the bronchoconstriction produced by an effective dose of acetylcholine causing 50% of maximal response, whereas application of 4 cmH2O negative end-expiratory pressure resulted in a marked enhancement of the bronchoconstrictor response to the same intravenous dose of acetylcholine. We conclude that cartilage elasticity and lung recoil are important determinants of the ability of airway smooth muscle to shorten and produce airway narrowing in vivo.

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Chronic inflation of ferret lungs with CPAP reduces airway smooth muscle contractility in vivo and in vitro

Journal of Applied Physiology ◽

10.1152/japplphysiol.00241.2007 ◽

2008 ◽

Vol 104 (3) ◽

pp. 610-615 ◽

Cited By ~ 31

Author(s):

Z. Xue ◽

L. Zhang ◽

Y. Liu ◽

S. J. Gunst ◽

R. S. Tepper

Keyword(s):

Smooth Muscle ◽

Mechanical Stress ◽

Chronic Stress ◽

Airway Smooth Muscle ◽

Structural Changes ◽

Airway Responsiveness ◽

Wall Structure ◽

Airway Wall

The mechanical stress imposed on the lungs during breathing is an important modulator of airway responsiveness in vivo. Our recent study demonstrated that continuous positive airway pressure applied to the lungs of nonanesthetized, tracheotomized rabbits for 4 days decreased lower respiratory system responsiveness to challenge with ACh (Xue Z, Zhang L, Ramchandani R, Liu Y, Antony VB, Gunst SJ, Tepper RS. J. Appl Physiol 99: 677–682, 2005). In addition, airway segments excised from the lungs of these animals and studied in vitro exhibited reduced contractility. However, the mechanism for this reduction in contractility was not determined. The stress-induced decrease in airway responsiveness could have resulted from alterations in the excitation-contraction coupling mechanisms of the smooth muscle cells, or it might reflect changes in the structure and/or composition of the airway wall tissues. In the present study, we assessed the effect of prolonged chronic stress of the lungs in vivo on airway smooth muscle force generation, myosin light chain phosphorylation, and airway wall structure. To enhance the potential development of stress-induced structural changes, we applied mechanical stress for a prolonged period of time of 2–3 wk. Our results demonstrate a direct connection between the decreased airway responsiveness caused by chronic mechanical stress of the lungs in vivo and a persistent decrease in contractile protein activation in the airway smooth muscle isolated from those lungs. The chronic stress also caused an increase in airway size but no detectable changes in the composition of the airway wall.

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Effect of time-varying load on degree of bronchoconstriction in the dog

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.4.1464 ◽

1998 ◽

Vol 85 (4) ◽

pp. 1464-1470 ◽

Cited By ~ 12

Author(s):

Norihiro Shinozuka ◽

Jean-Pierre Lavoie ◽

James G. Martin ◽

Jason H. T. Bates

Keyword(s):

Smooth Muscle ◽

Muscle Contraction ◽

Airway Smooth Muscle ◽

Lung Volume ◽

In Vitro Study ◽

Smooth Muscle Contraction ◽

Lung Mechanics ◽

Muscle Shortening

It is well established that the degree of airway smooth muscle shortening produced by a given dose of bronchial agonist is greatly affected by lung volume. The airways are tethered by parenchymal attachments, the tension of which increases progressively with lung volume, thereby presenting a commensurately increasing hindrance to smooth muscle contraction. Earlier studies (P. F. Dillon, M. O. Aksoy, S. P. Driska, and R. A. Murphy. Science 211: 495–497, 1981) presented evidence that smooth muscle contraction initially involves rapidly cycling cross bridges, which then change to noncycling (latch) bridges. They also suggested that most of the muscle shortening occurs during the early rapid cross-bridge phase. This implies that smooth muscle subject to a given load early in contraction should shorten less than when it is subject to the same load later on. An in vitro study (W. Li and N. L. Stephens. Can. J. Physiol. Pharmacol. 72: 1458–1463, 1994) obtained support for this notion. To test this hypothesis in vivo, we measured the changes in lung impedance at 1 and 6 Hz produced in dogs by a bolus intravenous injection of methacholine when lung volume was increased for 10 s at different times after injection. We found that the changes in mechanics were greatly inhibited, whereas lung volume was elevated. However, when lung volume was returned to its initial level, the lung mechanics continued to change at a rate unaffected by the preceding volume change. We conclude that temporary mechanical inhibition of airway smooth muscle shortening in the normal dog in vivo merely delays an otherwise normal course of contraction.

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Inhibition of dihydropyridine-sensitive calcium entry in hypoxic relaxation of airway smooth muscle

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1995.268.2.l201 ◽

1995 ◽

Vol 268 (2) ◽

pp. L201-L206 ◽

Cited By ~ 2

Author(s):

C. Vannier ◽

T. L. Croxton ◽

L. S. Farley ◽

C. A. Hirshman

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Muscle Tone ◽

Bay K 8644 ◽

O2 Concentration ◽

Voltage Dependent ◽

Progressive Hypoxia ◽

Carbamyl Choline

Hypoxia dilates airways in vivo and reduces active tension of airway smooth muscle in vitro. To determine whether hypoxia impairs Ca2+ entry through voltage-dependent channels (VDC), we tested the ability of dihydropyridines to modulate hypoxia-induced relaxation of KCl- and carbamyl choline (carbachol)-contracted porcine bronchi. Carbachol- or KCl-contracted bronchial rings were exposed to progressive hypoxia in the presence or absence of 1 microM BAY K 8644 (an L-type-channel agonist). In separate experiments, rings were contracted with carbachol or KCl, treated with nifedipine (a VDC antagonist), and finally exposed to hypoxia. BAY K 8644 prevented hypoxia-induced relaxation in KCl-contracted bronchi. Nifedipine (10(-5) M) totally relaxed KCl- contracted bronchi. Carbachol-contracted bronchi were only partially relaxed by nifedipine but were completely relaxed when the O2 concentration of the gas was reduced from 95 to 0%. These data indicate that hypoxia can reduce airway smooth muscle tone by limiting entry of Ca2+ through a dihydropyridine-sensitive pathway, but that other mechanisms also contribute to hypoxia-induced relaxation of carbachol-contracted bronchi.

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The Strain on Airway Smooth Muscle During a Deep Inspiration to Total Lung Capacity

Journal of Engineering and Science in Medical Diagnostics and Therapy ◽

10.1115/1.4042309 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Ynuk Bossé

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Total Lung Capacity ◽

In Vitro Studies ◽

Deep Inspiration ◽

Bronchodilator Effect ◽

Lung Capacity ◽

Residual Capacity

The deep inspiration (DI) maneuver entices a great deal of interest because of its ability to temporarily ease the flow of air into the lungs. This salutary effect of a DI is proposed to be mediated, at least partially, by momentarily increasing the operating length of airway smooth muscle (ASM). Concerningly, this premise is largely derived from a growing body of in vitro studies investigating the effect of stretching ASM by different magnitudes on its contractility. The relevance of these in vitro findings remains uncertain, as the real range of strains ASM undergoes in vivo during a DI is somewhat elusive. In order to understand the regulation of ASM contractility by a DI and to infer on its putative contribution to the bronchodilator effect of a DI, it is imperative that in vitro studies incorporate levels of strains that are physiologically relevant. This review summarizes the methods that may be used in vivo in humans to estimate the strain experienced by ASM during a DI from functional residual capacity (FRC) to total lung capacity (TLC). The strengths and limitations of each method, as well as the potential confounders, are also discussed. A rough estimated range of ASM strains is provided for the purpose of guiding future in vitro studies that aim at quantifying the regulatory effect of DI on ASM contractility. However, it is emphasized that, owing to the many limitations and confounders, more studies will be needed to reach conclusive statements.

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Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs

Journal of Applied Physiology ◽

10.1152/japplphysiol.00150.2002 ◽

2002 ◽

Vol 93 (4) ◽

pp. 1296-1300 ◽

Cited By ~ 12

Author(s):

Debra J. Turner ◽

Peter B. Noble ◽

Matthew P. Lucas ◽

Howard W. Mitchell

Keyword(s):

Smooth Muscle ◽

Airway Hyperresponsiveness ◽

Porcine Model ◽

Smooth Muscle Contraction ◽

Airway Wall ◽

Muscle Contractility ◽

Smooth Muscle Contractility ◽

Airway Narrowing

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0–20 cmH2O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls ( P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi ( P < 0.01) and smooth muscle strips ( P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.

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Adaptation to chronic length change in explanted airway smooth muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01180.2002 ◽

2003 ◽

Vol 95 (1) ◽

pp. 448-453 ◽

Cited By ~ 33

Author(s):

Jahanbakhsh Naghshin ◽

Lu Wang ◽

Peter D. Paré ◽

Chun Y. Seow

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Culture Media ◽

Length Change ◽

Functional Change ◽

Muscle Stiffness ◽

Airway Narrowing

It has been shown that airway smooth muscle in vitro is able to maintain active force over a large length range by adaptation in the absence of periodic stimulations at 4°C (Wang L, Paré PD, and Seow CY. J Appl Physiol 90: 734–740, 2001). In this study, we show that such adaptation also takes place at body temperature and that long-term adaptation results in irreversible functional change in the muscle that could lead to airway hyperresponsiveness. Rabbit tracheal muscle explants were passively maintained at shortened and in situ length for 3 and 7–8 days in culture media; the length-tension relationship was then examined. The length associated with maximal force generation decreased by 10.5 ± 3.8% (SE) after 3 days and 37.7 ± 8.5% after 7 or 8 days of passive shortening. At day 3, the left shift in the length-tension curve due to adaptation at short lengths was reversible by readapting the muscle at a longer length. The shift was, however, not completely reversible after 7 days. The results suggest that long-term adaptation of airway smooth muscle could lead to increased muscle stiffness and force-generating ability at short lengths. Under in vivo condition, this could translate into resistance to stretch-induced relaxation and excessive airway narrowing.

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