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

2003 ◽  
Vol 95 (2) ◽  
pp. 844-853 ◽  
Author(s):  
Darren J. Fernandes ◽  
Richard W. Mitchell ◽  
Oren Lakser ◽  
Maria Dowell ◽  
Alastair G. Stewart ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Inflammatory Mediators ◽  
Airway Hyperresponsiveness ◽  
Molecular Mechanisms ◽  
Normal Subjects ◽  
Smooth Muscle Contraction ◽  
Deep Inspiration ◽  
Contractile Apparatus ◽  
Muscle Shortening

It is now accepted that a host of cytokines, chemokines, growth factors, and other inflammatory mediators contributes to the development of nonspecific airway hyperresponsiveness in asthma. Yet, relatively little is known about how inflammatory mediators might promote airway structural remodeling or about the molecular mechanisms by which they might exaggerate smooth muscle shortening as observed in asthmatic airways. Taking a deep inspiration, which provides relief of bronchodilation in normal subjects, is less effective in asthmatic subjects, and some have speculated that this deficiency stems directly from an abnormality of airway smooth muscle and results in airway hyperresponsiveness to constrictor agonists. Here, we consider some of the mechanisms by which inflammatory mediators might acutely or chronically induce changes in the contractile apparatus that in turn might contribute to hyperresponsive airways in asthma.

Development and maintenance of force and stiffness in airway smooth muscle

2015 ◽  
Vol 93 (3) ◽  
pp. 163-169 ◽  
Author(s):  
Bo Lan ◽  
Brandon A. Norris ◽  
Jeffrey C.-Y. Liu ◽  
Peter D. Paré ◽  
Chun Y. Seow ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Solid State ◽  
Airway Smooth Muscle ◽  
Deep Inspiration ◽  
Contractile Apparatus ◽  
Tidal Breathing ◽  
Actomyosin Interaction ◽  
Filament Network

Airway smooth muscle (ASM) plays a central role in the excessive narrowing of the airway that characterizes the primary functional impairment in asthma. This phenomenon is known as airway hyper-responsiveness (AHR). Emerging evidence suggests that the development and maintenance of ASM force involves dynamic reorganization of the subcellular filament network in both the cytoskeleton and the contractile apparatus. In this review, evidence is presented to support the view that regulation of ASM contraction extends beyond the classical actomyosin interaction and involves processes within the cytoskeleton and at the interfaces between the cytoskeleton, the contractile apparatus, and the extracellular matrix. These processes are initiated when the muscle is activated, and collectively they cause the cytoskeleton and the contractile apparatus to undergo structural transformation, resulting in a more connected and solid state that allows force generated by the contractile apparatus to be transmitted to the extracellular domain. Solidification of the cytoskeleton also serves to stiffen the muscle and hence the airway. Oscillatory strain from tidal breathing and deep inspiration is believed to be the counter balance that prevents hypercontraction and stiffening of ASM in vivo. Dysregulation of this balance could lead to AHR seen in asthma.

scholarly journals ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice

2015 ◽  
Vol 309 (7) ◽  
pp. L736-L746 ◽  
Author(s):  
David I. Kasahara ◽  
Joel A. Mathews ◽  
Chan Y. Park ◽  
Youngji Cho ◽  
Gabrielle Hunt ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Matrix Protein ◽  
Pulmonary Inflammation ◽  
Inflammatory Cells ◽  
Smooth Muscle Contraction ◽  
Airway Smooth Muscle Cells ◽  
Wild Type

Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1+/−, and ROCK2+/− mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2+/− mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2+/− mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1+/− but not ROCK2+/− mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1+/− or ROCK2+/− mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction.

scholarly journals Molecular mechanisms underlying airway smooth muscle contraction and proliferation: Implications for asthma

2008 ◽  
Vol 102 (8) ◽  
pp. 1173-1181 ◽  
Author(s):  
Girolamo Pelaia ◽  
Teresa Renda ◽  
Luca Gallelli ◽  
Alessandro Vatrella ◽  
Maria Teresa Busceti ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Molecular Mechanisms ◽  
Smooth Muscle Contraction

Intrinsic and antigen-induced airway hyperresponsiveness are the result of diverse physiological mechanisms

2007 ◽  
Vol 102 (1) ◽  
pp. 221-230 ◽  
Author(s):  
Scott S. Wagers ◽  
Hans C. Haverkamp ◽  
Jason H. T. Bates ◽  
Ryan J. Norton ◽  
John A. Thompson-Figueroa ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Smooth Muscle Contraction ◽  
Airway Closure ◽  
Physiological Mechanisms ◽  
Airway Constriction ◽  
Normal Airway ◽  
Central Airway

Airway hyperresponsiveness (AHR) is a defining feature of asthma. We have previously shown, in mice sensitized and challenged with antigen, that AHR is attributable to normal airway smooth muscle contraction with exaggerated airway closure. In the present study we sought to determine if the same was true for mice known to have intrinsic AHR, the genetic strain of mice, A/J. We found that A/J mice have AHR characterized by minimal increase in elastance following aerosolized methacholine challenge compared with mice (BALB/c) that have been antigen sensitized and challenged [concentration that evokes 50% change in elastance (PC50): 22.9 ± 5.7 mg/ml for A/J vs. 3.3 ± 0.4 mg/ml for antigen-challenged and -sensitized mice; P < 0.004]. Similar results were found when intravenous methacholine was used (PC30 0.22 ± 0.08 mg/ml for A/J vs. 0.03 ± 0.004 mg/ml for antigen-challenged and -sensitized mice). Computational model analysis revealed that the AHR in A/J mice is dominated by exaggerated airway smooth muscle contraction and that when the route of methacholine administration was changed to intravenous, central airway constriction dominates. Absorption atelectasis was used to provide evidence of the lack of airway closure in A/J mice. Bronchoconstriction during ventilation with 100% oxygen resulted in a mean 9.8% loss of visible lung area in A/J mice compared with 28% in antigen-sensitized and -challenged mice ( P < 0.02). We conclude that the physiology of AHR depends on the mouse model used and the route of bronchial agonist administration.

scholarly journals Accumulating Evidence for Increased Velocity of Airway Smooth Muscle Shortening in Asthmatic Airway Hyperresponsiveness

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Gijs Ijpma ◽  
Oleg Matusovsky ◽  
Anne-Marie Lauzon
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Normal Subjects ◽  
Shortening Velocity ◽  
Tissue Samples ◽  
Velocity Increase ◽  
Human Lungs ◽  
Velocity Of Shortening ◽  
Muscle Shortening

It remains unclear whether airway smooth muscle (ASM) mechanics is altered in asthma. While efforts have originally focussed on contractile force, some evidence points to an increased velocity of shortening. A greater rate of airway renarrowing after a deep inspiration has been reported in asthmatics compared to controls, which could result from a shortening velocity increase. In addition, we have recently shown in rats that increased shortening velocity correlates with increased muscle shortening, without increasing muscle force. Nonetheless, establishing whether or not asthmatic ASM shortens faster than that of normal subjects remains problematic. Endobronchial biopsies provide excellent tissue samples because the patients are well characterized, but the size of the samples allows only cell level experiments. Whole human lungs from transplant programs suffer primarily from poor patient characterization, leading to high variability. ASM from several animal models of asthma has shown increased shortening velocity, but it is unclear whether this is representative of human asthma. Several candidates have been suggested as responsible for increased shortening velocity in asthma, such as alterations in contractile protein expression or changes in the contractile apparatus structure. There is no doubt that more remains to be learned about the role of shortening velocity in asthma.

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

1998 ◽  
Vol 85 (4) ◽  
pp. 1464-1470 ◽  
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.

A maturational model for the study of airway smooth muscle adaptation to mechanical oscillation

2005 ◽  
Vol 83 (10) ◽  
pp. 817-824 ◽  
Author(s):  
Lu Wang ◽  
Pasquale Chitano ◽  
Thomas M Murphy
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Actin Polymerization ◽  
Normal Subjects ◽  
Regulatory Proteins ◽  
Muscle Adaptation ◽  
Force Transmission ◽  
Specific Expression ◽  
Mechanical Oscillation

It has been shown that mechanical stretches imposed on airway smooth muscle (ASM) by deep inspiration reduce the subsequent contractile response of the ASM. This passive maneuver of lengthening and retraction of the muscle is beneficial in normal subjects to counteract bronchospasm. However, it is detrimental to hyperresponsive airways because it triggers further bronchoconstriction. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in ASM adaptability to mechanical oscillation. Healthy immature airways of both human and animal exhibit hyperresponsiveness, but whether the adaptative properties of hyperresponsive airway differ from normal is still unknown. In this article, we review the phenomenon of ASM adaptation to mechanical oscillation and its relevance and implication to airway hyperresponsiveness. We demonstrate that the age-specific expression of ASM adaptation is prominent using an established maturational animal model developed in our laboratory. Our data on immature ASM showed potentiated contractile force shortly after a length oscillation compared with the maximum force generated before oscillation. Several potential mechanisms such as myogenic response, changes in actin polymerization, or changes in the quantity of the cytoskeletal regulatory proteins plectin and vimentin, which may underlie this age-specific force potentiation, are discussed. We suggest a working model of the structure of smooth muscle associated with force transmission, which may help to elucidate the mechanisms responsible for the age-specific expression of smooth muscle adaptation. It is important to study the maturational profile of ASM adaptation as it could contribute to juvenile hyperresponsiveness.Key words: ASM adaptation, maturation, bronchoprotection, airway hyperresponsiveness.

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