Enhanced growth response of airway smooth muscle in inbred rats with airway hyperresponsiveness.

Zacour, Mary; Martin, James G.

doi:10.1165/ajrcmb.15.5.8918366

Cited by 28 publications

(26 citation statements)

References 40 publications

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“…When compared with Lewis, Fisher rats are known to exhibit higher airway responsiveness to various inhaled contractile agonists, such as methacholine [17] or 5-hydroxytryptamine [18,19]. In vivo, this relative AHR is manifested by a shift in the dose/response curve to the aerosolised agonist in both spontaneously breathing [17][18][19] and mechanically ventilated animals [20].…”

Section: Validation Of the Animal Modelsmentioning

confidence: 99%

“…When compared with the Lewis strain, the Fisher strain exhibited greater airway responsiveness to various inhaled contractile agonists, such as methacholine [17] and 5-hydroxytryptamine [18,19]. This relative AHR was manifested by a shift in the dose/ response curve to the aerosolised agonist in both spontaneously breathing [17][18][19] and mechanically ventilated animals [20].The aim of the present study was to determine whether the nonspecific in vivo AHR of the Fisher F-344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats. Therefore, the mechanical properties of isolated TSM of inbred Fisher and Lewis rats were studied, focusing on isotonic parameters (extent and velocity of shortening), and the hypothesis of whether potential, inherited, genetically…”

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confidence: 97%

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Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains

Fx¹,

Coirault²,

Salmeron³

et al. 2003

European Respiratory Journal

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Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains. F-X. Blanc, C. Coirault, S. Salmeron, D. Chemla, Y. Lecarpentier. #ERS Journals Ltd 2003. ABSTRACT: The aim of the study was to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats.Isotonic and isometric contractile properties of isolated TSM from Fisher and Lewis rats (each n=10) were investigated, and myosin crossbridge (CB) number, force and kinetics in both strains were calculated using Huxley9s equations adapted to nonsarcomeric muscles. Maximum unloaded shortening velocity and maximum extent of muscle shortening were higher in Fisher than in Lewis rats (y46% and y42%, respectively), whereas peak isometric tension was similar.The curvature of the hyperbolic force/velocity relationship did not differ between strains. Myosin CB number and unitary force were similar in both strains. The duration of CB detachment and attachment was shorter in Fisher than in Lewis rats (y-46% and -34%, respectively).In Fisher rats, these results show that inherited, genetically determined factors of airway hyperresponsiveness are associated with changes in crossbridge kinetics, contributing to an increased tracheal smooth muscle shortening capacity and velocity. Asthma is characterised by chronic inflammatory disorders of the airways associated with increased airway responsiveness to various stimuli [1]. The mechanisms underlying nonspecific airway hyperresponsiveness (AHR) remain poorly understood. Although it is clear that airway smooth muscle (ASM) is the key effector of excessive airway narrowing in asthma, it remains unclear whether or not AHR is attributable to ASM abnormality [2,3]. The amount of ASM has been reported to be increased in human asthmatics [4][5][6] and in animal models of AHR [7]. However, recent stereological studies using axial airway sections at high resolution have provided no evidence of increased ASM in large airways of human asthmatics [8]. Marked differences in isotonic contractile properties of isolated ASM have been reported in human asthmatic [9], and in human-[10] and animal-sensitised [11][12][13][14] tissues. In these studies, isolated ASM was found to shorten more and faster in asthmatic and sensitised tissues than in controls without any differences in the ability to generate force. Taken together, these findings suggest functional changes resulting in increased ASM shortening capacity and velocity in hyperresponsive airways, without increases in the amount of ASM [8] or in ASM force production capacity. Potential mechanisms involved in such an increased ASM shortening capacity and velocity include reduced bronchial stiffness [9], decreased resistance to internal shortening [15], and increased myosin crossbridge (CB) cycling rate possibly related to an increased content of smooth-muscle myosin light-chain kinase (smMLCK...

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Section: Validation Of the Animal Modelsmentioning

confidence: 99%

mentioning

confidence: 97%

Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains

Fx¹,

Coirault²,

Salmeron³

et al. 2003

European Respiratory Journal

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“…The augmentation of airway SM mass has been attributed to hyperplasia through evidence of cell proliferation quantified by bromodeoxyuridine incorporation or PCNA expression in vivo (11,19,28,37). Susceptibility to SM remodeling may be a risk factor for asthma; cultured airway SM cells from asthmatic subjects were shown to have a higher proliferation rate than cells from normal subjects (14), similarly to SM cells from hyperresponsive rats (38).…”

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confidence: 99%

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

Labonté

Hassan

Risse

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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The effects of remodeling of airway smooth muscle (SM) by hyperplasia on airway SM contractility in vivo are poorly explored. The aim of this study was to investigate the relationship between allergen-induced airway SM hyperplasia and its contractile phenotype. Brown Norway rats were sensitized with ovalbumin (OVA) or saline on day 0 and then either OVA-challenged once on day 14 and killed 24 h later or OVA-challenged 3 times (on days 14, 19, and 24) and killed 2 or 7 days later. Changes in SM mass, expression of total myosin, SM myosin heavy chain fast isoform (SM-B) and myosin light chain kinase (MLCK), tracheal contractions ex vivo, and airway responsiveness to methacholine (MCh) in vivo were assessed. One day after a single OVA challenge, the number of SM cells positive for PCNA was greater than for control animals, whereas the SM mass, contractile phenotype, and tracheal contractility were unchanged. Two days after three challenges, SM mass and PCNA immunoreactive cells were increased (3-and 10-fold, respectively; P Ͻ 0.05), but airway responsiveness to MCh was unaffected. Lower expression in total myosin, SM-B, and MLCK was observed at the mRNA level (P Ͻ 0.05), and total myosin and MLCK expression were lower at the protein level (P Ͻ 0.05) after normalization for SM mass. Normalized tracheal SM force generation was also significantly lower 2 days after repeated challenges (P Ͻ 0.05). Seven days after repeated challenges, features of remodeling were restored toward control levels. Allergen-induced hyperplasia of SM cells was associated with a loss of contractile phenotype, which was offset by the increase in mass. phenotype; animal model; myosin heavy chain isoform STRUCTURAL AIRWAY REMODELING has been widely reported in both human asthma (4, 13) and animal models of experimental asthma (11,23,37). Most tissues of the airway wall are affected by remodeling, and the observed changes include shedding of the epithelium, thickening of the reticular basement membrane, increased mucus gland size and number, goblet cell differentiation, angiogenesis, and augmentation of the airway smooth muscle (SM) mass (4). The changes in airway wall tissues are likely to be of clinical importance since they may control airway caliber, airway elasticity, and responsiveness and may cause symptoms related to mucus overproduction (4). Airway SM remodeling is a reported feature of several animal models of allergic asthma (11,12,22), including the Brown Norway (BN) rat (19,26,31). The increase in SM mass, observed in asthma of varying severity (5, 29, 36), has been proposed to be sufficient to account for altered airway responsiveness (16). The augmentation of airway SM mass has been attributed to hyperplasia through evidence of cell proliferation quantified by bromodeoxyuridine incorporation or PCNA expression in vivo (11,19,28,37). Susceptibility to SM remodeling may be a risk factor for asthma; cultured airway SM cells from asthmatic subjects were shown to have a higher proliferation rate than cells from normal subjects (14), sim...

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“…When compared with Lewis rats, Fisher rats are known to exhibit higher airway responsiveness to various inhaled contractile agonists such as methacholine [2] or 5-hydroxytryptamine [3,4]. In vitro, the ASM of these two rat strains exhibits marked differences: while isolated TSM develops similar peak isometric force in both strains [2,7], the TSM of Fisher rats has been shown to be more responsive to cumulative concentrations of carbachol [18] or serotonin [19] than the Lewis strain.…”

Section: Discussionmentioning

confidence: 99%

“…When compared with the Lewis strain, the Fisher strain exhibited greater airway responsiveness to various inhaled contractile agonists. This relative AHR was manifested by a shift in the dose-response curve to aerosolised agonists in both spontaneously breathing [2][3][4] and mechanically ventilated animals [5]. Thus, the Fisher and Lewis model can be seen as a paradigm similar to asthmatic and normal humans [6].…”

mentioning

confidence: 99%

Relaxation of tracheal smooth muscle is impaired in innate airway hyperresponsiveness

Blanc

Coirault²,

Oliviéro³

et al. 2009

European Respiratory Journal

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The current study was designed to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain is associated with impaired spontaneous relaxation of airway smooth muscle.Strips of the posterior portion of the trachea from 10 adult Fisher and 10 adult Lewis rats were electrically stimulated at pH 7.4, 2.5 mM Ca 2+ concentration, at 37uC. Both isotonic and isometric relaxations of tracheal smooth muscle (TSM) were investigated. Half time for isotonic relaxation at preload was markedly prolonged in Fisher rats (8.33¡3.21 s) compared with Lewis rats (3.53¡0.54 s; p,0.001). Maximum lengthening velocity at preload and peak rate of isometric tension decline were significantly decreased in Fisher rats compared with Lewis rats. The ratio of shortening velocity to lengthening velocity at preload, as well as the ratio of the isometric peak rates of tension development to tension decline were higher in Fisher rat TSM than in Lewis rat TSM. These differences were associated with a six-fold higher expression of myosin light chain kinase in Fisher rats than in Lewis rats.In Fisher rats, these results suggest that innate airway hyperresponsiveness is associated with both a reduced level and a slower rate of TSM spontaneous relaxation, promoting maintenance of airway constriction.

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Enhanced growth response of airway smooth muscle in inbred rats with airway hyperresponsiveness.

Cited by 28 publications

References 40 publications

Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains

Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

Relaxation of tracheal smooth muscle is impaired in innate airway hyperresponsiveness

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