In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta‐adrenoceptor agonists and theophylline.

Goldie, Roy G.; Spina, Dom; Henry, Peter J.; Lulich, Karmelo M.; Paterson, J. W.

doi:10.1111/j.1365-2125.1986.tb02956.x

Cited by 253 publications

(136 citation statements)

References 28 publications

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“…The concentration range of salbutamol used in this study is about half a log unit lower than that which has been reported previously to relax isolated human airway smooth muscle (Raffestin et al, 1985;Goldie et al, 1986). Therefore, the therapeutic dose may be supramaximal for the direct inhibitory effect of salbutamol on proliferation of airway smooth muscle.…”

Section: Discussionmentioning

confidence: 84%

Inhibition by salbutamol of the proliferation of human airway smooth muscle cells grown in culture

Tomlinson

Wilson

Stewart

1994

British J Pharmacology

113

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1 P2-Adrenoceptor agonists may exacerbate asthma by reducing the release of the anti-proliferative and anti-inflammatory molecule, heparin from mast cells in the airway. In this study, the direct effects of the clinically used bronchodilator, salbutamol, on the proliferation of airway smooth muscle cells grown in culture and stimulated with a range of mitogens have been examined.2 In mitogen-stimulated cells, salbutamol (0.1-I00 nM) inhibited [3H]-thymidine incorporation in a concentration-dependent manner. Salbutamol (100 nM) pretreatment reduced the mitogenic responses to thrombin (0.3 u ml-1), epidermal growth factor (EGF) (300 pM) and U46619 (100 nM) by 61.7 ± 6.1%, 46.9 ± 13.9% and 57.6 ± 12.7%, respectively. However, salbutamol pretreatment did not appear to reduce the small mitogenic response to endothelin-1. 3 Increases in [3H]-leucine incorporation in thrombin (0.3 u ml-')-stimulated cells were reduced by salbutamol (100 nM) by 27.7 ± 2.8%. Similarly, thrombin (0.3 u ml`)-stimulated increases in cell number were also inhibited by salbutamol (100 nM) pretreatment. Thus, the effect of salbutamol in decreasing thrombin-induced [3H]-leucine incorporation may, at least in part, be explained by inhibition of cell proliferation. 4 The inhibition of cell proliferation by salbutamol was prevented by pretreatment with either the non-selective P-adrenoceptor antagonist, propranolol (0.3 JAM) or the selective P2-adrenoceptor antagonist, ICI 118551 (50 nM).5 These results indicate that salbutamol, through activation of a P2-adrenoceptor, has a direct inhibitory effect on proliferation elicited by the mitogens thrombin, EGF, and U46619. Thus, it seems likely that this direct inhibitory action of P2-adrenoceptor agonists would override any indirect action to accelerate airway smooth muscle proliferation. These observations lead us to suggest that R2-adrenoceptor agonists exacerbate asthma by mechanisms unrelated to airway smooth muscle proliferation.

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Section: Discussionmentioning

confidence: 84%

Inhibition by salbutamol of the proliferation of human airway smooth muscle cells grown in culture

Tomlinson

Wilson

Stewart

1994

British J Pharmacology

113

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“…Bronchial asthma is characterized by exaggerated agonist-induced bronchoconstriction, attenuated ␤-adrenoceptor-mediated airway relaxation and airway inflammation, the latter principally involving infiltration of the airways with T lymphocytes, mast cells, and eosinophils (1)(2)(3)(4)(5)(6)(7)(8)(25)(26)(27)(28). Although the mechanistic interplay between airway inflammation and the associated changes in ASM responsiveness remains to be fully characterized, the wealth of evidence accumulated to date suggests that the altered airway responsiveness in asthma is primarily attributed to the actions of various cytokines, which are primarily produced by infiltrating CD4 ϩ T lymphocytes expressing the Th2 profile of cytokine release (1-8, 27, 28).…”

Section: Discussionmentioning

confidence: 99%

Bi-Directional Activation Between Human Airway Smooth Muscle Cells and T Lymphocytes: Role in Induction of Altered Airway Responsiveness

Hákonarson

Kim

Whelan

et al. 2001

The Journal of Immunology

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Because both T lymphocyte and airway smooth muscle (ASM) cell activation are events fundamentally implicated in the pathobiology of asthma, this study tested the hypothesis that cooperative intercellular signaling between activated T cells and ASM cells mediates proasthmatic changes in ASM responsiveness. Contrasting the lack of effect of resting human T cells, anti-CD3-activated T cells were found to adhere to the surface of naive human ASM cells, increase ASM CD25 cell surface expression, and induce increased constrictor responsiveness to acetylcholine and impaired relaxation responsiveness to isoproterenol in isolated rabbit ASM tissues. Comparably, exposure of resting T cells to ASM cells prestimulated with IgE immune complexes reciprocally elicited T cell adhesion to ASM cells and up-regulated T cell expression of CD25. Extended studies demonstrated that: 1) ASM cells express mRNAs and proteins for the cell adhesion molecules (CAMs)/costimulatory molecules, CD40, CD40L, CD80, CD86, ICAM-1 (CD54), and LFA-1 (CD11a/CD18); 2) apart from LFA-1, ASM cell surface expression of the latter molecules is up-regulated in the presence of activated T cells; and 3) pretreatment of ASM cells and tissues with mAbs directed either against CD11a or the combination of CD40 and CD86 completely abrogated both the activated T cell-induced changes in expression of the above CAMs/costimulatory molecules in ASM cells and altered ASM tissue responsiveness. Collectively, these observations identify the presence of bi-directional cross-talk between activated T cells and ASM cells that involves coligation of specific CAMs/costimulatory molecules, and this cooperative intercellular signaling mediates the induction of proasthmatic-like changes in ASM responsiveness.

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“…Most studies have not shown any correlation between in vivo and in vitro airway responsiveness [47±49]. Smooth muscle from cases of asthma has been shown to exhibit reduced responsiveness to smooth muscle relaxants in some studies [50,51], with only isolated cases reporting increased responses to agonists in vitro. These studies are confounded by difficulties in normalizing for the amount and length/tension properties of the smooth muscle.…”

Section: The Relationship Between Airway Structure and Functionmentioning

confidence: 99%

Airway smooth muscle in health and disease; methods of measurement and relation to function

James¹,

Carroll²

2000

Eur Respir J

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Smooth muscle is present and probably functional in the airways in utero and increases in absolute area during growth with little further change during adulthood. It encircles the entire airway below the level of the main bronchus, in a roughly circular orientation, except at high lung volumes. It occupies relatively more of the airway wall in the peripheral airways, reaching a maximum in the membranous bronchioles. Measurement of smooth muscle area in the airway wall is confounded by clinical classification of cases, methods of tissue retrieval and preparation, staining and orientation of sections, magnification, image analysis and statistical methods of comparison between groups. Airway smooth muscle area is pathologically increased in inflammatory conditions of the airways such as chronic obstructive pulmonary disease, in relation to airways obstruction, and asthma, in relation to severity and airway size (between 25 and 250% compared with control cases). It is increased in sudden infant death syndrome, but there are few studies in other conditions such as bronchiectasis. In asthma, smooth muscle must shorten (not necessarily to an abnormal degree) for the structural abnormalities of the airway to manifest as excessive airway narrowing. Not surprisingly there is renewed interest in the relationships between the mechanical and contractile properties of smooth muscle, parenchymal properties and lung volume and how these interact to determine smooth muscle length. The relative importance of smooth muscle area and mechanical properties, altered airway structure and airway inflammation in disease are yet to be determined.

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In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta‐adrenoceptor agonists and theophylline.

Cited by 253 publications

References 28 publications

Inhibition by salbutamol of the proliferation of human airway smooth muscle cells grown in culture

Inhibition by salbutamol of the proliferation of human airway smooth muscle cells grown in culture

Bi-Directional Activation Between Human Airway Smooth Muscle Cells and T Lymphocytes: Role in Induction of Altered Airway Responsiveness

Airway smooth muscle in health and disease; methods of measurement and relation to function

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