Airway smooth muscle function in asthma and COPD
Synthetic responses in airway smooth muscle

https://doi.org/10.1016/j.jaci.2004.04.041Get rights and content

Abstract

Human airway smooth muscle (ASM) has several properties and functions that contribute to asthma pathogenesis, and increasing attention is being paid to its synthetic capabilities. ASM can promote the formation of the interstitial extracellular matrix, and in this respect, ASM from asthmatic subjects compared with normal subjects responds differently, both qualitatively and quantitatively. Thus, ASM cells are important regulating cells that potentially contribute to the known alterations within the extracellular matrix in asthma. In addition, through integrin-directed signaling, extracellular matrix components can alter the proliferative, survival, and cytoskeletal synthetic function of ASM cells. ASM also functions as a rich source of biologically active chemokines and cytokines that are capable of perpetuating airway inflammation in asthma and chronic obstructive pulmonary disease by promoting recruitment, activation, and trafficking of inflammatory cells in the airway milieu. Emerging evidence shows that airway remodeling may also be a result of the autocrine action of secreted inflammatory mediators, including TH2 cytokines, growth factors, and COX-2–dependent prostanoids. Finally, ASM cells contain both β2-adrenergic receptors and glucocorticoid receptors and may represent a key target for β2-adrenergic receptor agonist/corticosteroid interactions. Combinations of long-acting β2-agonists and corticosteroids appear to have additive and/or synergistic effects in inhibiting inflammatory mediator release and the migration and proliferation of ASM cells.

Section snippets

Extracellular matrix and ASM in asthma

The term extracellular matrix encompasses all that is not cellular within tissue and includes both basement membrane connective tissue and interstitial connective tissue (Fig 2). The interstitial extracellular matrix (ECM) surrounds ASM, and there are bidirectional interactions: human ASM has synthetic capabilities of modulating ECM, and the composition of the ECM can influence ASM responses to stimulation, affecting its proliferative, migratory, and synthetic capabilities (Fig 3). Exposure of

Chemokine and cytokine production by ASM

When an inflammatory process is initiated in an organ such as the lung, low-molecular-weight cytokines (chemokines) are produced that are responsible for recruiting inflammatory cells along diffusion gradients (Fig 4). Chemokines, which can be divided into several categories on the basis of their molecular structure,21 exhibit a degree of selectivity for distinct inflammatory cell populations. For example, eotaxin, RANTES, and IL-5 have been primarily considered to recruit eosinophils, although

Autocrine regulation of ASM function

As described, various T-cell–derived and mast cell–derived cytokines present in high levels in asthmatic airways, such as IL-4, IL-5, IL-13, and TNF-α, are believed to orchestrate both acute and chronic inflammatory responses by altering myocyte function.59., 60. Although airway remodeling may be influenced by cytokines acting indirectly by promoting the recruitment, activation, and trafficking of leukocytes, evidence now suggests that cytokines may also exert paracrine or autocrine effects by

ASM: a target for β2-agonist/corticosteroid interactions

β2-Agonists and corticosteroids are widely used in the treatment of bronchial asthma and COPD. The combination of LABAs and inhaled corticosteroids (ICSs) results in improved lung function, better symptom control, and reduced exacerbations compared with LABAs or higher doses of ICSs alone.121., 122. Several studies have shown that LABAs potentiate the anti-inflammatory actions of corticosteroids in either an additive or a synergistic manner.123., 124. Recent evidence suggests that ASM cells may

Summary and implications for future research

Airway smooth muscle clearly can contribute to the formation of the ECM, and in this respect, ASM from asthmatic patients has both qualitative and quantitative differences in its response to stimuli. Thus, the ASM cells are important regulating cells potentially contributing to the known alterations within the ECM in asthma. In addition, through integrin-directed signaling, ECM components can change human ASM function, altering the proliferative, survival, and cytoskeletal synthetic function.

Acknowledgements

Dr Knox thanks Dan Duthie for help with graphics.

References (161)

  • W.A. Wuyts et al.

    Involvement of p38 MAPK, JNK, p42/p44 ERK and NF-kappaB in IL-1beta-induced chemokine release in human airway smooth muscle cells

    Respir Med

    (2003)
  • D.A. Bradbury et al.

    Cyclooxygenase-2 induction by bradykinin in human pulmonary artery smooth muscle cells is mediated by the cyclic AMP response element through a novel autocrine loop involving endogenous prostaglandin E2, E-prostanoid 2 (EP2), and EP4 receptors

    J Biol Chem

    (2003)
  • S. Holgate et al.

    Epithelial-mesenchymal interactions in the pathogenesis of asthma

    J Allergy Clin Immunol

    (2000)
  • S. McFarlane et al.

    Stimulation of stress-activated but not mitogen-activated protein kinases by tumour necrosis factor receptor subtypes in airway smooth muscle

    Biochem Pharmacol

    (2001)
  • G. Chen et al.

    In vitro wounding of airway smooth muscle cell monolayers increases expression of TGF-[beta] receptors

    Respir Physiol Neurobiol

    (2002)
  • H. Hakonarson et al.

    Autocrine regulation of airway smooth muscle responsiveness

    Respir Physiol Neurobiol

    (2003)
  • C. Duvernelle et al.

    Transforming growth factor-beta and its role in asthma

    Pulm Pharmacol Ther

    (2003)
  • N.C. Thomson

    Neurogenic and myogenic mechanisms of nonspecific bronchial hyperresponsiveness

    Eur J Respir Dis Suppl

    (1983)
  • S.T. Holgate et al.

    The pathogenesis and significance of bronchial hyper-responsiveness in airways disease

    Clin Sci (Lond)

    (1987)
  • P.R. Johnson et al.

    The production of extracellular matrix proteins by human passively sensitized airway smooth-muscle cells in culture: the effect of beclomethasone

    Am J Respir Crit Care Med

    (2000)
  • A. Coutts et al.

    Release of biologically active TGF-beta from airway smooth muscle cells induces autocrine synthesis of collagen

    Am J Physiol Lung Cell Mol Physiol

    (2001)
  • R.A. Panettieri et al.

    Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists

    Am J Respir Cell Mol Biol

    (1998)
  • J.K. Burgess et al.

    Expression of connective tissue growth factor in asthmatic airway smooth muscle cells

    Am J Respir Crit Care Med

    (2003)
  • S. Potter-Perigo et al.

    Regulation of proteoglycan synthesis by leukotriene d4 and epidermal growth factor in bronchial smooth muscle cells

    Am J Respir Cell Mol Biol

    (2004)
  • H.D. Foda et al.

    Regulation of gelatinases in human airway smooth muscle cells: mechanism of progelatinase A activation

    Am J Physiol

    (1999)
  • S. Johnson et al.

    Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation

    Am J Physiol

    (1999)
  • C.E. Brightling et al.

    Mast-cell infiltration of airway smooth muscle in asthma

    N Engl J Med

    (2002)
  • J.W. Ferguson et al.

    The extracellular matrix protein betaIG-H3 is expressed at myotendinous junctions and supports muscle cell adhesion

    Cell Tissue Res

    (2003)
  • M.A. Gibson et al.

    Immunohistochemical and ultrastructural localization of MP78/70 (betaig-h3) in extracellular matrix of developing and mature bovine tissues

    J Histochem Cytochem

    (1997)
  • E.H. Danen et al.

    Integrins in regulation of tissue development and function

    J Pathol

    (2003)
  • S.J. Hirst et al.

    Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype

    Am J Respir Cell Mol Biol

    (2000)
  • A.M. Freyer et al.

    Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells

    Am J Respir Cell Mol Biol

    (2001)
  • C.D. Huang et al.

    Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone

    Am J Respir Cell Mol Biol

    (2003)
  • M. Nie et al.

    Transcriptional regulation of cyclooxygenase 2 by bradykinin and interleukin-1beta in human airway smooth muscle cells: involvement of different promoter elements, transcription factors, and histone h4 acetylation

    Mol Cell Biol

    (2003)
  • T. Tran et al.

    Protease-activated receptor (PAR)-independent growth and pro-inflammatory actions of thrombin on human cultured airway smooth muscle

    Br J Pharmacol

    (2003)
  • S. Maruoka et al.

    PAF-induced RANTES production by human airway smooth muscle cells requires both p38 MAP kinase and Erk

    Am J Respir Crit Care Med

    (2000)
  • H. Zhong et al.

    A2B adenosine receptors increase cytokine release by bronchial smooth muscle cells

    Am J Respir Cell Mol Biol

    (2004)
  • L. Pang et al.

    Regulation of TNF-alpha-induced eotaxin release from cultured human airway smooth muscle cells by beta2-agonists and corticosteroids

    FASEB J

    (2001)
  • K.F. Chung et al.

    Induction of eotaxin expression and release from human airway smooth muscle cells by IL-1beta and TNFalpha: effects of IL-10 and corticosteroids

    Br J Pharmacol

    (1999)
  • N. Lazzeri et al.

    Effects of prostaglandin E2 and cAMP elevating drugs on GM-CSF release by cultured human airway smooth muscle cells: relevance to asthma therapy

    Am J Respir Cell Mol Biol

    (2001)
  • O. Ghaffar et al.

    Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells

    Am J Respir Crit Care Med

    (1999)
  • W.A. Wuyts et al.

    Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells

    Eur Respir J

    (2003)
  • P.E. Moore et al.

    IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK

    Am J Physiol Lung Cell Mol Physiol

    (2002)
  • M. John et al.

    Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids

    J Immunol

    (1997)
  • A.J. Ammit et al.

    Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells: modulation by cyclic adenosine monophosphate

    Am J Respir Cell Mol Biol

    (2000)
  • U. Oltmanns et al.

    Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells

    Br J Pharmacol

    (2003)
  • J.L. Pype et al.

    Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells: modulation by corticosteroids and T-helper 2 cytokines

    Am J Respir Cell Mol Biol

    (1999)
  • L. Pang et al.

    Synergistic inhibition by beta(2)-agonists and corticosteroids on tumor necrosis factor-alpha-induced interleukin-8 release from cultured human airway smooth-muscle cells

    Am J Respir Cell Mol Biol

    (2000)
  • M. John et al.

    Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids

    Am J Respir Cell Mol Biol

    (1998)
  • L. Pang et al.

    Bradykinin stimulates IL-8 production in cultured human airway smooth muscle cells: role of cyclooxygenase products

    J Immunol

    (1998)
  • Cited by (0)

    Disclosure of potential conflict of interest: A. J. Knox has consultant arrangements with GlaxoSmithKline and Astra Zeneca; he receives grants/research support from GlaxoSmithKline. Y. Amrani receives grants/research support from NIH and Centocor; he is employed by the University of Pennsylvania. R. A. Panettieri has consultant arrangements with Merck, GlaxoSmithKline, Schering, and Epigenesis; he receives grants/research support from Merck, GlaxoSmithKline, and Centocor; is employed by the University of Pennsylvania; and is on the Speakers' Bureau of Merck, GlaxoSmithKline, Schering, and Epigenesis. M. Johnson is employed by GlaxoSmithKline Research and Development. P. H. Howarth and O. Tliba have no conflict of interest to disclose.

    Supported by the Medical Research Council, the Wellcome Trust, the National Asthma Campaign, and Glaxo Smith Kline (Dr Knox); National Institutes of Health grants 2R01-HL55301 and 1P50-HL67663 (Dr Panettieri); and American Lung Association grant RG-062-N (Dr Amrani). Dr Amrani is a Parker B. Francis Fellow in Pulmonary Research.

    View full text