Airway smooth muscle—its relationship to the extracellular matrix

https://doi.org/10.1016/S1569-9048(03)00157-5Get rights and content

Abstract

The airway smooth muscle cell has a variety of properties, which confer on it the ability to participate actively in the inflammatory process and the remodeling events, which accompany severe, persistent asthma. Among these properties is its relationship to the extracellular matrix (ECM) with which it interacts by releasing matrix proteins, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Muscle cells derived from asthmatic subjects proliferate faster, release a different profile of matrix proteins, produce more connective tissue growth factor (CTGF) in response to TGFβ stimulation and these changes may impact on airway smooth muscle contraction and proliferation. Integrins on the surface of the airway smooth muscle transduce signals between the muscle cell and the ECM, but whether the expression and/or function of these is altered in asthma is not known. It is unlikely that current therapy is effective in preventing or reversing remodeling, and therefore, understanding the pathophysiological events, which underlie its mechanism is critical.

Section snippets

Multifunctional properties of the airway smooth muscle cell

A new era in airway smooth muscle cell biology began when it was acknowledged that the airway smooth muscle cell did not merely fulfill a structural function, participating in the contraction and relaxation events occurring in the asthmatic airway, but that it had the potential to be an active participant in the inflammatory process which is widely acknowledged to accompany asthma (Hirst, 2003). The muscle mass in the airway wall of individuals with asthma is greatly increased and this is in

Role of the extracellular matrix

Recently it has become important to acknowledge that the muscle is physically associated with a bed of ECM. The ECM consists of a complex network of interlacing macromolecules, which forms a supporting structure for the airway wall. In addition, the ECM has the potential to influence a number of pivotal cellular functions including proliferation, differentiation and migration. The proteins, which constitute the matrix are mainly interstitial collagens, glycoproteins such as fibronectin, laminin

Production and modulation of airway smooth muscle derived matrix proteins

A number of groups have reported that human airway smooth muscle cells in culture can secrete ECM proteins. Panettieri et al. (1998) demonstrated expression of collagens types I and IV, fibronectin, elastin and the chondroitin sulfate proteoglycans biglycan and decorin. TGFβ upregulated expression of collagens I and IV as well as elastin, fibronectin and biglycan. Messenger RNA for decorin, however, was markedly decreased by TGFβ. Johnson et al. (2000) in contrast measured protein release from

Matrix metalloproteinases, their tissue inhibitors and the airway smooth muscle

The MMPs are a large family of enzymes involved in regulation of proteolytic activity and they are a subgroup of a metalloproteinase superfamily which includes ADAM33 (Van Eerdewegh et al., 2002). There are more than 20 MMPs and they share a prodomain and a catalytic domain which contains an active Zn2+ binding site (Parks and Shapiro, 2001). MMPs are secreted as inactive forms, which are activated by proteolytic cleavage of a propeptide sequence capping the catalytic Zn2+ binding domain.

Effects of ECM components on airway smooth muscle properties

It has recently become apparent that, at least in culture, the ECM proteins either secreted by the cells themselves or provided artificially as a coating in culture plates or wells can profoundly influence smooth muscle cell behavior. Hirst et al. (2000) examined the proliferative response of airway smooth muscle cells to mitogens after they had been seeded onto a matrix of variable composition. Whereas fibronectin and collagen I increased the proliferative response, laminin caused a reduction.

Potential for functional consequences

In asthma there are both quantitative and qualitative abnormalities in the ECM. These can be localized external to the airway smooth muscle, within the muscle bundles (Bai et al., 2000) or between the muscle and the epithelial layer. Increased matrix deposition external to the smooth muscle may decrease airway-parenchymal interdependence and this may result in exaggerated airway narrowing (Macklem, 1995). The effects of collagen deposition are most likely to depend on the architecture of the

Acknowledgements

The authors are supported by the NH&MRC Australia, Glaxo Smith Kline UK and AstraZeneca, Sweden.

References (39)

  • J. Bousquet et al.

    Asthma: a disease remodeling the airways

    Allergy

    (1992)
  • J. Bousquet et al.

    Airways remodelling in asthma: no doubt, no more

    Int. Arch. Allergy Immunol.

    (1995)
  • A.M. Bramley et al.

    Collagenase increases shortening of human bronchial smooth muscle in vitro

    Am. J. Respir. Crit. Care Med.

    (1995)
  • Burgess, J.K., Johnson, P.R.A., Ge, Q., Au, W.W., Poniris, M.H., Mc Parland, B.E., Roth, M., Black, J.L., 2003....
  • 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)
  • M. Ebina et al.

    Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study

    Am. Rev. Respir. Dis.

    (1993)
  • 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)
  • S.J. Hirst

    Airway smooth muscle cell culture: application to studies of airway wall remodelling and phenotype plasticity in asthma

    Eur. Respir. J.

    (1996)
  • S.J. Hirst

    Airway smooth muscle as a target in asthma

    Clin. Exp. Allergy

    (2000)
  • Cited by (62)

    • The role of interleukin-6/interleukin-6 receptor signaling in the mechanical stress-induced extracellular matrix remodeling of bladder smooth muscle

      2021, Archives of Biochemistry and Biophysics
      Citation Excerpt :

      Therefore, we focused on the role of IL-6 in the mechanical stress-induced ECM remodeling of bladder smooth muscle. IL-6 not only is an inflammatory cytokine but also has various other functions in physiological and pathological processes [26,27]. Many studies have investigated the role of IL-6 in the ECM remodeling of smooth muscle cells.

    • Phenotype modulation of airway smooth muscle in asthma

      2013, Pulmonary Pharmacology and Therapeutics
    View all citing articles on Scopus
    View full text