Airway smooth muscle function in asthma and COPD
Proliferative aspects of airway smooth muscle

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Abstract

Increased airway smooth muscle (ASM) mass is perhaps the most important component of the airway wall remodeling process in asthma. Known mediators of ASM proliferation in cell culture models fall into 2 categories: those that activate receptors with intrinsic receptor tyrosine kinase activity and those that have their effects through receptors linked to heterotrimeric guanosine triphosphate–binding proteins. The major candidate signaling pathways activated by ASM mitogens are those dependent on extracellular signal-regulated kinase and phosphoinositide 3′-kinase. Increases in ASM mass may also involve ASM migration, and in culture, the key signaling mechanisms have been identified as the p38 mitogen-activated protein kinase and the p21-activated kinase 1 pathways. New evidence from an in vivo rat model indicates that primed CD4+ T cells are sufficient to trigger ASM and epithelial remodeling after allergen challenge. Hyperplasia has been observed in an equine model of asthma and may account for the increase in ASM mass. Reduction in the rate of apoptosis may also play a role. β2-Adrenergic receptor agonists and glucocorticoids have antiproliferative activity against a broad spectrum of mitogens, although it has become apparent that mitogens are differentially sensitive. Culture of ASM on collagen type I has been shown to enhance proliferative activity and prevent the inhibitory effect of glucocorticoids, whereas β2-agonists are minimally affected. There is no evidence that long-acting β2-agonists are more effective than short-acting agonists, but persistent stimulation of the β2-adrenergic receptor probably helps suppress growth responses. The maximum response of fluticasone propionate against thrombin-induced proliferation is increased when it is combined with salmeterol.

Section snippets

Mechanisms and mediators driving growth and migration of ASM in asthma

The first report documenting increases in ASM content in asthma appeared >75 years ago.5 More than 50 years later, increased ASM content was recognized as a prominent pathological feature and major component of the structural changes that result in airway luminal narrowing in fatal6., 7., 8., 9., 10., 11., 12., 13. and nonfatal13., 14., 15. asthma. The mechanisms underlying such increases involve multiple processes that likely include both hyperplastic and hypertrophic changes. Their anatomical

Mediators driving ASM growth

The basis of excessive ASM growth is presumed to lie in stimulation of ASM by mitogenic or inflammatory stimuli. However, few reports have examined either mitogenic indices for ASM cells in human asthmatic airways or the presence of ASM mitogenic activity in the airways. Benayoun et al14 recently examined ASM proliferation by immunodetection of the nuclear antigen Ki67, which was distributed in the airway epithelium and bronchial submucosa of control volunteers or patients with varying

Migration contributing to ASM accumulation

Cellular migration is a process characterized by substantial cytoskeletal remodeling with consequent spatially directed filopodia and lamellipodia to allow increased nondirected movement (chemokinesis) or directed movement along a concentration gradient (chemotaxis). Cellular migration is a newly recognized function of ASM, identified only in the past 3 to 4 years. Although vascular smooth muscle cell migration from the media to the neointima is widely accepted as key in the pathogenesis of

Modeling of ASM growth

A variety of small animal models of asthma have been used to study ASM growth. Most studies have been performed in the Brown Norway rat, whose immune system is TH2-biased. It exhibits exuberant IgE production on active sensitization93 and typical eosinophilic airway inflammation after allergen challenge.94., 95. Repeated exposure to a sensitizing antigen such as ovalbumin results in an increase in ASM mass, assessed by morphometric analysis.96 The increase in ASM mass in the large airways

Regulation of cell cycle progression by β2-agonists

As described, the regulation of cell cycle progression by growth factors occurs through a complex set of signals that are closely regulated temporally and possibly spatially, including activation of ERK and PI3K and degradation of cdk inhibitors. Each of these key signaling cascades has been proposed as a target for regulation by asthma drugs (Fig 5).

β2-Agonists attenuate the DNA synthesis and increases in ASM cell number in response to a diverse range of mitogenic stimuli.115., 116., 117., 118.

Factors limiting the antiproliferative actions of β2-agonists and glucocorticoids

It has become apparent that different mitogens are differentially sensitive to the action of the β2-agonists and glucocorticoids. In general, thrombin and other GPCR stimuli are more sensitive to the antiproliferative actions of either glucocorticoids or β2-agonists.123 The effects of the glucocorticoids are influenced by concurrent exposure of the ASM to cytokines, such as IL-1, that induce PGE2 synthesis via increasing the expression of COX-2.125 Concurrent treatment of cells with cytokines

Summary and implications for future research

Significant overlap exists between the groups of mediators and candidate intracellular signaling intermediates that drive both the proliferation and migration of cultured ASM cells. In recent years, substantial progress has been made, and key signaling events regulating ASM growth have been elucidated. PI3K and ERK have emerged as major, but independent, signaling pathways required for ASM cell proliferation induced by a wide range of mitogens and appear to be well conserved across species. The

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    Disclosure of potential conflict of interest: J. G. Martin receives grants/research support from the Canadian Institute of Health Research and the Merck Medical School Grant Program. A. G. Stewart receives grants/research support from GlaxoSmithKline. S. J. Hirst, J. V. Bonacci, V. Chan, E. D. Fixman, Q. A. Hamid, B. Herszberg, J.-P. Lavoie, C. G. McVicker, L. M. Moir, T. T.-B. Nguyen, Q. Peng, and D. Ramos-Barbón have no conflict of interest to disclose.

    Supported by grants from the National Asthma Campaign, United Kingdom (#00/44; 01/063; Dr Hirst et al), and from the Asthma Foundation Victoria, National Health and Medical Research Council, and GlaxoSmithKline, United Kingdom (Dr Stewart and Dr Bonacci).

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