Collagen‐induced resistance to glucocorticoid anti‐mitogenic actions: a potential explanation of smooth muscle hyperplasia in the asthmatic remodelled airway

Bonacci, John V; Harris, Trudi; Wilson, John W.; Stewart, Alastair G.

doi:10.1038/sj.bjp.0705135

Cited by 54 publications

(50 citation statements)

References 20 publications

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“…Exploring the effects of known proliferative agents contained within serum on GM-CSF production was therefore interesting. This was especially so in light of a recent report showing that, with a much longer exposure time, some mitogens have the ability to both induce GM-CSF secretion by and cause cell cycle progression of ASMC (3).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Lalor¹,

Truong²,

Henness³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammation and vascular leakage are prevalent in asthma. This study aimed to elucidate the mechanisms involved in serum potentiation of cytokine-induced granulocyte macrophage colony stimulating factor (GM-CSF) production by human airway smooth muscle cells and to identify possible factors responsible. Serum-deprived cells at low density were stimulated with TNF-α and IL-1β for 24 h. Human AB serum (10%), inhibitors of RNA and protein synthesis or specific signaling molecules, or known smooth muscle mitogens were then added for 24 h. Culture supernatants were analyzed for GM-CSF levels, and cells were harvested to assess viability, cell cycle progression, GM-CSF-specific mRNA content, and p38 phosphorylation. Serum potentiated GM-CSF release when added before, together with (maximal), or after the cytokines. The potentiation involved both new GM-CSF-specific mRNA production and protein synthesis. The mitogens IGF, PDGF, and thrombin all potentiated GM-CSF release, and neutralizing antibodies for EGF, IGF, and PDGF reduced the serum potentiation. Inhibitor studies ruled as unlikely the involvement of p70S6kinase and the MAPK p42/p44, two signaling pathways implicated in proliferation, and the involvement of the MAPK JNK, while establishing roles for p38 MAPK and NF-κB in the potentiation of GM-CSF release. Detection of significant p38 phosphorylation in response to serum stimulation, through Western blotting, further demonstrated the involvement of p38. These studies have provided evidence to support p38 being targeted to interrupt the cycle of inflammation, vascular leakage and cytokine production in asthma.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Lalor¹,

Truong²,

Henness³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Interestingly, proliferation is reduced in cells grown on laminin and subjected to lower strains of 4% compared with cells grown on collagen with either 0 or 4% strain. Conversely, proliferation is enhanced in cells grown on collagen subjected to 10% strain, which indicates that the response to strain is sensitive to both strain magnitude and ECM [242,251]. While these results point to the importance to cell function of strain profile and magnitude, how relevant are the strain conditions experienced by cells in culture to strain experienced in vivo, and do strain conditions change in disease?…”

Section: Chronic Oscillatory Length Change In Cultured Asm Cellsmentioning

confidence: 94%

“…The ECM may also modulate drug-responsiveness of remodelling responses, such as proliferation and migration [111,112], as cells cultured on monomeric collagen show steroidresistance whereas cells cultured directly on plastic or on laminin are highly steroid-responsive [113]. Interest in migration of smooth muscle is increasing in light of the possibility that smooth muscle proliferation does not appear to take place in the muscle bundle, but rather in the subepithelial tissue, where the source of the proliferating cells may be stem cells recruited from the bone marrow [114], fibroblasts that have undergone differentiation [115] or smooth muscle cells that have migrated off the potentially antiproliferative ECM that is rich in proteoglycans and laminins [89].…”

Section: Asm Growth Responsesmentioning

confidence: 99%

“…Hence, it needs to be investigated whether the benefits of steroids in asthma are based on changing the dynamics in structure and function of ASM rather than suppressing the surrounding airway inflammation alone. As suggested by the recent reports regarding the lack of antiproliferative activity of steroids on smooth muscle cells from asthmatics [320] and the impairment of glucocorticoid action by type I monomeric collagen (presumably present in the micro-environment where ASM cells reside in asthmatic airways) [251,321], the efficacy of steroids in modulating smooth muscle gene transcription may be diminished in asthmatics. This indicates a need to look for alternative mechanisms for steroid action that are beneficial to (at least some) asthmatics.…”

Section: Stretch-induced Release Of Transmitters In the Parenchyma Anmentioning

confidence: 99%

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Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

An¹,

Bai²,

Bates³

et al. 2007

Eur Respir J

344

298

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Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

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“…In addition, glucocorticoids, such as fluticasone propionate, synergise with salmeterol to suppress chemotaxis. Our recent investigations indicates that a collagen I-rich ECM reduces glucocorticoid regulation of migration as well as proliferation [23,24], but b 2 -adrenoceptor agonists, such as salmeterol, retain their efficacy in cells exposed to collagen I rich matrices [23].…”

mentioning

confidence: 99%

Emigration and immigration of mesenchymal cells: a multicultural airway wall

Stewart¹

2004

Eur Respir J

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Chronic inflammatory disease is accompanied by structural changes that appear to relate to disease severity and duration, and are often considered to be poorly reversible, if at all. The processes underpinning the structural changes are varied, complex and not well understood. It is clear that these structural changes contribute to tissue dysfunction.In asthma, remodelling comprises changes in all compartments of the airway wall, with the epithelium potentially orchestrating a persistent cycle of inflammatory injury and repair [1]. The epithelium is thought to influence the underlying mesenchymal cell network through the release of transforming growth factor-b resulting in the activation of myofibroblasts that secrete excessive amounts of collagen and contribute to the burden of pro-inflammatory cytokines. Such changes in the superficial aspect of the airway recapitulate aspects of the pathogenesis of neointima formation, in which damage to the endothelium initiates a repair response that ultimately may compromise vessel function [2].The most significant cellular component of the airway wall remodelling is an increase in the volume of airway smooth muscle (ASM), which is considered to play a dominant role in the consequences of the airway wall thickening for airway reactivity [3]. The mechanisms of the increase in volume of ASM remain ill-defined despite extensive investigation over the last 15 yrs. Hyperplasia of ASM is well evidenced, but there is also evidence for a more limited hypertrophy [4,5]. The hyperplasia has been ascribed to proliferation in situ of ASM in response to growth factors and inflammatory mediators released during exacerbations of chronic asthma. Several investigations of antigen-induced airway inflammation in experimental animals, particularly those in Brown Norway rats, have demonstrated an increase in proliferation of ASM [6] resulting in an increase in the total number of ASM cells [7]. More recent evidence suggests that a decrease in the rate of ASM apoptosis may also contribute to the hyperplasia [8]. However, recent findings suggest the need to re-evaluate in situ proliferation as the major mechanism underlying the ASM hyperplasia. Neither we [9], nor others [10] have been able to detect increased rates of proliferation of ASM cells in biopsies using Ki67, proliferating cell nuclear antigen or cyclin D1 expression. It may be argued that in chronic asthma the rates of proliferation would be too small to detect an increase over the baseline level of cell turnover. Nevertheless, the lack of evidence for in situ proliferation of ASM in human asthmatic airways is consistent with the antiproliferative nature of the laminin and proteoglycan-rich extracellular matrix (ECM) surrounding the ASM cells in muscle bundles [11,12]. An alternative mechanism for the hyperplasia was identified in a biopsy study by GIZYCKI et al.[13], in which an increase in the number of myofibroblasts was detected within 24 h of segmental challenge of the airways. These myofibroblasts were considered to have differe...

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Collagen‐induced resistance to glucocorticoid anti‐mitogenic actions: a potential explanation of smooth muscle hyperplasia in the asthmatic remodelled airway

Cited by 54 publications

References 20 publications

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

Emigration and immigration of mesenchymal cells: a multicultural airway wall

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