Serum deprivation induces a unique hypercontractile  phenotype of cultured smooth muscle cells

Ma, Xuefei; Wang, Ying; Stephens, N. L.

doi:10.1152/ajpcell.1998.274.5.c1206

Cited by 116 publications

(88 citation statements)

References 19 publications

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“…This is evident following prolonged withdrawal of serum (up to 20 days) from primary cultures of confluent canine tracheal smooth muscle. A subset of these cells (~20±25% of the total) reacquire the contractile protein content, shortening velocity and elongated morphology (maximal after 15±18 days of serum deprivation) that is reminiscent of contractile cells derived from the original intact tissue [28,29]. Flow cytometric examination of their DNA content, by staining with propidium iodide, confirmed that these cells do not proliferate (S.J.…”

Section: Heterogeneity and Phenotypic Modulation Of Airway Smooth Musclementioning

confidence: 99%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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Chronic persistent asthma is characterized by poorly reversible airflow obstruction and airways inflammation and remodelling. Histopathological studies of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result of hyperplastic and/or hypertrophic growth, is believed to be one of the principal contributors to airway wall thickening. In recent years, significant advances have been made in elucidating the mediators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent airflow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversible phenotypic modulation and increased heterogeneity of airway smooth muscle function may also be a feature of the asthmatic airway. This review focuses on possible mechanisms controlling smooth muscle phenotype heterogeneity as well as on the mediators and intracellular pathways implicated in its cellular proliferation. Particular attention is paid to mechanisms involving activation of the extracellular signal regulated kinase‐, protein kinase C‐ and phosphoinositide 3‐kinase‐dependent pathways, since these appear to be the major candidate second messenger pathways for G protein‐ and tyrosine kinase‐coupled receptor‐stimulated proliferation.

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Section: Heterogeneity and Phenotypic Modulation Of Airway Smooth Musclementioning

confidence: 99%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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“…The approach affords the opportunity to manipulate conditions, such as soluble biomarkers and ECM composition, to assess their effects on a defined cell population, thus eliminating many difficult-to-control variables associated with in situ and in vivo experimental models. It must be kept in mind, however, that cells in culture undergo phenotype modulation such that their contractile protein expression is quite different from that in vivo, and this could significantly alter cell mechanics [218][219][220][221][222][223][224][225][226]. Nevertheless, as a way to study the effects of mechanical strain on ASM contractility and mechanical plasticity, in vitro models offer some advantages including the ability to apply acute or chronic mechanical strain varying in magnitude, frequency and direction.…”

Section: Chronic Oscillatory Length Change In Cultured Asm Cellsmentioning

confidence: 99%

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

An¹,

Bai²,

Bates³

et al. 2007

European Respiratory Journal

342

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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“…ASMs from individuals with asthma exhibit increased synthetic capacity (8,9), mitochondrial biogenesis (10), altered calcium homeostasis (10,11), and in some reports (10)(11)(12), but not all (13,14), increased proliferation. Critically, there is emerging evidence that ASM from individuals with asthma is hypercontractile as demonstrated by an increased velocity of contraction in response to electrical field stimulation at the single-cell level (15) and in cell populations using gel contraction assays (16).…”

mentioning

confidence: 99%

Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma

Sutcliffe

Hollins²,

Gomez³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Asthma is characterized by disordered airway physiology as a consequence of increased airway smooth muscle contractility. The underlying cause of this hypercontractility is poorly understood. Objectives: We sought to investigate whether the burden of oxidative stress in airway smooth muscle in asthma is heightened and mediated by an intrinsic abnormality promoting hypercontractility. Methods: We examined the oxidative stress burden of airway smooth muscle in bronchial biopsies and primary cells from subjects with asthma and healthy controls. We determined the expression of targets implicated in the control of oxidative stress in airway smooth muscle and their role in contractility. Measurements and Main Results: We found that the oxidative stress burden in the airway smooth muscle in individuals with asthma is heightened and related to the degree of airflow obstruction and airway hyperresponsiveness. This was independent of the asthmatic environment as in vitro primary airway smooth muscle from individuals with asthma compared with healthy controls demonstrated increased oxidative stress-induced DNA damage together with an increased production of reactive oxygen species. Genome-wide microarray of primary airway smooth muscle identified increased messenger RNA expression in asthma of NADPH oxidase (NOX) subtype 4. This NOX4 overexpression in asthma was supported by quantitative polymerase chain reaction, confirmed at the protein level. Airway smooth muscle from individuals with asthma exhibited increased agonist-induced contraction. This was abrogated by NOX4 small interfering RNA knockdown and the pharmacological inhibitors diphenyleneiodonium and apocynin. Conclusions: Our findings support a critical role for NOX4 overexpression in asthma in the promotion of oxidative stress and consequent airway smooth muscle hypercontractility. This implicates NOX4 as a potential novel target for asthma therapy.Keywords: asthma; airway smooth muscle; airway hyperresponsiveness; NOX4; SOD2 Asthma affects over 300 million people worldwide. Importantly, asthma control is suboptimal in about half of sufferers, and 10% are refractory to current antiinflammatory and bronchodilator therapies (1, 2). There is therefore an urgent need for new therapies. Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness as a consequence of increased airway smooth muscle contractility (1, 2). This heightened airway smooth muscle (ASM) contraction is considered to be largely due to the local asthmatic milieu with infiltration by inflammatory cells, in particular eosinophils and T cells, into the submucosa (2-4), to mast cells in the ASM bundle (4, 5), and to up-regulation of Th2 cytokines (6, 7).Interestingly, there is an increasing body of evidence that ASM is fundamentally altered in asthma compared with healthy controls, suggesting that abnormalities in these structural cells may also play a critical role in the development of the abnormal physiology in asthma and may contribute to the persistent airway ...

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Serum deprivation induces a unique hypercontractile phenotype of cultured smooth muscle cells

Cited by 116 publications

References 19 publications

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

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

Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma

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