How Do Corticosteroids Work in Asthma?

Barnes, Peter J.; Adcock, Ian M.

doi:10.7326/0003-4819-139-5_part_1-200309020-00012

Cited by 317 publications

(237 citation statements)

References 72 publications

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“…We have recently, using a murine in-vitro model of chronic airway inflammation, demonstrated that prolonged exposure to TNF-α markedly enhanced contractile responses to des-Arg 9 -bradykinin and bradykinin in tracheal smooth muscle. This increase was paralleled with elevated mRNA levels for the bradykinin B 1 and B 2 receptors. In addition, mitogen-activated protein kinase (MAPK) pathways c-Jun Nterminal kinase (JNK) and extracellular signal-regulated kinase 1 and 2 (ERK 1/2) pathways were shown to be involved in this process [5].…”

Section: Introductionmentioning

confidence: 82%

“…It can be defined as an increase in the ease and degree of airway narrowing in response to various bronchoconstrictor stimuli [1,2]. Tumor necrosis factor-alpha (TNF-α) is recognized as an important pro-inflammatory cytokine with a large spectrum of activities, including the ability to induce airway hyperresponsiveness [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Activation of MAPK pathway is known to induce gene transcription via stimulation of "down-stream" transcriptional factors [10][11][12]. TNF-α induced up-regulation of bradykinin B 1 and B 2 receptors might also partly depend on de novo transcription and synthesis of bradykinin B 1 and B 2 receptors.…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoids suppress transcriptional up‐regulation of bradykinin receptors in a murine in vitro model of chronic airway inflammation

Zhang

Adner

Cardell

2005

Clin Experimental Allergy

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Glucocorticoids suppress transcriptional up‐regulation of bradykinin receptors in a murine in vitro model of chronic airway inflammation

Zhang

Adner

Cardell

2005

Clin Experimental Allergy

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“…Neutrophils were found to be less responsive to these drugs [6][7][8]. In vitro studies have shown that glucocorticoids inhibit neutrophil apoptosis [1,2,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Effects of glucocorticoids on the neutrophil count: A cohort study among hospitalized patients

Velthove

Leufkens

Souverein

et al. 2010

Pulmonary Pharmacology & Therapeutics

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Please cite this article as: Velthove KJ, Leufkens HGM, Souverein PC, Schweizer RC, Bracke M, van Solinge WW. Effects of glucocorticoids on the neutrophil count: a cohort study among hospitalized patients, Pulmonary Pharmacology & Therapeutics (2009), doi: 10.1016/j.pupt.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. with glucocorticoid use or that other factors, like disease and severity of disease, should be considered. The objective of this study was to investigate the effect of systemic glucocorticoids on the absolute neutrophil count in hospitalized patients. M A N U S C R I P T A C C E P T E D ARTICLE IN PRESSMethods: A cohort study was conducted using data from the Utrecht Patient OrientedDatabase which comprises clinical data of patients of the University Medical Center Utrecht.We identified all adult patients, hospitalized in 2005 with at least two blood samples for hematological testing during admission and compared in hospital glucocorticoid use with nonuse.Results: A total of 809 glucocorticoid users and 2,658 non-users were included in the study with comparable neutrophil counts at admission (8.2.10 9 /l for glucocorticoid users and 8.0.10 9 /l for non-users). Overall analysis showed a slight association between glucocorticoid use and an increase in neutrophil count (RR 1.3; 95% CI 1.1-1.5). However, within diagnostic subgroups there was no increase in neutrophil count in glucocorticoid users. Furthermore, among all no dose response relationship, no effect of time between the two samples, and no effect of anti-inflammatory/sodium retaining potency was found. Conclusion:Observed neutrophilia in users of systemic glucocorticoids is probably associated with underlying disease, rather than glucocorticoid use itself.

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“…There have been important advances in understanding the molecular mechanisms whereby corticosteroids suppress inflammation so effectively in asthma, based on recent developments in understanding the fundamental mechanisms of gene transcription and cell signalling in inflammation [1,2]. This new understanding of these molecular mechanisms also helps to explain how corticosteroids are able to switch off multiple inflammatory pathways, yet remain a safe treatment.…”

mentioning

confidence: 99%

Corticosteroid effects on cell signalling

Barnes¹

2006

Eur Respir J

363

245

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Corticosteroids are the most effective anti-inflammatory therapy for asthma. Inflammation in asthma is characterised by the increased expression of multiple inflammatory genes regulated by pro-inflammatory transcription factors, such as nuclear factor-kB and activator protein-1, which bind to and activate coactivator molecules that acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways, mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase 2 to the activated transcription complex.Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes in order to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase-1, which inhibits mitogen-activated protein kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side-effects.In some patients with steroid-resistant asthma, there are abnormalities in glucocorticoid receptor signalling pathways. In chronic obstructive pulmonary disease patients and asthmatic patients who smoke, histone deacetylase 2 is markedly impaired as a result of oxidative/nitrative stress, and so inflammation is resistant to the anti-inflammatory effects of corticosteroids.The therapeutic implications of these new findings are discussed.

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How Do Corticosteroids Work in Asthma?

Cited by 317 publications

References 72 publications

Glucocorticoids suppress transcriptional up‐regulation of bradykinin receptors in a murine in vitro model of chronic airway inflammation

Glucocorticoids suppress transcriptional up‐regulation of bradykinin receptors in a murine in vitro model of chronic airway inflammation

Effects of glucocorticoids on the neutrophil count: A cohort study among hospitalized patients

Corticosteroid effects on cell signalling

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