Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes.

Lane, Stephen; Adcock, Ian M.; Richards, David F.; Hawrylowicz, Catherine M.; Barnes, Peter J.; Lee, T H

doi:10.1172/jci2680

Cited by 135 publications

(66 citation statements)

References 31 publications

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“…In a subsequent study using nuclear run-on, RT-PCR and Western blotting, we demonstrated a two-to fourfold greater increase in the c-fos transcription rate and mRNA and protein expression in PBMCs isolated from CR compared with CS asthmatics and normal subjects (Lane et al 1998). When cells were stimulated with phorbol 12-myristate 13-acetate (PMA), the time-and concentration-dependent induction of c-Fos was greater in the CR group.…”

Section: Cross-talk With Other Transcription Factorsmentioning

confidence: 85%

Corticosteroid-insensitive asthma: molecular mechanisms

Adcock

Sj²

2003

Journal of Endocrinology

163

105

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Corticosteroids are the most potent anti-inflammatory agents used to treat chronic inflammatory diseases such as bronchial asthma. However, there are a small number (,5%) of asthmatic patients who do not respond well, or at all, to corticosteroid therapy -the corticosteroidresistant and corticosteroid-dependent patients. Although this phenomenon is relatively uncommon, it poses a difficult therapeutic problem because few alternative therapies are available and these patients account for .50% of the health care costs of asthma. If the mechanisms for corticosteroid insensitivity are understood they may, in turn, provide insight into the key mechanism of corticosteroid action and allow a rational way to treat these individuals whose disease tends to be severe. Corticosteroid insensitivity is not limited to asthma and is a feature of other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Thus, elucidation of the cause for the relative lack of corticosteroid response in this subgroup of asthmatic individuals may have important implications for other diseases.

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Section: Cross-talk With Other Transcription Factorsmentioning

confidence: 85%

Corticosteroid-insensitive asthma: molecular mechanisms

Adcock

Sj²

2003

Journal of Endocrinology

163

105

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“…Thus, severe asthma that is refractory to treatment with corticosteroids may be associated with the persistent expression of key disease causality and severity genes. Consistent with this concept, dysregulated gene expression has been documented in peripheral blood mononuclear cells and bronchoalveolar lavage cells from corticosteroid-resistant patients with asthma (8)(9)(10). Murine asthma models have also identified corticosteroid-unresponsive genes and the dissociation of airway inflammation from airway hyperreactivity (AHR) and remodeling responses in response to corticosteroid treatment (11)(12)(13).…”

mentioning

confidence: 78%

Apolipoprotein E Negatively Regulates House Dust Mite–induced Asthma via a Low-Density Lipoprotein Receptor–mediated Pathway

Yao

Fredriksson²,

Yu³

et al. 2010

Am J Respir Crit Care Med

115

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Rationale: Distinct sets of corticosteroid-unresponsive genes modulate disease severity in asthma. Objectives: To identify corticosteroid-unresponsive genes that provide new insights into disease pathogenesis and asthma therapeutics. Methods: Experimental murine asthma was induced by nasal administration of house dust mite for 5 days per week. Dexamethasone and apolipoprotein E (apo E) mimetic peptides were administered via osmotic minipumps. Measurements and Main Results: Genome-wide expression profiling of the lung transcriptome in a house dust mite-induced model of murine asthma identified increases in apo E mRNA levels that persisted despite corticosteroid treatment. House dust mite-challenged apo E 2/2 mice displayed enhanced airway hyperreactivity and goblet cell hyperplasia, which could be rescued by administration of an apo E(130-149) mimetic peptide. Administration of the apo E(130-149) mimetic peptide to house dust mite-challenged apo E 2/2 mice also inhibited eosinophilic airway inflammation, IgE production, and the expression of Th2 and Th17 cytokines. House dust mite-challenged low-density lipoprotein receptor (LDLR) knockout mice displayed a similar phenotype as apo E 2/2 mice with enhanced airway hyperreactivity, goblet cell hyperplasia, and mucin gene expression, but could not be rescued by the apo E(130-149) mimetic peptide, consistent with a LDLR-dependent mechanism. Conclusions: These findings for the first time identify an apo E-LDLR pathway as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma. Furthermore, our results demonstrate that strategies that activate the apo E-LDLR pathway, such as apo E mimetic peptides, might be developed into a novel treatment approach for patients with asthma.

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“…AP-1, a heterodimer of Fos and Jun proteins, is increased in PBMCs and bronchial biopsies of steroid-resistant compared to steroid-sensitive asthma, with no reduction in JNK activity or c-Jun after high doses of oral steroids [94].…”

Section: Mechanisms Of Corticosteroid Insensitivitymentioning

confidence: 97%

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Chung

Caramori

Adcock

2009

Eur J Clin Pharmacol

121

106

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International audienceInhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 μg daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 μg daily, and addition of the LABA formoterol to budesonide (800 μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV and the rate of exacerbations. A reduction in the rate of decline in FEV of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases

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Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes.

Cited by 135 publications

References 31 publications

Corticosteroid-insensitive asthma: molecular mechanisms

Corticosteroid-insensitive asthma: molecular mechanisms

Apolipoprotein E Negatively Regulates House Dust Mite–induced Asthma via a Low-Density Lipoprotein Receptor–mediated Pathway

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

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