Increased expression of nuclear factor- B in bronchial biopsies from smokers and patients with COPD

Stefano, Antonino Di; Caramori, Gaetano; Oates, Thomas W.; Capelli, A; Lusuardi, Mirco; Gnemmi, Isabella; Ioli, F.; Chung, Kian Fan; Donner, Claudio F.; Barnes, Peter J.; Adcock, Ian M.

doi:10.1183/09031936.02.00272002

Cited by 407 publications

(303 citation statements)

References 31 publications

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“…2d) Total STAT4 and phospho-(Y-693)STAT4 proteins were below the detection limits for Western blotting (data not shown). This was in contrast with data seen previously for other transcription factors, such as GATA3 [17] and nuclear factor-kB [18], and possibly reflects the enhanced sensitivity of immunohistochemistry compared with Western blotting. …”

Section: Double-staining Immunohistochemistry In the Bronchial Submucosacontrasting

confidence: 56%

STAT4 activation in smokers and patients with chronic obstructive pulmonary disease

Stefano¹,

Caramori²,

Capelli³

et al. 2004

European Respiratory Journal

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126

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Activation of the transcription factor signal transducer and activator of transcription (STAT)-4 is critical for the differentiation of T-helper 1 cells/type-1 cytotoxic T-cells and the production of interferon (IFN)-c.Expression of STAT4, phospho-STAT4, IFN-c and T-box expressed in T-cells (Tbet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)-derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59¡16% predicted), 14 smokers with normal lung function (FEV1 106¡12% pred) and 12 nonsmoking subjects (FEV1 111¡14% pred), was examined by immunohistochemistry and immunocytochemistry.In bronchial biopsies of COPD patients, the number of submucosal phospho- 6103 ). In all smokers who underwent lavage, phospho-STAT4z lymphocytes correlated with airflow obstruction and the number of IFNcz lymphocytes. T-bet expression was not altered in bronchial biopsies and BAL-derived lymphocytes between the three groups.In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T-helper 1 cell/type-1 cytotoxic T-cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.

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Section: Double-staining Immunohistochemistry In the Bronchial Submucosacontrasting

confidence: 56%

STAT4 activation in smokers and patients with chronic obstructive pulmonary disease

Stefano¹,

Caramori²,

Capelli³

et al. 2004

European Respiratory Journal

Self Cite

126

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“…These proinflammatory transcription factors are activated in all inflammatory diseases and play a critical role in amplifying and perpetuating the inflammatory process. Thus, NF-kB is activated in the airways of asthmatic patients and COPD patients [6,7]. More disease-specific proteins are more likely to be regulated by cell-specific transcription factors, such as nuclear factor of activated T-cells, which regulates certain cytokine genes in T-lymphocytes [8], or GATA-3, which regulates the differentiation and expression of type-2 T-helper cell cytokines in allergic diseases [9].…”

Section: The Molecular Basis Of Inflammationmentioning

confidence: 99%

Corticosteroid effects on cell signalling

Barnes¹

2006

European Respiratory Journal

354

233

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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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“…HDACs suppress the expression of proinflammatory genes not only by maintaining chromatin condensation but also by directly modifying pro-inflammatory transcription factors (such as NF-kB) 12 . Moreover, HDACs, and particularly HDAC2, seem to have important roles in the inflammatory responses associated with COPD 11,17,18 . Furthermore, because corticosteroids use HDAC2 to suppress the activity of NF-kB 11,12,19 , the inhibitory effect of CS on HDAC2 may be responsible for the reduced sensitivity of COPD patients to steroid treatment 11 .…”

mentioning

confidence: 99%

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

et al. 2013

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The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. We show that intratracheal administration or inhalation of mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Based on these results, we propose that mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.

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Increased expression of nuclear factor- B in bronchial biopsies from smokers and patients with COPD

Cited by 407 publications

References 31 publications

STAT4 activation in smokers and patients with chronic obstructive pulmonary disease

STAT4 activation in smokers and patients with chronic obstructive pulmonary disease

Corticosteroid effects on cell signalling

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

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