Systemic steroids in COPD-the beauty and the beast

Vogelmeier, Claus

doi:10.1186/1465-9921-15-38

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…A reduction in adverse side effects of GCS, for example, may be achieved by reducing GCS dose due to the additive anti-inflammatory effects of the other agents. 30 SIRT1/GCR deficient lymphocytes enumerated using our ex vivo assays may identify COPD patients that may benefit from these drug combinations and post-therapy lymphocyte phenotyping could identify therapeutic effectiveness. The very recent finding that reduced levels of SIRT1 destabilize the expression and function of transcription factor FoxO1 to enhance the pro-inflammatory and cytotoxic capacity of CD28nullCD8+ T cells, thereby contributing to immune dysfunctions of this cell type, may explain its pathophysiological role in age-related chronic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes

Hodge

Tran

Reynolds

et al. 2020

Ther Adv Respir Dis

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Background: The class III NAD-dependent histone deacetylase (HDAC) sirtuin 1 (SIRT1) is an important regulator of senescence, aging, and inflammation. SIRT1de-acetylates chromatin histones, thereby silencing inflammatory gene transcription. We have reported increased steroid-resistant senescent pro-inflammatory CD28nullCD8+ T cells in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that SIRT1 is reduced in these cells in COPD, and that treatment with SIRT1 activators (resveratrol, curcumin) and agents preventing NAD depletion (theophylline) would upregulate SIRT1 and reduce pro-inflammatory cytokine expression in these steroid-resistant cells. Methods: Blood was collected from n = 10 COPD and n = 10 aged-matched controls. Expression of CD28, SIRT1, and pro-inflammatory cytokines was determined in CD8+ and CD8– T and natural killer T (NKT)-like cells cultured in the presence of ±1 µM prednisolone, ±5 mg/L theophylline, ±1 µM curcumin, ±25 µM resveratrol, using flow cytometry and immunofluorescence. Results: There was an increase in the percentage of CD28nullCD8+ T and NKT-like cells in COPD patients compared with controls. Decreased SIRT1 expression was identified in CD28nullCD8+T and NKT-like cells compared with CD28+ counterparts from both patients and controls (e.g. CD28null 11 ± 3% versus CD28+ 57 ± 9%). Loss of SIRT1 was associated with increased production of IFNγ and TNFα, steroid resistance, and disease severity. SIRT1 expression was upregulated in the presence of all drugs and was associated with a decrease in steroid resistance and IFNγ and TNFα production by CD28nullCD8+T and NKT-like cells. The presence of the SIRT1 inhibitor, EX-527 negated [by 92 ± 12% (median ± SEM)] the effect of the SIRT1 activator SRT720 on the percentage of CD8+ T cells producing IFNγ and TNFα. Conclusions: Steroid resistance in pro-inflammatory CD28nullCD8+ T and NKT-like cells is associated with decreased SIRT1 expression. Treatment with prednisolone, in combination with theophylline, curcumin or resveratrol increases SIRT1 expression, restores steroid sensitivity, and inhibits pro-inflammatory cytokine production from these cells and may reduce systemic inflammation in COPD. The reviews of this paper are available via the supplemental material section.

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Section: Discussionmentioning

confidence: 99%

Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes

Hodge

Tran

Reynolds

et al. 2020

Ther Adv Respir Dis

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“…A previous study showed treatment with low dose theophylline upregulated total HDAC in peripheral blood monocytes and increased FEV1% predicted when combined with inhaled fluticasone propionate in patients with COPD compared with theophylline alone [ 28 ] consistent with our current findings where theophylline alone had no effect on HDAC2 but combined with prednisolone and/or very low dose cyclosporine A resulted in synergistic upregulation of HDAC2 and subsequent sensitivity to prednisolone. Furthermore, our results indicate treatment with low dose CsA with theophylline alone may increase HDAC2 and reduce inflammation and help overcome the reported adverse effects of steroids in COPD [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes

et al. 2015

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BackgroundHistone acetyltransferases (HAT) and histone deacetylases (HDAC) are enzymes that upregulate and down-regulate pro-inflammatory gene transcription respectively. HDAC2 is required by corticosteroids to switch off activated inflammatory genes and is reduced in lung macrophages in COPD. We have shown that COPD patients have increased steroid resistant CD28null (senescent) pro-inflammatory T and NKT-like peripheral blood cells (particularly CD8+ subsets) and we hypothesized that these changes would be associated with a loss of HDAC2 from these senescent pro-inflammatory lymphocytes.MethodsBlood was collected from 10 COPD and 10 aged-matched controls. Intracellular pro-inflammatory cytokines, IFNγ and TNFα, and expression of CD28, HDAC2 and HAT, were determined in lymphocyte subsets in the presence of ± 5 mg/ml theophylline (HDAC2 activator), 10 μM prednisolone and 2.5 ng/ml cyclosporine A (immunosuppressant), using flow cytometry.ResultsThere was a loss of HDAC2 from CD28null CD8+ T and NKT-like cells in COPD. There was a significant negative correlation between HDAC2 expression and the percentage of CD28null CD8+ T and NKT-like cells producing IFNγ or TNFα in all subjects (eg, COPD: R = −.763, p < 0.001 for T-cell IFNγ). There was a synergistic upregulation of HDAC2 and associated decrease in pro-inflammatory cytokine production in CD28nullCD8+ T and NKT-like cells in the presence of 5 mg/L theophylline + 10−6 M prednisolone or 2.5 ng/mL cyclosporine A (CsA).ConclusionsLymphocyte senescence in COPD is associated with loss of HDAC2 in CD28nullCD8+ T and NKT-like cells. Alternative treatment options such as combined theophylline with low-dose CsA, that inhibit these pro-inflammatory cells, may reduce systemic inflammation in COPD.

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“…При этом, возможно, увеличение дозы или частоты введения ИГКС обеспечит повышение их эффективности. При этом нельзя не учитывать, что повторные курсы СГКС, которые требуются больным с частыми обострениями, создают дополнительный риск, особенно для пациентов с сопутствующей патологией, так как чреваты побочными действиями, зависящими от кумулятивной дозы [18][19][20]. В отличие от преднизолона НБ показал более благоприятный профиль безопасности, в частности по влиянию на углеводный обмен, что согласуется с результатами других авторов [15,21].…”

Section: Discussionunclassified

Nebulized budesonide in the treatment of exacerbations of chronic obstructive pulmonary disease: Efficacy, safety, and effects on the serum levels of soluble differentiation molecules

Makarova

et al. 2016

Ter. arkh.

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Systemic steroids in COPD-the beauty and the beast

Cited by 6 publications

References 16 publications

Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes

Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes

Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes

Nebulized budesonide in the treatment of exacerbations of chronic obstructive pulmonary disease: Efficacy, safety, and effects on the serum levels of soluble differentiation molecules

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