Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen‐activated protein kinase (<scp>MAPK</scp>) inhibitor

Lea, Simon; Harbron, Chris; Khan, Noor; Booth, George H.; Armstrong, Jane; Singh, Dave

doi:10.1111/bcp.12536

Cited by 25 publications

(26 citation statements)

References 27 publications

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“…Ratcliffe and Dougall reported similar findings with COPD lung macrophages; there was a subset of patients with a reduced response to corticosteroids [ 28 ]. Similarly, corticosteroids have heterogeneous effects on alveolar macrophage cytokine production in patients with asthma [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

The effects of corticosteroids on COPD lung macrophages: a pooled analysis

et al. 2015

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BackgroundThere is large variation in the therapeutic response to inhaled corticosteroids (ICS) in COPD patients. We present a pooled analysis of our previous studies investigating the effects of corticosteroids on lung macrophages, in order to robustly determine whether corticosteroid sensitivity in COPD cells is reduced compared to controls, and also to evaluate the degree of between individual variation in drug response.MethodsData from 20 never smokers (NS), 27 smokers (S) and 45 COPD patients was used. Lung macropahges had been stimulated with lipopolysaccharide (LPS), with or without the corticosteroid dexamethasone, and tumour necrosis factor (TNF)-α, interleukin (IL)-6 and chemokine C-X-C motif ligand (CXCL) 8 production was measured.ResultsThere was no difference in the anti-inflammatory effects of corticosteroids when comparing group mean data of COPD patients versus controls. The inhibition of TNF-α and IL-6 was greater than CXCL8. The effects of corticosteroids varied considerably between subjects, particularly at lower corticosteroid concentrations.ConclusionsWe confirm that overall corticosteroid sensitivity in COPD lung macrophages is not reduced compared to controls. The varied effect of corticosteroids between subjects suggests that some individuals have an inherently poor corticosteroid response. The limited suppression of lung macrophage derived CXCL8 may promote neutrophilic inflammation in COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0260-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The effects of corticosteroids on COPD lung macrophages: a pooled analysis

et al. 2015

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“…The combination studies with dexamethasone showed synergistic anti-inflammatory effects on cytokine production in poly I:C-stimulated epithelial cells. Birb796 has anti-inflammatory synergistic effects with dexamethasone in LPS-stimulated COPD macrophages [7], and p38 MAPK inhibition can reverse corticosteroid insensitivity in cellular models and cells from asthma patients [22][23][24]. P38 MAPK phosphorylates the glucocorticoid receptor (GR) [25].…”

Section: Cellular Modelsmentioning

confidence: 99%

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation

Charron¹,

Russell²,

Ito³

et al. 2017

Eur Respir J

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Novel anti-inflammatory approaches targeting chronically activated kinase pathways in chronic obstructive pulmonary disease (COPD) are needed. We evaluated RV568, a p38 mitogen-activated protein kinase-α and -γ and SRC family kinase inhibitor, in cellular and models relevant to COPD and examined its safety and efficacy in COPD patients.The anti-inflammatory activities of RV568 were tested in primary cultured monocytes, macrophages and bronchial epithelial cells and in lipopolysaccharide and cigarette smoke-exposed murine models. RV568 was evaluated in a 14-day trial in COPD patients.RV568 showed potent anti-inflammatory effects in monocytes and macrophages, which were often greater than those of corticosteroids or the p38 inhibitor Birb796. RV568 combined with corticosteroid had anti-inflammatory effects suggestive of a synergistic interaction in poly I:C-stimulated BEAS-2B cells and in the cigarette smoke model. In COPD patients, inhaled RV568 (50 µg and 100 µg) improved pre-bronchodilator forced expiratory volume in 1 s (69 mL and 48 mL respectively) and significantly reduced sputum malondialdehyde (p<0.05) compared to placebo, although there were no changes in sputum cell counts. Adverse events during RV568 and placebo treatment were similar.RV568 shows potent anti-inflammatory effects on cell and animal models relevant to COPD. RV568 was well-tolerated and demonstrated a modest clinical benefit in a 14-day COPD clinical trial.

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“…Despite the demonstrable benefit of inhaled glucocorticoids (GCs) for improving asthma symptoms and lung function in patients with asthma, referred to as steroid-sensitive (SS) asthma, it is estimated that ≤5% of asthma cases are relatively insensitive to steroid therapy (1). Aside from Th17-induced airway inflammation, it is apparent that activation of monocytes and macrophages is associated with steroid-resistant (SR) asthma (2,3). Macrophage-induced airway inflammation in mice is associated with SR airway inflammation and airway hyperresponsiveness (AHR) (4).…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that p38 MAPK pathway activation in peripheral blood mononuclear cells (PBMCs) is significantly increased in patients with SR asthma compared with patients with SS asthma (8). In addition, previous studies showed that inhibition of p38 MAPK pathway activation using vitamin D or p-p38 MAPK inhibitor significantly enhanced dexamethasone (DEX)-induced inhibition of cellular responsiveness to GCs in patients with SR asthma (3,12,13). Therefore, targeting the GRE-based signaling pathway may be a novel therapeutic strategy for SR asthma.…”

Section: Introductionmentioning

confidence: 99%

Interleukin‑35 sensitizes monocytes from patients with asthma to glucocorticoid therapy by regulating p38 MAPK

Qian

Xue

et al. 2020

Exp Ther Med

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The activation of monocytes and macrophages is associated with steroid-resistant (SR) asthma. Interleukin-35 (IL-35) is an important anti-inflammatory cytokine, but its regulatory effects on monocytes in patients with SR asthma is not fully understood. Based on clinical response to oral prednisolone, 34 patients with steroid-sensitive (SS) asthma and 20 patients with SR asthma were enrolled in the present study. Serum IL-35 levels were analyzed using the Luminex 200 platform. Monocytes from patients with asthma were pretreated with IL-35 followed by dexamethasone (DEX) and lipopolysaccharide (LPS), then corticosteroid sensitivity was evaluated according to the half-maximal inhibitory concentration of DEX with respect to LPS-induced IL-6 maximal production in monocytes (DEX-IC 50). The percentage of maximal inhibition of IL-6 by DEX was presented as E max. Phosphorylated-P38 mitogen activated kinase (p-p38 MAPK) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were examined by flow cytometry and reverse transcription-quantitative PCR analysis, respectively. Glucocorticoid receptor (GR) binding to the glucocorticoid response element (GRE) was assessed by chromatin immunoprecipitation. Compared with patients with SS asthma, patients with SR asthma had lower IL-35 expression levels (P<0.05). Correlation analysis results demonstrated that the expression levels of IL-35 showed a weak negative correlation with log DEX-IC 50 (r=-0.351; P<0.01) and a moderate positive correlation with E max value (r=0.4501; P<0.01) in all patients with asthma. Moreover, IL-35 enhanced DEX-suppressed IL-6 production and the DEX-induced upregulation of the MKP-1 mRNA expression level in monocytes from both patient groups (P<0.01). In addition, IL-35 inhibited p-p38 MAPK expression in monocytes, and these effects were mediated via an increase in DEX-induced GR binding to GRE. Therefore, IL-35 may be involved in the corticosteroid enhancing effects in monocytes of patients with SR and SS asthma, suggesting potential benefits of IL-35 supplementation in asthmatics with DEX.

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Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen‐activated protein kinase (MAPK) inhibitor

Cited by 25 publications

References 27 publications

The effects of corticosteroids on COPD lung macrophages: a pooled analysis

The effects of corticosteroids on COPD lung macrophages: a pooled analysis

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation

Interleukin‑35 sensitizes monocytes from patients with asthma to glucocorticoid therapy by regulating p38 MAPK

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