Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Bhavsar, Pankaj; Khorasani, Nadia; Hew, Mark; Johnson, M. Brittany; Chung, Kian Fan

doi:10.1183/09031936.00071309

Cited by 103 publications

(81 citation statements)

References 33 publications

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“…Inhibition of PI3K/p38 lowers tobacco/CS-induced lung inflammatory response (34). Interestingly, PI3K inhibition significantly increased the steroid efficacy to inhibit an inflammatory response under oxidative stress (14,82,151). Therefore, in addition to p38 MAPK and PKCf, oxidants/CSmediated activation of the PI3K signaling pathway may be a target for intervention in COPD.…”

Section: Oxidative Stress and Kinases Signaling In Chromatin Remodelingmentioning

confidence: 99%

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Sundar

Yao

Rahman

2013

Antioxidants & Redox Signaling

162

107

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Significance: Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance. Recent Advances: Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/ demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress. Critical Issues: Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress. Future Directions: Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.

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Section: Oxidative Stress and Kinases Signaling In Chromatin Remodelingmentioning

confidence: 99%

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Sundar

Yao

Rahman

2013

Antioxidants & Redox Signaling

162

107

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“…Inhibitors of protein kinases involved in cellular signalling of pro-inflammatory cytokines implicated in the pathogenesis of asthma may have a role in the treatment of severe asthma [61][62][63][64][65] . Several p38 mitogen-activated protein kinase (MAPK) inhibitors restore corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and alveolar macrophages from patients with severe asthma 63,66 .…”

Section: Protein Kinase Inhibitorsmentioning

confidence: 99%

“…Several p38 mitogen-activated protein kinase (MAPK) inhibitors restore corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and alveolar macrophages from patients with severe asthma 63,66 . A phase II trial is registered as investigating the efficacy and safety of the inhaled p38MAPK inhibitor AZD7624 in corticosteroid resistant asthma (ClinicalTrials.gov Identifier: NCT02753764) 33 .…”

Section: Protein Kinase Inhibitorsmentioning

confidence: 99%

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

Thomson

2017

Expert Opinion on Pharmacotherapy

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IntroductionInhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma. Areas coveredNew and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA.Data was reviewed from studies published up until November 2016. Expert opinionTiotropium improves lung function and has a modest effect in reducing exacerbations when

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“…Novel analogues of macrolides have been developed that have greater anti-inflammatory effects than current macrolides, such as solithromycin (CEM-101) [115,116] or that lack anti-bacterial properties but retain anti-inflammatory activity, such as the non-antibiotic azithromycin derivative CSY0073 [120]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Protein kinase inhibitors Inhibition of protein kinase, such as p38MAPK, narrow spectrum kinase and tyrosine kinase, that are involved in cellular signaling of pro-inflammatory cytokines, may have a role in the treatment of severe asthma associated with corticosteroid insensitivity [121][122][123]. Several p38MAPK inhibitors restore corticosteroid sensitivity in PBMCs from patients with severe asthma [121,124] and COPD [125].…”

Section: Macrolidesmentioning

confidence: 99%

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Protein kinase inhibitors Inhibition of protein kinase, such as p38MAPK, narrow spectrum kinase and tyrosine kinase, that are involved in cellular signaling of pro-inflammatory cytokines, may have a role in the treatment of severe asthma associated with corticosteroid insensitivity [121][122][123]. Several p38MAPK inhibitors restore corticosteroid sensitivity in PBMCs from patients with severe asthma [121,124] and COPD [125]. Clinical trials of p38MAPK inhibitors, such as oral losmapimod (GW856553) and inhaled AZD7624 are underway in COPD, although none are registered in asthma.…”

Section: Macrolidesmentioning

confidence: 99%

Addressing corticosteroid insensitivity in adults with asthma

Thomson

2016

Expert Review of Respiratory Medicine

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Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one third of patients showing evidence of insensitivity to corticosteroids. This article summarizes information on genetic, environmental and asthma-related factors as well as demographic and pharmacokinetic variables associated with corticosteroid insensitivity in asthma. Molecular mechanisms proposed to explain corticosteroid insensitivity are reviewed including alterations in glucocorticoid receptor subtype, binding and nuclear translocation, increased proinflammatory transcription factors and defective histone acetylation. Current therapies and future interventions that may restore corticosteroid sensitivity in asthma are discussed, including small molecule drugs and biological agents. In the future, biomarkers may be used in the clinic to predict corticosteroid sensitivity in patients with poorly controlled asthma. Word count: 120 wordsKey words: Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroids; corticosteroid insensitivity; corticosteroid resistance; small molecule drugs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionAsthma is a chronic inflammatory disease of the airways that affects 300 million people worldwide. Both national and international guidelines recommend daily inhaled corticosteroid as the preferred controller treatment for adults and adolescents with asthma who have poor symptom control or who at risk of exacerbations [201, 202]. Inhaled corticosteroid use in asthma reduces symptoms, improves quality of life and increases lung function as well as decreases the rate of exacerbations [201, 202]. The majority of the therapeutic benefits of inhaled corticosteroids are achieved at low to medium doses [1], although higher doses are often required in patients with more severe asthma [2] [202]. Short courses of oral corticosteroids are administered to treat severe exacerbations and daily oral corticosteroids are used in the lowest dose providing adequate control to treat patients with severe asthma when symptoms are uncontrolled despite maximal therapy [201, 202].Guideline recommendations for inhaled and oral corticosteroid use in asthma are based on average therapeutic responses from clinical trial populations that may not be representative of 'real-life' patients [3]. Numerous studies in adults and children with asthma have noted a considerable patient-to-patient variability in improvements in lung function and airway hyperreactivity with inhaled and oral corticosteroid treatment in patients with apparently similar levels of disease severity [4][5][6] (Figure 1). The findings from these studies suggest that corticosteroid insensitivity may be present in approximately one third of patients with asthma.Inhaled corticosteroids exhib...

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Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Cited by 103 publications

References 33 publications

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

Addressing corticosteroid insensitivity in adults with asthma

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