Cellular mechanisms underlying steroid-resistant asthma

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Abstract

Severe steroid-resistant asthma is clinically important, as patients with this form of the disease do not respond to mainstay corticosteroid therapies. The heterogeneity of this form of asthma and poor understanding of the pathological mechanisms involved hinder the identification of therapeutic targets and the development of more effective therapies. A major limiting factor in the understanding of severe steroid-resistant asthma is the existence of multiple endotypes represented by different immunological and inflammatory phenotypes, particularly in adults. Several clinical and experimental studies have revealed associations between specific respiratory infections and steroid-resistant asthma in adults. Here, we discuss recent findings from other authors as well as our own studies that have developed novel experimental models for interrogating the association between respiratory infections and severe steroid-resistant asthma. These models have enabled the identification of new therapies using macrolides, as well as several novel disease mechanisms, including the microRNA-21/phosphoinositide 3-kinase/histone deacetylase 2 axis and NLRP3 inflammasomes, and highlight the potential of these mechanisms as therapeutic targets.

Abstract

Severe steroid-resistant asthma is a significant clinical problem and recent advances in understanding the mechanisms of pathogenesis enable the identification of novel therapeutic approaches http://bit.ly/2mQpF3n

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The inflammasomes.

Kate Schroder, Jurg Tschopp (2010)

Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.

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A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

Rebecca Coll, Avril A B Robertson, Jae Jin Chae … (2015)

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

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Mepolizumab treatment in patients with severe eosinophilic asthma.

Hector G. Ortega, Mark C Liu, Ian Pavord … (2014)

Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

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Author and article information

Journal

Journal ID (nlm-ta): Eur Respir Rev

Journal ID (iso-abbrev): Eur Respir Rev

Journal ID (publisher-id): ERR

Journal ID (hwp): errev

Title: European Respiratory Review

Publisher: European Respiratory Society

ISSN (Print): 0905-9180

ISSN (Electronic): 1600-0617

Publication date Collection: 30 September 2019

Publication date (Electronic): 18 October 2019

Volume: 28

Issue: 153

Electronic Location Identifier: 190096

Affiliations

[1 ]Centre for Inflammation, Centenary Institute, Sydney, Australia

[2 ]Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia

[3 ]Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

[4 ]The Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK

[5 ]Faculty of Science, University of Technology Sydney, Sydney, Australia

[6 ]Both authors contributed equally

Author notes

Philip M. Hansbro, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia. E-mail: philip.hansbro@ 123456uts.edu.au

Article

Publisher ID: ERR-0096-2019

DOI: 10.1183/16000617.0096-2019

PMC ID: 9488801

PubMed ID: 31636089

SO-VID: 89a44bb8-e326-4021-8b5a-922bb7559e9d

License:

This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

History

Date received : 01 August 2019

Date accepted : 19 September 2019

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Cellular mechanisms underlying steroid-resistant asthma

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Most cited references 104

The inflammasomes.

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

Mepolizumab treatment in patients with severe eosinophilic asthma.

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