Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host Defense Mechanisms With Potential Therapeutic Application In COPD

Abstract

Background

Unlike p38 mitogen-activated protein Kinases (MAPK) that has been extensively studied in the context of lung-associated pathologies in COPD, the role of the dual-specificity mitogen-activated protein kinase kinase (MEK1/2) or its downstream signaling molecule extracellular signal-regulated kinases 1/2 (ERK1/2) in COPD is poorly understood.

Objectives

The aim of this study was to address whether MEK1/2 pathway activation is linked to COPD and that targeting this pathway can improve lung inflammation through decreased immune-mediated inflammatory responses without compromising bacterial clearance.

Methods

Association of MEK1/2 pathway activation to COPD was investigated by immunohistochemistry using lung tissue biopsies from COPD and healthy individuals and through analysis of sputum gene expression data from COPD patients. The anti-inflammatory effect of MEK1/2 inhibition was assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages. The effect of MEK1/2 inhibition on bacterial clearance was assessed using Staphylococcus aureus killing assays with RAW 264.7 macrophage cell line and human neutrophils.

Results

We report here MEK1/2 pathway activation demonstrated by increased pERK1/2 staining in bronchial epithelium and by the presence of MEK gene activation signature in sputum samples from COPD patients. Inhibition of MEK1/2 resulted in a superior anti-inflammatory effect in human alveolar macrophages in comparison to a p38 inhibitor. Furthermore, MEK1/2 inhibition led to an increase in bacterial killing in human neutrophils and RAW 264.7 cells that was not observed with the p38 inhibitor.

Conclusion

Our data demonstrate the activation of MEK1/2 pathway in COPD and highlight a dual function of MEK1/2 inhibition in improving host defense responses whilst also controlling inflammation.

Journal

Journal ID (nlm-ta): Int J Chron Obstruct Pulmon Dis

Journal ID (iso-abbrev): Int J Chron Obstruct Pulmon Dis

Journal ID (publisher-id): COPD

Journal ID (pmc): copd

Title: International Journal of Chronic Obstructive Pulmonary Disease

Publisher: Dove

ISSN (Print): 1176-9106

ISSN (Electronic): 1178-2005

Publication date (Electronic): 26 November 2019

Publication date Collection: 2019

Volume: 14

Pages: 2611-2624

Affiliations

[1 ]Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca , Gothenburg, Sweden

[2 ]Microbial Sciences, Medimmune , Gaithersburg, MD, USA

[3 ]Translational Science and Experimental Medicine, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca , Gothenburg, Sweden

[4 ]Bioscience, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca , Gothenburg, Sweden

[5 ]Drug Metabolism and Pharmacokinetics, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca , Gothenburg, Sweden

[6 ]Bioscience, Oncology R&D, AstraZeneca , Cambridge, UK

Author notes

Correspondence: Nisha Kurian Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca , Gothenburg, SwedenTel [phone] Email [e-mail]

Article

Publisher ID: 211619

DOI: 10.2147/COPD.S211619

PMC ID: 6885002

Copyright statement: © 2019 Kurian et al.

License:

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Page count

Figures: 5, Tables: 2, References: 61, Pages: 14

Funding

Funded by: AstraZeneca 10.13039/100004325

The study was funded solely by AstraZeneca.

Categories

Subject: Original Research