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.

Keywords:

• exacerbation
• infection
• alveolar macrophage
• p38 MAPK
• steroid
• transcriptomics
• sputum

Acknowledgments

We thank the Transplant Institute and Department of Cardiothoracic Surgery in the Sahlgrenska University Hospital for excellent collaboration on tissue acquisition led by Dr Göran Dellgren. A special gratitude to Linda Thimour-Bergström for her great contribution to the smooth logistics which made this work possible. We thank the patients that took part in the study without which this work would not have been possible.

Author Contributions

Conceptualization and study design: NK, TSC, PDS, BB, OV, DMC. Data acquisition and interpretation: NK, TSC, LÖ, EDZ, GS, PS, EB, SV, DMC. Drafting and review of manuscript: NK, TSC, GS, LÖ, EDZ, EB, PS, SV, PDS, BB, OV, DMC. All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

All authors (NK, LÖ, EDZ, GS,  SV,  EB, PS, BB, PDS, OV, and DMC) were full-time employees of the commercial company AstraZeneca and its subsidiary Medimmune (TSC). The Authors report no other conflicts of interest in this work.