Nisha Kurian,1 Taylor S Cohen,2 Lisa berg,3 Erica De Zan,3 Gabriel Skogberg,4 Stefan Vollmer,3 Engin Baturcam,3 Petter Svanberg,5 Britta Bonn,5 Paul D Smith,6 Outi Vaarala,3 Danen M Cunoosamy3
1Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, Sweden; 2Microbial Sciences, Medimmune, Gaithersburg, MD, USA; 3Translational Science and Experimental Medicine, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 4Bioscience, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 5Drug Metabolism and Pharmacokinetics, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
Correspondence: Nisha KurianRespiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, SwedenTel +46 72 197 9662Email Nisha.e.kurian@astrazeneca.com
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
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Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host | COPD - Dove Medical Press
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