Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host Defense Mechanisms With Potential Therapeutic Application In COPD
| Autor: | Taylor S. Cohen, Lisa Öberg, Nisha Kurian, Erica De Zan, Britta Bonn, Petter Svanberg, Engin Baturcam, Gabriel Skogberg, Paul D. Smith, Outi Vaarala, Danen Cunoosamy, Stefan Vollmer |
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| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
business.industry Kinase MEK inhibitor p38 mitogen-activated protein kinases medicine.medical_treatment Inflammation General Medicine respiratory tract diseases 03 medical and health sciences 0302 clinical medicine Cytokine 030228 respiratory system medicine Cancer research Alveolar macrophage 030212 general & internal medicine medicine.symptom Protein kinase A business |
| Zdroj: | International Journal of Chronic Obstructive Pulmonary Disease. 14:2611-2624 |
| ISSN: | 1178-2005 |
| DOI: | 10.2147/copd.s211619 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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