Gene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo-controlled clinical trial.

Joanna C Betts, Ruth J Mayer, Ruth Tal-Singer, Linda Warnock, Chris Clayton, Stewart Bates, Bryan E Hoffman, Christopher Larminie, Dave Singh

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway responds to a variety of extracellular stimuli, including cytokines, Toll-like receptor agonists, and components of cigarette smoke to influence the expression of proinflammatory mediators. Activation of p38 MAPK is increased within the lungs of chronic obstructive pulmonary disease (COPD) patients. In clinical trials, treatment of COPD patients with p38 MAPK inhibitors has been shown to reduce systemic inflammation plasma biomarkers C-reactive protein (CRP) and fibrinogen. As CRP and fibrinogen have been associated with poor clinical outcomes in COPD patients, such as mortality, exacerbation, and hospitalization, we analyzed gene expression data from COPD subjects treated with dilmapimod with the aim of understanding the effects of p38 MAPK inhibition on the inflammatory genome of immune cells within the systemic circulation. Whole blood and induced sputum samples were used to measure mRNA levels by gene array and PCR. Pathway and network analysis showed STAT1, MMP-9, CAV1, and IL-1β as genes regulated by dilmapimod that could also influence fibrinogen levels, while only IL-1β was identified as a gene regulated by dilmapimod that could influence CRP levels. This suggests that p38 MAPK inhibits specific inflammatory pathways, leading to to differential effects on CRP and fibrinogen levels in COPD patients.
    Original languageEnglish
    JournalPharmacology research & perspectives
    Volume3
    Issue number1
    DOIs
    Publication statusPublished - Feb 2015

    Keywords

    • C-reactive protein
    • P38 mitogen activated protein kinase
    • dilmapimod
    • gene expression

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