title: 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.
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.
authors.affiliation: R&D, GlaxoSmithKline Stevenage, United Kingdom.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Betts
authors.affiliation: R&D, GlaxoSmithKline King of Prussia, Pennsylvania, USA.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Mayer
authors.affiliation: R&D, GlaxoSmithKline King of Prussia, Pennsylvania, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: R&D, GlaxoSmithKline Stevenage, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: Warnock
authors.affiliation: R&D, GlaxoSmithKline Stevenage, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Clayton
authors.affiliation: R&D, GlaxoSmithKline Stevenage, United Kingdom.
authors.forename: Stewart
authors.initials: S
authors.lastname: Bates
authors.affiliation: R&D, GlaxoSmithKline King of Prussia, Pennsylvania, USA.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Hoffman
authors.affiliation: R&D, GlaxoSmithKline Stevenage, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Larminie
authors.affiliation: University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundations Trust Manchester, United Kingdom.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
keywords: C-reactive protein; P38 mitogen activated protein kinase; dilmapimod; gene expression