Systemic inflammation in COPD visualised by gene profiling in peripheral blood neutrophils

Abstract

Background: The inflammatory process in chronic obstructive pulmonary disease (COPD) is characterised by the presence of neutrophils in the lung that are able to synthesise de novo several inflammatory mediators. The local chronic persistent inflammatory response is accompanied by systemic effects such as cytokine induced priming of peripheral leucocytes and muscle wasting. The preactivation or priming of peripheral blood neutrophils was used to gain more insight into the mechanisms of this systemic inflammatory response. Methods: Gene arrays were performed on peripheral blood neutrophils obtained from healthy donors after stimulation in vitro with tumour necrosis factor (TNF)-α, granulocyte-macrophage colony stimulating factor (GM-CSF), or both. The expression of many inflammatory genes was regulated in these cells following stimulation. The expression of inflammatory genes in peripheral blood neutrophils in healthy subjects and those with COPD was measured by real time RT-PCR after stimulation with TNFα, GM-CSF, interleukin (IL)-8, fMLP, TNFα + GM-CSF, and lipopolysaccharide (LPS). Results: The genes regulated in the gene array with TNFα/GM-CSF stimulated neutrophils included cytokines (such as IL-1β), chemokines (such as IL-8), and adhesion molecules (such as ICAM-1). Disease severity as measured by forced expiratory volume in 1 second (FEV1) in COPD patients correlated with expression of several of these genes including IL-1β (r = -0.540; p = 0.008), MIP-1β (r = -0.583; p = 0.003), CD83 (r = -0.514; p = 0.012), IL-1 receptor 2 (r = -0.546; p = 0.007), and IL-1 receptor antagonist (r = -0.612; p = 0.002). Conclusions: These data are consistent with the hypothesis that progression of COPD is associated with the activation of neutrophils in the systemic compartment. De novo expression of inflammatory mediators by peripheral blood neutrophils suggests a pro-inflammatory role for these cells in the pathogenesis of COPD.