Systemic inflammation in COPD visualised by gene profiling in peripheral blood neutrophils.
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)-alpha, 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 TNFalpha, GM-CSF, interleukin (IL)-8, fMLP, TNFalpha + GM-CSF, and lipopolysaccharide (LPS).


RESULTS
The genes regulated in the gene array with TNFalpha/GM-CSF stimulated neutrophils included cytokines (such as IL-1beta), chemokines (such as IL-8), and adhesion molecules (such as ICAM-1). Disease severity as measured by forced expiratory volume in 1 second (FEV(1)) in COPD patients correlated with expression of several of these genes including IL-1beta (r = -0.540; p = 0.008), MIP-1beta (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.
Department of Pulmonary Diseases, Heart Lung Center Utrecht, University Medical Centre, Utrecht, The Netherlands.
E-J D
EJ
Oudijk
E H J
EH
Nijhuis
M D
MD
Zwank
E A
EA
van de Graaf
H J
HJ
Mager
P J
PJ
Coffer
J-W J
JW
Lammers
L
L
Koenderman
D016207:Cytokines / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D014797:Vital Capacity / Q000502:physiology
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor