Sputum biomarkers in IPF: Evidence for raised gene expression and protein level of IGFBP-2, IL-8 and MMP-7.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a rare lung disease of unknown origin leading rapidly to death. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in IPF compared to COPD, a fibrosing airway wall disease.


METHODS
In a cross-sectional analysis, 15 IPF patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- β, IGF-1, IGF-2, IGFBP-1, IGFBP-2, IGFBP-3, IL-8, IL-13, MMP-7, MMP-9, YKL-40, TNF-α and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-β, MMP-7, YKL-40, IGFBP-2, IL-6, IL-8 and TNF-α.


RESULTS
IPF patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. IPF sputum supernatants had increased concentrations of IGFBP-2, IL-8, TGF-β, MMP-7, MMP-9 and KL-6 (p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively) when compared to healthy subjects where COPD had higher IL-6 and TNF-α levels than IPF (p<0.05 and p<0.05 respectively) and HS (p<0.0001 and p<0.001 respectively) and higher IL-8 and MMP-9 than HS (p<0.0001 and p<0.001 respectively). Conversely to IL-6 and TNF-α, MMP-7 was increased in IPF compared to COPD (p<0.05). The KL-6 and MMP-7 protein levels in sputum were inversely correlated with total lung capacity (TLC, % of predicted) in IPF patients (r = -0.73 and r = -0.53 respectively). Sputum gene expression analysis identified a significant increase for IGFBP-2, IL-6, IL-8 and MMP-7 in IPF compared to HS (p<0.05, p<0.01, p<0.05 and p<0.0001 respectively) and for IGFBP-2, YKL-40, IL-6, IL-8 and MMP-7 compared to COPD (p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively). Furthermore, gene expression of TGF-β was increased in IPF compared to COPD (p<0.001) but not to HS.


CONCLUSIONS
Our data show clear increase in expression and production of IGFBP-2, IL-8 and MMP-7 in sputum from patients with IPF that may contribute to the disease.
Pneumology Department, CHU Liège, Liège, Belgium, CHU Liège, Pneumology Department, Domaine universitaire du Sart-Tilman, Liège, Belgium.
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http://orcid.org/0000-0001-7800-1730
J
Guiot
Pneumology Department, CHU Liège, Liège, Belgium, CHU Liège, Pneumology Department, Domaine universitaire du Sart-Tilman, Liège, Belgium.
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M
Henket
Pneumology Department, CHU Liège, Liège, Belgium, CHU Liège, Pneumology Department, Domaine universitaire du Sart-Tilman, Liège, Belgium.
J L
JL
Corhay
Pneumology Department, CHU Liège, Liège, Belgium, CHU Liège, Pneumology Department, Domaine universitaire du Sart-Tilman, Liège, Belgium.
C
C
Moermans
Pneumology Department, CHU Liège, Liège, Belgium, CHU Liège, Pneumology Department, Domaine universitaire du Sart-Tilman, Liège, Belgium.
R
R
Louis
D015415:Biomarkers; D003430:Cross-Sectional Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D013183:Sputum / Q000166:cytology / Q000378:metabolism*
D015415:Biomarkers; D018971:Insulin-Like Growth Factor Binding Protein 2; D016209:Interleukin-8; D020783:Matrix Metalloproteinase 7