Sputum Cytokine Profiling in COPD: Comparison Between Stable Disease and Exacerbation

Imre Barta,1,* Csilla Paska,1,* Balazs Antus1,2 1Department of Pathophysiology, National Koranyi Institute of Pulmonology, Budapest, Hungary; 2Department of Pulmonology, National Koranyi Institute of Pulmonology, Budapest, Hungary*These authors contributed equally to this workCorrespondence: Balazs Antus, Department of Pathophysiology, National Koranyi Institute of Pulmonology, Koranyi Frigyes ut 1, Tel +36 1 391 3309, Fax +36 1 200 7060, Email antusb@hotmail.comPurpose: Cytokines are extracellular signaling proteins that have been widely implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we investigated cytokine expression both at the mRNA and protein level in the sputum of healthy individuals, stable COPD patients, and those experiencing a severe acute exacerbation (AECOPD) requiring hospitalization.Patients and Methods: Sputum was collected in 19 healthy controls, 25 clinically stable COPD patients, and 31 patients with AECOPD. In AECOPD patients sample collection was performed both at the time of hospital admission and at discharge following treatment. Sputum supernatant was analyzed by an antibody microarray detecting 120 cytokines simultaneously, while the mRNA expression of 14 selected cytokines in sputum cells was investigated by real-time PCR (qPCR).Results: Proteomic analysis identified interleukin (IL)-6 and growth-regulated oncogene (GRO)α as the only sputum cytokines that were differentially expressed between stable COPD patients and healthy controls. At the onset of AECOPD, several cytokines exhibited altered sputum expression compared to stable COPD. Recovery from AECOPD induced significant changes in the sputum cytokine protein profile; however, the length of hospitalization was insufficient for most cytokines to return to stable levels. With regard to gene expression analysis by qPCR, we found that bone morphogenetic protein (BMP)-4 was up-regulated, while IL-1α, monokine-induced by interferon-γ (MIG), and BMP-6 were down-regulated at the mRNA level in patients with AECOPD compared to stable disease.Conclusion: The sputum cytokine signature of AECOPD differs from that of stable COPD. Protein level changes are asynchronous with changes in gene expression at the mRNA level in AECOPD. The observation that the levels of most cytokines do not stabilize with acute treatment of AECOPD suggests a prolonged effect of exacerbation on the status of COPD patients.Keywords: airway, biomarker, gene, inflammation, microarray, PCR