title: A Sputum Proteomic Signature That Associates with Increased IL-1β Levels and Bacterial Exacerbations of COPD.
abstract: Activation of the interleukin-1β (IL-1β) signaling pathway has been implicated in COPD, but the proportion of COPD subjects whose disease is principally driven by activation of this pathway is poorly understood. In this study, we sought to differentiate an IL-1β-associated sputum signature from other inflammation-associated COPD phenotypes.
  
  
  
  Luminex-multiplex assays were used to study IL-1β-mediated signature proteins within airway epithelium, smooth muscle, and vascular endothelial cell cultures. The IL-1β-mediated signature was tested in a longitudinal study comprising of 35 paired stable-COPD and acute exacerbation (AECOPD) sputum samples. The presence of respiratory pathogens (H. influenzae, M. catarrhalis, S. pneumoniae, and P. aeruginosa) was evaluated by sputum cultures.
  
  
  
  Five proteins namely TNF-α, GCSF, IL-6, CD-40L, and MIP-1β were found to be IL-1β-regulated across all donors and cell types. All five of these IL-1β-mediated proteins were significantly increased (p < 0.05) in sputum corresponding to AECOPD events showing at least a twofold increase in IL-1β (IL-1β(+) events, 18 of 35 total events), relative to preceding stable-COPD state. Sputum IL-1β levels showed no significant association (p > 0.05, spearman) with known markers of other major COPD inflammation phenotypes. In addition, there was a significant association with bacterial presence in sputum culture with an odds ratio of 9 (95 % CI 1.56, 51.9) in IL-1β(+) events versus IL-1β(-) events.
  
  
  
  Our findings provide insights into potential markers of IL-1β-associated AECOPD, and reaffirm association between IL-1β pathway activation and airway bacterial infection in COPD. Taken together, our findings could help identify COPD patient subsets who may benefit from therapies targeting IL-1β pathway.
authors.affiliation: Translational Medicine - Respiratory, Inflammation, Autoimmunity, MedImmune LLC, One Medimmune Way, Gaithersburg, MD, 20878, USA. DameraG@medimmune.com.
authors.forename: Gautam
authors.initials: G
authors.lastname: Damera
authors.affiliation: Translational Medicine - Respiratory, Inflammation, Autoimmunity, MedImmune LLC, One Medimmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Tuyet-Hang
authors.initials: TH
authors.lastname: Pham
authors.affiliation: Nonclinical Statistics, MedImmune LLC, One Medimmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Translational Medicine - Respiratory, Inflammation, Autoimmunity, MedImmune LLC, One Medimmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Ward
authors.affiliation: Translational Medicine - Respiratory, Inflammation, Autoimmunity, MedImmune LLC, One Medimmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Newbold
authors.affiliation: Translational Medicine - Respiratory, Inflammation, Autoimmunity, MedImmune LLC, One Medimmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Koustubh
authors.initials: K
authors.lastname: Ranade
authors.affiliation: VA WNY Healthcare System and University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sethi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006193:Haemophilus influenzae / Q000302:isolation & purification; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D001936:Moraxella catarrhalis / Q000302:isolation & purification; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D020543:Proteome; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000382:microbiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D013183:Sputum / Q000378:metabolism* / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000302:isolation & purification; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054407:Chemokine CCL4; D053583:Interleukin-1beta; D015850:Interleukin-6; D020543:Proteome; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D023201:CD40 Ligand
keywords: Airway inflammation; COPD; IL-1β; Sputum biomarkers