title: Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients.
abstract: BACKGROUND
  The major limitation to survival after lung transplantation is bronchiolitis obliterative syndrome (BOS). BOS is a chronic inflammatory/immunologic process characterized by fibroproliferation, matrix deposition, and obliteration of the airways. The mechanism(s) that lead to fibro-obliteration of allograft airways have not been fully elucidated. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of the pro-inflammatory cytokine IL-1 and has been associated with a number of fibroproliferative diseases.
  
  
  METHODS
  We determined whether IL-1Ra, as compared to IL-1beta, IL-10, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha, in the bronchoalveolar lavage fluid (BALF) from lung transplant recipients was associated with BOS. BALF was collected from three groups of patients: BOS (n=22), acute rejection (n=33), and healthy transplant recipients (n=30).
  
  
  RESULTS
  IL-1Ra levels were significantly elevated in patients with BOS compared to healthy lung transplant recipients and patients with acute rejection (P<0.001 and P<0.05, respectively). Furthermore, when patients with BOS had their BALF analyzed from their last bronchoscopy before the development of BOS (Future BOS [FBOS] group) (n=20), their levels of IL-1Ra were also significantly elevated compared to healthy lung transplant recipients and patients with acute rejection (P<0.001 and P<0.05, respectively). Importantly, the elevated levels of IL-1Ra in the BOS and FBOS groups were not accompanied by any significant increases in IL-1beta, IL-10, TGF-beta, or TNF-alpha.
  
  
  CONCLUSIONS
  These findings suggest that elevated levels of IL-1Ra may be attenuating IL-1 bioactivity during the pathogenesis of BOS and creating a local environment that favors fibroproliferation and matrix deposition.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI 48208, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
authors.forename: Bruno
authors.initials: B
authors.lastname: DiGiovine
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keane
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.forename: Ying
authors.initials: Y
authors.lastname: Ying Xue
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D000208:Acute Disease; D000890:Anti-Infective Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D001989:Bronchiolitis Obliterans / Q000175:diagnosis* / Q000453:epidemiology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000032:analysis; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood; D007958:Leukocyte Count; D016040:Lung Transplantation / Q000502:physiology*; D011183:Postoperative Complications / Q000175:diagnosis / Q000453:epidemiology; D012016:Reference Values; D012795:Sialoglycoproteins / Q000032:analysis*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000890:Anti-Infective Agents; D015415:Biomarkers; D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha