Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients.
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.
Belperio
John A
JA
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI 48208, USA.
DiGiovine
Bruno
B
Keane
Michael P
MP
Burdick
Marie D
MD
Ying Xue
Ying
Y
Ross
David J
DJ
Lynch
Joseph P
JP
Kunkel
Steven L
SL
Strieter
Robert M
RM
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
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