The presence of a matrix-derived neutrophil chemoattractant in bronchiolitis obliterans syndrome after lung transplantation.
Lung transplantation is a therapeutic modality frequently used in end-stage lung disease. Unfortunately, lung transplant recipients have poor clinical outcomes, often due to the development of bronchiolitis obliterans syndrome (BOS). This process is often characterized by the pathologic findings of obliterative bronchiolitis: neutrophil influx and extracellular matrix remodeling leading to luminal obstruction and airway inflammation. The molecular mechanisms underlying BOS are poorly understood and disease-specific biomarkers are lacking. We report that in addition to increased levels of IL-8, the level of the neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in BOS patient bronchoalveolar lavage (BAL) fluid. The enzymes responsible for generating PGP, matrix metalloproteases 8 and -9 and prolyl endopeptidase, are also elevated in these samples. Together, IL-8 and PGP account for most of the neutrophil chemoattractant capacity seen in BOS BAL fluid. Using specific neutralizing Abs to both IL-8 and PGP, we demonstrate that PGP is a prominent neutrophil chemoattractant found in BAL fluid from individuals at the time of diagnosis of BOS. These findings highlight the influence of a matrix-derived neutrophil chemoattractant in posttransplantation BOS and provide opportunities for the development of unique diagnostics and therapeutics to potentially improve disease outcomes.
Hardison
Matthew T
MT
Department of Physiology and Biophysics, University of Alabama at Birmingham, 35294, USA.
Galin
F Shawn
FS
Calderon
Christopher E
CE
Djekic
Uros V
UV
Parker
Suzanne B
SB
Wille
Keith M
KM
Jackson
Patricia L
PL
Oster
Robert A
RA
Young
K Randall
KR
Blalock
J Edwin
JE
Gaggar
Amit
A
D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D009842:Oligopeptides / Q000032:analysis* / Q000276:immunology / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000032:analysis / Q000276:immunology / Q000378:metabolism
D015415:Biomarkers; D016209:Interleukin-8; D009842:Oligopeptides; C113164:prolyl-glycyl-proline; D011392:Proline; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9