title: Heterogeneity of chronic lung allograft dysfunction: insights from protein expression in broncho alveolar lavage.
abstract: BACKGROUND
  Chronic lung allograft dysfunction (CLAD) remains a major risk factor for death after lung transplantation. Previous data suggested that within CLAD at least 2 phenotypes are present: a neutrophilic type (nCLAD or neutrophilic reversible allograft dysfunction [NRAD]), reversible with azithromycin therapy, vs a low neutrophilic type, non-responsive to azithromycin (fibrotic bronchiolitis obliterans syndrome [fBOS]). We aimed to further characterize this dichotomy by measuring multiple proteins in the bronchoalveolar lavage (BAL) fluid of 28 lung recipients.
  
  
  METHODS
  Patients were retrospectively subdivided by the absence or presence of CLAD and subsequently by their response to azithromycin, resulting in 3 groups: 10 stable, 9 responsive (nCLAD/NRAD), and 9 non-responsive (fBOS). Enzyme-linked immunosorbent assay was used to measure 32 different proteins.
  
  
  RESULTS
  Protein variations were predominantly present in the nCLAD/NRAD group, whereas no differences were observed in the fBOS group compared with control. MCP-1 (p < 0.01), RANTES (p < 0.05), IL-1β (p < 0.01), IL-8 (p < 0.01), TIMP-1 (p < 0.01), MMP-8 (p < 0.01), MMP-9 (p < 0.01), HGF (p < 0.001), MPO (p < 0.01), and bile acid (p < 0.05) concentrations were upregulated in nCLAD/NRAD compared with fBOS, whereas PDGF-AA (p < 0.05) was downregulated.
  
  
  CONCLUSIONS
  These data provide further evidence that within CLAD there is a heterogeneity of phenotypes with different mechanisms involved. Further investigation is warranted to unravel the pathophysiology of both phenotypes.
authors.affiliation: Laboratory of Pneumology, Katholieke Universiteit Leuven and University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Stijn E
authors.initials: SE
authors.lastname: Verleden
authors.forename: Robin
authors.initials: R
authors.lastname: Vos
authors.forename: Veerle
authors.initials: V
authors.lastname: Mertens
authors.forename: Anna
authors.initials: A
authors.lastname: Willems-Widyastuti
authors.forename: Stéphanie I
authors.initials: SI
authors.lastname: De Vleeschauwer
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Dupont
authors.forename: Geert M
authors.initials: GM
authors.lastname: Verleden
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Van Raemdonck
authors.forename: Bart M
authors.initials: BM
authors.lastname: Vanaudenaerde
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D017963:Azithromycin / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000188:drug therapy / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D055031:Primary Graft Dysfunction / Q000188:drug therapy / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D012307:Risk Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; C111835:CCL2 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; C066855:HGF protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D011506:Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D017228:Hepatocyte Growth Factor; D017963:Azithromycin; D009195:Peroxidase; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9