Heterogeneity of chronic lung allograft dysfunction: insights from protein expression in broncho alveolar lavage

J Heart Lung Transplant. 2011 Jun;30(6):667-73. doi: 10.1016/j.healun.2010.12.008. Epub 2011 Jan 26.

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.

MeSH terms

  • Adult
  • Anti-Bacterial Agents / therapeutic use
  • Azithromycin / therapeutic use
  • Bile Acids and Salts / metabolism
  • Bronchiolitis Obliterans / drug therapy
  • Bronchiolitis Obliterans / metabolism*
  • Bronchoalveolar Lavage Fluid / chemistry*
  • Chemokine CCL2 / metabolism
  • Chemokine CCL5 / metabolism
  • Female
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Interleukin-1beta / metabolism
  • Interleukin-8 / metabolism
  • Lung Transplantation* / adverse effects
  • Male
  • Matrix Metalloproteinase 8 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Middle Aged
  • Peroxidase / metabolism
  • Phenotype*
  • Primary Graft Dysfunction / drug therapy
  • Primary Graft Dysfunction / metabolism*
  • Proteins / metabolism*
  • Retrospective Studies
  • Risk Factors
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transplantation, Homologous
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Bile Acids and Salts
  • CCL2 protein, human
  • CCL5 protein, human
  • Chemokine CCL2
  • Chemokine CCL5
  • HGF protein, human
  • Interleukin-1beta
  • Interleukin-8
  • Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Hepatocyte Growth Factor
  • Azithromycin
  • Peroxidase
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9