title: Aspiration, localized pulmonary inflammation, and predictors of early-onset bronchiolitis obliterans syndrome after lung transplantation.
abstract: BACKGROUND
  We hypothesized that immune mediator concentrations in the bronchoalveolar fluid (BALF) are predictive of bronchiolitis obliterans syndrome (BOS) and demonstrate specific patterns of dysregulation, depending on the presence of acute cellular rejection, BOS, aspiration, and timing of lung transplantation.
  
  
  METHODS
  We prospectively collected 257 BALF samples from 105 lung transplant recipients. The BALF samples were assessed for absolute and differential white blood cell counts and 34 proteins implicated in pulmonary immunity, inflammation, fibrosis, and aspiration.
  
  
  RESULTS
  There were elevated BALF concentrations of interleukin (IL)-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-α, and myeloperoxidase, and reduced concentrations of α1-antitrypsin, which were predictive of early-onset BOS. Patients with BOS had an increased percentage of BALF lymphocytes and neutrophils, with a reduced percentage of macrophages (p < 0.05). The BALF concentrations of IL-1β; IL-8; interferon-γ-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; neutrophil elastase; and pepsin were higher in patients with BOS (p < 0.05). Among those with BOS, BALF concentrations of IL-1RA; IL-8; eotaxin; interferon-γ-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; myeloperoxidase; and neutrophil elastase were positively correlated with time since transplantation (p < 0.01). Those with worse grades of acute cellular rejection had an increased percentage of lymphocytes in their BALF (p < 0.0001) and reduced BALF concentrations of IL-1β, IL-7, IL-9, IL-12, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, and vascular endothelial growth factor (p ≤ 0.001). Patients with aspiration based on detectable pepsin had increased percentage of neutrophils (p < 0.001) and reduced BALF concentrations of IL-12 (p < 0.001).
  
  
  CONCLUSIONS
  The BALF levels of IL-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-α, myeloperoxidase, and α1-antitrypsin at 6 to 12 months after lung transplantation are predictive of early-onset BOS, and those with BOS and aspiration have an augmented chemotactic and inflammatory balance of pulmonary leukocytes and immune mediators. These data justify the surgical prevention of aspiration and argue for the refinement of antirejection regimens.
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, IL 60153, USA. pfisichella@lumc.edu
authors.forename: P Marco
authors.initials: PM
authors.lastname: Fisichella
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Davis
authors.forename: Erin
authors.initials: E
authors.lastname: Lowery
authors.forename: Luis
authors.initials: L
authors.lastname: Ramirez
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kovacs
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007958:Leukocyte Count; D016015:Logistic Models; D016040:Lung Transplantation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D011446:Prospective Studies; D053120:Respiratory Aspiration / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D013577:Syndrome
chemical_list: D015415:Biomarkers