title: Alveolar macrophage dysregulation in Hermansky-Pudlak syndrome type 1.
abstract: BACKGROUND
  Individuals with Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, develop an accelerated form of progressive fibrotic lung disease. The etiology of pulmonary fibrosis associated with HPS-1 is unknown.
  
  
  OBJECTIVE
  To investigate the potential pathogenesis of pulmonary fibrosis in HPS-1, lung cells and proteins from individuals with HPS-1 were studied.
  
  
  METHODS
  Forty-one subjects with HPS-1 with and without pulmonary fibrosis were evaluated with pulmonary function tests, high-resolution computed tomography scan, and bronchoscopy. Bronchoalveolar lavage cells and analytes were analyzed.
  
  
  RESULTS
  Concentrations of total bronchoalveolar lavage cells and alveolar macrophages were significantly higher in epithelial lining fluid from subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers. Concentrations of cytokines and chemokines (i.e., monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and granulocyte-macrophage colony-stimulating factor) in alveolar epithelial lining fluid were significantly higher in subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers (P < 0.001). In vitro, HPS-1 pulmonary fibrosis alveolar macrophages, which did not express HPS1 mRNA, secreted significantly higher concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and regulated upon activation, normal T cell expressed and secreted (RANTES) protein compared with normal cells (P = 0.001, P = 0.014, and P = 0.011, respectively). Pirfenidone suppressed HPS-1 alveolar macrophage cytokine and chemokine secretion in vitro in a dose-dependent manner.
  
  
  CONCLUSIONS
  In HPS-1, alveolar inflammation predominantly involves macrophages and is associated with high lung concentrations of cytokines and chemokines. HPS-1 alveolar macrophages provide a model system in which to study the pathogenesis and treatment of HPS pulmonary fibrosis.
authors.affiliation: Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Farshid N
authors.initials: FN
authors.lastname: Rouhani
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.forename: Amanda
authors.initials: A
authors.lastname: Helip-Wooley
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Brien
authors.forename: Richard
authors.initials: R
authors.lastname: Hess
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
mesh_terms: D000328:Adult; D015152:Blotting, Northern; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D001999:Bronchoscopy / Q000379:methods; D018929:Cell Culture Techniques; D018925:Chemokines / Q000032:analysis / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D022861:Hermanski-Pudlak Syndrome / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging; D016676:Macrophages, Alveolar / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000150:complications; D012129:Respiratory Function Tests / Q000379:methods / Q000706:statistics & numerical data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D018925:Chemokines; D016207:Cytokines