Alveolar macrophage dysregulation in Hermansky-Pudlak syndrome type 1.
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.
Rouhani
Farshid N
FN
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Brantly
Mark L
ML
Markello
Thomas C
TC
Helip-Wooley
Amanda
A
O'Brien
Kevin
K
Hess
Richard
R
Huizing
Marjan
M
Gahl
William A
WA
Gochuico
Bernadette R
BR
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
D018925:Chemokines; D016207:Cytokines