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Alveolar Macrophage Dysregulation in Hermansky-Pudlak Syndrome Type 1

¹ Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, and ² Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Bernadette R. Gochuico, M.D., 10 Center Drive, MSC 1851, Bethesda, MD 20892-1851. E-mail: gochuicb{at}mail.nih.gov

Rationale: 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.

Objectives: 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.

Measurements and Main 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-1, 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-1, 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.

Key Words: inflammation • cytokines • chemokines • bronchoalveolar lavage • pirfenidone

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Limited information is available regarding the pathogenesis of Hermansky-Pudlak syndrome pulmonary fibrosis, a progressive and often fatal disease. What This Study Adds to the Field This study demonstrates that high concentrations of activated alveolar macrophages, cytokines, and chemokines are found in individuals with Hermansky-Pudlak syndrome type 1. Dysregulation of alveolar macrophages may contribute to the pathogenesis of Hermansky-Pudlak syndrome pulmonary fibrosis.