title: Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky-Pudlak syndrome.
abstract: BACKGROUND
  The pulmonary phenotype of Hermansky-Pudlak syndrome (HPS) in adults includes foamy alveolar type 2 cells, inflammation, and lung remodeling, but there is no information about ontogeny or early disease mediators.
  
  
  OBJECTIVE
  To establish the ontogeny of HPS lung disease in an animal model, examine disease mediators, and relate them to patients with HPS1.
  
  
  METHODS
  Mice with mutations in both HPS1/pale ear and HPS2/AP3B1/pearl (EPPE mice) were studied longitudinally. Total lung homogenate, lung tissue sections, and bronchoalveolar lavage (BAL) were examined for phospholipid, collagen, histology, cell counts, chemokines, surfactant protein D (SP-D), and S-nitrosylated SP-D. Isolated alveolar epithelial cells were examined for expression of inflammatory mediators, and chemotaxis assays were used to assess their importance. Pulmonary function test results and BAL from patients with HPS1 and normal volunteers were examined for clinical correlation.
  
  
  RESULTS
  EPPE mice develop increased total lung phospholipid, followed by a macrophage-predominant pulmonary inflammation, and lung remodeling including fibrosis. BAL fluid from EPPE animals exhibited early accumulation of both SP-D and S-nitrosylated SP-D. BAL fluid from patients with HPS1 exhibited similar changes in SP-D that correlated inversely with pulmonary function. Alveolar epithelial cells demonstrated expression of both monocyte chemotactic protein (MCP)-1 and inducible nitric oxide synthase in juvenile EPPE mice. Last, BAL from EPPE mice and patients with HPS1 enhanced migration of RAW267.4 cells, which was attenuated by immunodepletion of SP-D and MCP-1.
  
  
  CONCLUSIONS
  Inflammation is initiated from the abnormal alveolar epithelial cells in HPS, and S-nitrosylated SP-D plays a significant role in amplifying pulmonary inflammation.
authors: Division of Pulmonary and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Elena N
authors: EN
authors: Atochina-Vasserman
authors: Sandra R
authors: SR
authors: Bates
authors: Peggy
authors: P
authors: Zhang
authors: Helen
authors: H
authors: Abramova
authors: Zhenguo
authors: Z
authors: Zhang
authors: Linda
authors: L
authors: Gonzales
authors: Jian-Qin
authors: JQ
authors: Tao
authors: Bernadette R
authors: BR
authors: Gochuico
authors: William
authors: W
authors: Gahl
authors: Chang-Jiang
authors: CJ
authors: Guo
authors: Andrew J
authors: AJ
authors: Gow
authors: Michael F
authors: MF
authors: Beers
authors: Susan
authors: S
authors: Guttentag
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