Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky-Pudlak syndrome

Am J Respir Crit Care Med. 2011 Aug 15;184(4):449-58. doi: 10.1164/rccm.201011-1882OC.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aging / metabolism
  • Animals
  • Cell Movement
  • Chemokine CCL2 / metabolism
  • Chemotactic Factors / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal*
  • Fibrosis
  • Hermanski-Pudlak Syndrome* / physiopathology
  • Humans
  • Lung / metabolism
  • Macrophages / pathology
  • Mice*
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nitroso Compounds / metabolism
  • Phospholipids / metabolism
  • Pneumonia / etiology*
  • Pulmonary Alveoli / pathology
  • Pulmonary Alveoli / physiopathology*
  • Pulmonary Surfactant-Associated Protein D / metabolism*
  • Respiratory Mucosa / physiopathology*
  • Severity of Illness Index
  • Time Factors


  • CCL2 protein, human
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemotactic Factors
  • Cytokines
  • Nitroso Compounds
  • Phospholipids
  • Pulmonary Surfactant-Associated Protein D