Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Abstract

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.

Orphan G Protein–Coupled Receptor GPR116 Regulates Pulmonary Surfactant Pool Size

“…Mouse models of the human disease Hermansky-Pudlak syndrome also demonstrate altered surfactant homeostasis. However, unlike Gpr116 Dexon17 , Sftpd 2/2 , and Csf2 2/2 mice, mice with mutations in HermanskyPudlak syndrome-associated genes exhibit decreased alveolar pools of surfactant phospholipids and increased tissue phospholipid levels due to defects in surfactant trafficking and decreased secretion in type II cells (42)(43)(44). Taken together, our data support the hypothesis that GPR116 controls alveolar surfactant pool sizes by negatively regulating surfactant secretion from type II cells.…”

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

“…As noted above and in studies from other groups, HPS mouse models do not spontaneously develop fibrosis (37). However, they consistently manifest exaggerated sensitivity to fibrogenic, injurious, and apoptotic stimuli, and these exaggerated injury responses are believed to lead to the pulmonary fibrosis that follows (14,29,34,(37)(38)(39)(40)(41)(42). Our studies add to this body of data by demonstrating, for the first time to our knowledge, that the CHI3L1 axis plays an essential role in the regulation of epithelial apoptosis and that this response is blunted in pale ear mice.…”

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

“…A key study from the National Institutes of Health Clinical Center demonstrated that BAL fluid from HPS1 patients with relatively preserved lung function contained increased numbers of activated macrophages (9). Macrophage-mediated inflammation is also present in HPS1 and HPS2 mouse models, which have been shown to reliably model the subtype-specific fibrotic susceptibility observed in HPS patients (7,8,20). Therefore, we utilized HPS mouse models as a platform to define the role of activated macrophages in fibrosis in a human disease model.…”