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Pulmonary lipidosis due to Niemann‐Pick Type C1 (NPC1) deficiency in mice
Author(s) -
Roszell Blair R.,
Tao JianQin,
Ning Yue,
Yu Kevin J.,
Gao Ling,
Huang Shaohui,
Feinstein Sheldon I.,
Bates Sandra R.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.914.2
Subject(s) - lamellar granule , npc1 , pulmonary surfactant , pulmonary alveolar proteinosis , cholesterol , niemann–pick disease, type c , niemann–pick disease , lung , chemistry , phospholipid , endocrinology , medicine , pathology , biology , biochemistry , cell , membrane , endosome
NPC1, a member of the NPC pathway that facilitates the release of cholesterol from lysosomes, is also found in the limiting membrane of alveolar type II cell (AT2) lamellar bodies (LB). Cholesterol is critical for surface viscosity of pulmonary surfactant but excess cholesterol interferes with surfactant function. Patients with NPC disease and gene‐targeted NPC2 mutant mice exhibit cholesterol accumulation in lysosomes and lung alveolar proteinosis. The goal of this study was to examine the lung disease in the gene‐targeted NPC1‐null mice using histological and biochemical analysis. Compared to wild type (WT) mice, NPC1 mouse lungs were characterized by: a) areas of both severe and mild pathology with thickened septae, excess surfactant in the alveoli, and alveolar macrophages containing surfactant‐like material; b) a 1.5‐fold elevation in phospholipid (PL) and cholesterol in lung tissue; a 4‐ fold increase in PL and a striking increase in cholesterol (40‐fold) in the alveolar surfactant and isolated LBs; and c) a marked increase (160%) in mean area size of the LBs, in contrast to the reduction in LB size in NPC2 mutant mice (50% decrease vs. WT). Thus, an absence of NPC1 protein results in abnormal lung morphology and surfactant composition, indicating that the activity of NPC1 protein is important for the maintenance of normal lung homeostasis. [HL 19737 and NRSA T32–07748]