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Pulmonary abnormalities due to Niemann‐Pick Type C2 (NPC2) gene‐targeted deficiency in mice
Author(s) -
Bates Sandra R.,
Tao Jian-Qin,
Ning Yue,
Yu Kevin J.,
Gao Ling,
Styer Christina,
Huang Shaohui,
Feinstein Sheldon I.,
Roszell Blair R.
Publication year - 2012
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.26.1_supplement.698.9
Subject(s) - lamellar granule , pulmonary alveolar proteinosis , pulmonary surfactant , lung , cholesterol , pathology , chemistry , surfactant protein c , phospholipid , surfactant protein a , medicine , biochemistry , membrane
NPC2 is a luminal protein shown to facilitate cholesterol transport. Patients deficient in this protein demonstrate cholesterol accumulation in lysosomes, neuropathy and lung alveolar proteinosis. This work examined the characteristics of lung disease in the NPC2 gene‐targeted mice. Compared to wild type mice, the NPC2‐deficient mice demonstrated: a) by histology, areas of both severe and mild pathology characterized by thickened septae, “nests” of foam‐filled macrophages, and alveolar macrophages containing excessive surfactant‐like material; b) by electron microscopy, alveolar spaces with alveolar proteinaceous material and type II cells with smaller lamellar bodies (mean area 50% of normal); and c) by biochemical analysis, a 2‐fold elevation in phospholipid (PL) and cholesterol in lung tissue; a 3‐fold enrichment in PL and cholesterol in isolated alveolar macrophages; a 2‐fold increase in protein, a 4‐fold increase in PL and a striking increase in cholesterol (16‐fold) in the broncho‐alveolar lavage fluid, observations characteristic of alveolar proteinosis; with a similar enrichment in lipid profile found in isolated lamellar bodies. Thus, near absence of NPC2 has a detrimental effect on the surfactant system demonstrated by abnormal lung morphology and surfactant composition indicating that the activity of NPC2 is important for the maintenance of normal lung homeostasis. [HL 19737 and NRSA T32‐07748]