Abstract
Niemann-Pick C (NPC) disease is due to loss of NPC1 or NPC2 protein function that is required for unesterified cholesterol transport from the endosomal/lysosomal compartment. Though lung involvement is a recognized characteristic of Niemann-Pick type C disease, the pathological features are not well understood. We investigated components of the surfactant system in both NPC1 mutant mice and felines and in NPC2 mutant mice near the end of their expected life span. Histological analysis of the NPC mutant mice demonstrated thickened septae and foamy macrophages/leukocytes. At the level of electron microscopy, NPC1-mutant type II cells had uncharacteristically larger lamellar bodies (LB, mean area 2-fold larger), while NPC2-mutant cells had predominantly smaller lamellar bodies (mean area 50% of normal) than wild type. Bronchoalveolar lavage from NPC1 and NPC2 mutant mice had an approx. 4-fold and 2.5-fold enrichment in phospholipid, respectively, and an approx. 9-fold and 35-fold enrichment in cholesterol, consistent with alveolar lipidosis. Phospholipid and cholesterol also were elevated in type II cell LBs and lung tissue while phospholipid degradation was reduced. Enrichment of surfactant protein-A in the lung and surfactant of the mutant mice was found. Immunocytochemical results showed that cholesterol accumulated in the LBs of the type II cells isolated from the affected mice. Alveolar macrophages from the NPC1 and NPC2 mutant mice were enlarged compared to those from wild type mice and were enriched in phospholipid and cholesterol. Pulmonary features of NPC1 mutant felines reflected the disease described in NPC1 mutant mice. Thus, with the exception of lamellar body size, the lung phenotype seen in the NPC1 and NPC2 mutant mice were similar. The lack of NPC1 and NPC2 proteins resulted in a disruption of the type II cell surfactant system contributing to pulmonary abnormalities.
Highlights
Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder marked by excess intralysosomal cholesterol, progressive neurodegeneration and hepatosplenomegaly that has no effective approved treatments [1]
The Niemann-Pick C pathway has been shown to regulate the removal of low density lipoprotein (LDL)-derived cholesterol from the lumen of the late endosome/ lysosome system to the cytosolic compartment [17,18]. We hypothesized that this pathway may play a role in surfactant cholesterol transport since we showed that the Niemann-Pick C (NPC) proteins, Niemann-Pick Type C1 (NPC1) and NPC2 were present in lamellar bodies [19]
We examined the lung tissue of NPC1 and NPC2 mutant mice by Western blot in homozygous mutant animals near the end of their lifespan
Summary
Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder marked by excess intralysosomal cholesterol, progressive neurodegeneration and hepatosplenomegaly that has no effective approved treatments [1]. The two types of NPC disorders are thought to be clinically and biochemically indistinguishable, with reports of pulmonary involvement in both with alveolar proteinosis and foamy macrophages, NPC2 disease seems to have a more severe phenotype [2,3,4]. Whereas the pulmonary disease can be acute, the surfactant system in Niemann-Pick disease has not been fully described in detail. The bronchoalveolar lavage fluid from this patient was analyzed and a marked accumulation of surfactant phospholipid and cholesterol was shown [2]. PAP is a rare lung disorder characterized by abnormal accumulation of surfactant with little to no inflammation and fibrosis
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