Pulmonary function and pathology in hydroxypropyl-beta-cyclodextin-treated and untreated Npc1−/− mice

Muralidhar, Akshay; Borbon, Ivan A.; Esharif, Dyadin M.; Ke, Wangjing; Manacheril, Rinu; Daines, Michael O.; Erickson, Robert P.

doi:10.1016/j.ymgme.2011.03.001

Cited by 26 publications

(19 citation statements)

References 41 publications

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“…Disrupted copper homeostasis is widespread in all Npc1 −/− mouse tissue types examined, with the most dramatic change of a 170 ± 17% increase in the lungs. It is possible that the copper-induced oxidative stress in the lungs may contribute to the pulmonary abnormalities reported in animal model studies 47, 48 .…”

Section: Discussionmentioning

confidence: 99%

Altered transition metal homeostasis in Niemann–Pick disease, type C1

et al. 2014

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The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1−/− mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1−/− mouse model. NPC1 deficiency in the Npc1−/− mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1−/− mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C.

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Section: Discussionmentioning

confidence: 99%

Altered transition metal homeostasis in Niemann–Pick disease, type C1

et al. 2014

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“…Additionally, the susceptibility to HPBCD was different between Npc1 +/+ and Npc1 +/ − , and Npc1 −/− mice. Muralidhar et al [15] and Ramirez et al [4] reported that treatment of Npc1 −/− mice with HPBCD had little or no effect on the development of progressive pulmonary disease. Therefore, when evaluating the safety of HPBCD therapy for NPC disease, the difference of NPC1 genotype should be considered.…”

Section: Discussionmentioning

confidence: 99%

Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models

Tanaka

Ishitsuka

Yamada

et al. 2014

Molecular Genetics and Metabolism Reports

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Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1+/+) or Npc1+/− mice died by 72 h after the injection. In contrast, all of the Npc1−/− mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1+/+ or Npc1+/− mice. However, these pathophysiological changes were significantly alleviated in Npc1−/− mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1−/− mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1+/+ or Npc1+/− mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.

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“…While there was also a slowing of cerebellar neurodegeneration and an increase in lifespan, systemic 2HPβCD treatment had little to no effect on the development of progressive pulmonary disease [26]. Subsequent studies further demonstrated lack of impact of systemically administered 2HPβCD on a number of parameters of lung function and pathology in the Npc1 −/− mouse [27]. There is nothing intrinsically different about UC sequestration in the lungs in NPC1 or NPC2 deficiency because NPC2 replacement therapy in a mouse model of NPC2 disease resulted in a striking reduction in the cholesterol content of several organs including the lungs [28].…”

Section: Introductionmentioning

confidence: 99%

Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann–Pick type C disease

Ramirez¹,

Lopez²,

Le³

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Niemann-Pick Type C (NPC) disease is caused by a deficiency of either NPC1 or NPC2. Loss of function of either protein results in the progressive accumulation of unesterified cholesterol in every tissue leading to cell death and organ damage. Most literature on NPC disease focuses on neurological and liver manifestations. Pulmonary dysfunction is less well described. The present studies investigated how Npc1 deficiency impacts the absolute weight, lipid composition and histology of the lungs of Npc1−/− mice (Npc1nih) at different stages of the disease, and also quantitated changes in the rates of cholesterol and fatty acid synthesis in the lung over this same time span (8 to 70 days of age). Similar measurements were made in Npc2−/− mice at 70 days. All mice were of the BALB/c strain and were fed a basal rodent chow diet. Well before weaning, the lung weight, cholesterol and phospholipid (PL) content, and cholesterol synthesis rate were all elevated in the Npc1−/− mice and remained so at 70 days of age. In contrast, lung triacylglycerol content was reduced while there was no change in lung fatty acid synthesis. Despite the elevated PL content, the composition of PL in the lungs of the Npc1−/− mice was unchanged. H&E staining revealed an age-related increase in the presence of lipid-laden macrophages in the alveoli of the lungs of the Npc1−/− mice starting as early as 28 days. Similar metabolic and histologic changes were evident in the lungs of the Npc2−/− mice. Together these findings demonstrate an intrinsic lung pathology in NPC disease that is of early onset and worsens over time.

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Pulmonary function and pathology in hydroxypropyl-beta-cyclodextin-treated and untreated Npc1−/− mice

Cited by 26 publications

References 41 publications

Altered transition metal homeostasis in Niemann–Pick disease, type C1

Altered transition metal homeostasis in Niemann–Pick disease, type C1

Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models

Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann–Pick type C disease

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