In Vivo Effect of Selective Macrophage Suppression on the Development of Intrahepatic Cholestasis in Mice

Короленко, Т. А.; Klishevich, M. S.; Черканова, М. С.; Alexeenko, T. V.; Zhanaeva, S. Ya.; Savchenko, N. G.; Goncharova, I. A.; Filjushina, Elena E.

doi:10.1007/s10517-009-0312-x

Cited by 3 publications

(2 citation statements)

References 16 publications

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“…Nanoparticulate contrast agents that are too big for renal filtration (>6 nm) typically gather in the liver [43]. It is not known if Gd-loaded nanoparticles will result in any kind of toxicity in the liver; in some liver studies, administration of high doses of GdCl 3 has exacerbated pre-existing disease [44], but in other studies it has had a therapeutic effect [45]. However, IO nanoparticles are already used in patients [46] and, therefore, IO-loaded HDL might be most easily accepted for use in the clinic.…”

Section: Critical Discussionmentioning

confidence: 99%

HDL as a contrast agent for medical imaging

Cormode¹,

Frías²,

Ma³

et al. 2009

Clinical Lipidology

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Contrast-enhanced MRI of atherosclerosis can provide valuable additional information on a patient's disease state. As a result of the interactions of HDL with atherosclerotic plaque and the flexibility of its reconstitution, it is a versatile candidate for the delivery of contrast-generating materials to this pathogenic lesion. We herein discuss the reports of HDL modified with gadolinium to act as an MRI contrast agent for atherosclerosis. Furthermore, HDL has been modified with fluorophores and nanocrystals, allowing it to act as a contrast agent for fluorescent imaging techniques and for computed tomography. Such modified HDL has been found to be macrophage specific, and, therefore, can provide macrophage density information via noninvasive MRI. As such, modified HDL is currently a valuable contrast agent for probing preclinical atherosclerosis. Future developments may allow the application of this particle to further diseases and pathological or physiological processes in both preclinical models as well as in patients. Keywords contrast agent; HDL; lipoproteins; medical imaging; MRI; nanoparticleThe noninvasive imaging of atherosclerotic plaques by MRI has obvious preclinical and clinical applications. In addition to diagnostic applications, noninvasive imaging would also allow the assessment of the responses to therapies [1]. In the preclinical setting, an immediate obstacle for MRI of atherosclerosis is the small size of the arteries of the most common model of the human disease, namely genetically engineered mice. The mice are made deficient in a lipoprotein clearance factor, such as ApoE or the LDL receptor, which results in elevated plasma levels of the atherogenic (non-HDL) lipoproteins. If the mice are placed on a cholesterol-and fat-enriched diet (the so-called 'Western diet'), plasma non-HDL levels are further elevated and atherosclerotic plaque progression accelerates [2]. In the mid-1990s, we were successful in demonstrating that noncontrast-enhanced MRI could detect mouse aortic atherosclerosis [3], which led to a series of papers demonstrating both practical applications [4] , further encouraging our strategy. Gadolinium is widely used to generate contrast for MRI and was available in a form in which it was chelated to a diethylene triamine pentaacetic acidphosphatidyl ethanolamine (DPTA-PE) molecule, which could be included in the phospholipids layer of HDL. Therefore, an integrated gadolinium-HDL particle was proposed as an initial MRI contrast agent for atherosclerosis. First-generation HDL nanoparticlesThe first gadolinium-labeled HDL was formed by reconstituting human HDL with gadolinium (Gd)-DPTA-PE and also with a fluorescent dye, NBD, which would allow convenient ex vivo analyses of the distribution of the particle in the plaque [9]. The labeled HDL we termed Gd-HDL. The reconstitution procedure followed the classical cholate dialysis method, with the components used including phosphatidyl choline and ApoA-I to form the surface and cholesteryl ester to form the core [9]. These s...

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Section: Critical Discussionmentioning

confidence: 99%

HDL as a contrast agent for medical imaging

Cormode¹,

Frías²,

Ma³

et al. 2009

Clinical Lipidology

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“…Agents such as gadolinium chloride and CLO liposomes are effective at depleting macrophages in vivo and have been used in numerous studies 19,23 to investigate the role of KCs in hepatic physiology. However, to our knowledge, the effects of these agents on serum enzyme levels have not been reported.…”

Section: No Changes In Clinical Signs Physical Examination Findingsmentioning

confidence: 99%

Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury

Radi

Koza-Taylor

Bell

et al. 2011

The American Journal of Pathology

124

101

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Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of serum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury. Specifically, neutralizing M-CSF activity via a novel human monoclonal antibody reduced the CD14 ؉ CD16 ؉ monocyte population, depleted KCs, and increased aspartate aminotransferase and creatine kinase serum enzyme levels in cynomolgus macaques. In addition, the treatment of rats with clodronate liposomes depleted KCs and led to increased serum enzyme levels, again without evidence of tissue injury. Finally, in the osteopetrotic (Csf1 op /Csf1 op ) mice lacking functional M-CSF and having reduced levels of KCs, the levels of serum enzymes are higher than in wild-type littermates. Together, these findings support a mechanism for increases in serum enzyme levels through M-CSF regulation of tissue macrophage homeostasis without concomitant histopathological changes in either the hepatic or skeletal system.

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Dahm

2018

Comprehensive Toxicology

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In Vivo Effect of Selective Macrophage Suppression on the Development of Intrahepatic Cholestasis in Mice

Cited by 3 publications

References 16 publications

HDL as a contrast agent for medical imaging

HDL as a contrast agent for medical imaging

Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury

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