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Effects of zinc oxide nanoparticles on Kupffer cell phagosomal motility, bacterial clearance, and liver function.

Watson CY, Molina RM, Louzada A, Murdaugh KM, Donaghey TC, Brain JD - Int J Nanomedicine (2015)

Bottom Line: We found that the liver was the major site of initial uptake of (65)ZnO ENPs.In vivo magnetometry showed a time-dependent and transient reduction in Kupffer cell phagosomal motility.Administration of ZnO ENPs transiently inhibited Kupffer cell phagosomal motility and later induced hepatocyte injury, but did not alter bacterial clearance from the blood or killing in the liver, spleen, lungs, or kidneys.

View Article: PubMed Central - PubMed

Affiliation: Center for Nanotechnology and Nanotoxicology, Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

ABSTRACT

Background: Zinc oxide engineered nanoparticles (ZnO ENPs) have potential as nanomedicines due to their inherent properties. Studies have described their pulmonary impact, but less is known about the consequences of ZnO ENP interactions with the liver. This study was designed to describe the effects of ZnO ENPs on the liver and Kupffer cells after intravenous (IV) administration.

Materials and methods: First, pharmacokinetic studies were conducted to determine the tissue distribution of neutron-activated (65)ZnO ENPs post-IV injection in Wistar Han rats. Then, a noninvasive in vivo method to assess Kupffer cell phagosomal motility was employed using ferromagnetic iron particles and magnetometry. We also examined whether prior IV injection of ZnO ENPs altered Kupffer cell bactericidal activity on circulating Pseudomonas aeruginosa. Serum and liver tissues were collected to assess liver-injury biomarkers and histological changes, respectively.

Results: We found that the liver was the major site of initial uptake of (65)ZnO ENPs. There was a time-dependent decrease in tissue levels of (65)Zn in all organs examined, refecting particle dissolution. In vivo magnetometry showed a time-dependent and transient reduction in Kupffer cell phagosomal motility. Animals challenged with P. aeruginosa 24 hours post-ZnO ENP injection showed an initial (30 minutes) delay in vascular bacterial clearance. However, by 4 hours, IV-injected bacteria were cleared from the blood, liver, spleen, lungs, and kidneys. Seven days post-ZnO ENP injection, creatine phosphokinase and aspartate aminotransferase levels in serum were significantly increased. Histological evidence of hepatocyte damage and marginated neutrophils were observed in the liver.

Conclusion: Administration of ZnO ENPs transiently inhibited Kupffer cell phagosomal motility and later induced hepatocyte injury, but did not alter bacterial clearance from the blood or killing in the liver, spleen, lungs, or kidneys. Our data show that diminished Kupffer cell organelle motion correlated with ZnO ENP-induced liver injury.

No MeSH data available.


Related in: MedlinePlus

Electron micrographs and hydrodynamic diameter (DH) distributions.Notes: Electron micrographs of ferromagnetic Fe2O3 (A) and ZnO nanoparticles (B). DH distributions of (C) Fe2O3, (D) ZnO and (E) Fe2O3 and ZnO.
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f1-ijn-10-4173: Electron micrographs and hydrodynamic diameter (DH) distributions.Notes: Electron micrographs of ferromagnetic Fe2O3 (A) and ZnO nanoparticles (B). DH distributions of (C) Fe2O3, (D) ZnO and (E) Fe2O3 and ZnO.

Mentions: ZnO ENPs and iron oxide were characterized to determine surface charge, as well as primary particle and agglomerate size, prior to IV injections. The crystallite primary particle size of ZnO determined by X-ray diffraction was 20±3 nm. After dispersion in distilled water and sonication at 242 J/mL, we observed a mean agglomerate DH of 217±22.9 nm, PDI of 0.224, and zeta potential of 19.1±2.2 mV for ZnO ENPs. Fe2O3 ENPs had a primary particle size of 19.6±2.9 nm, and when dispersed and sonicated in sterile water had a DH of 163.1±49.0 nm, PDI of 0.257, and zeta potential of −28±0.3 mV. To ensure that the tracer particle Fe2O3 and ZnO ENP had the same uptake pattern by hepatic and splenic macrophages, they were mixed together at a ratio of 1:1. The combined suspensions had a DH of 518.9±36.5 nm, PDI of 0.606, and zeta potential of 3.31±0.5 mV. The interval between sonication of ENPs and rat injection was 1–2 minutes. Therefore, these agglomerate DHs were representative of what was injected IV. Transmission electron microscopy revealed the hexagonal and rod-shaped structure of Fe2O3 (Figure 1A) and ZnO ENPs (Figure 1B), respectively. Figure 1C–E displays the size distribution of Fe2O3, ZnO, and combined suspension of Fe2O3 and ZnO, respectively.


Effects of zinc oxide nanoparticles on Kupffer cell phagosomal motility, bacterial clearance, and liver function.

Watson CY, Molina RM, Louzada A, Murdaugh KM, Donaghey TC, Brain JD - Int J Nanomedicine (2015)

Electron micrographs and hydrodynamic diameter (DH) distributions.Notes: Electron micrographs of ferromagnetic Fe2O3 (A) and ZnO nanoparticles (B). DH distributions of (C) Fe2O3, (D) ZnO and (E) Fe2O3 and ZnO.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492628&req=5

f1-ijn-10-4173: Electron micrographs and hydrodynamic diameter (DH) distributions.Notes: Electron micrographs of ferromagnetic Fe2O3 (A) and ZnO nanoparticles (B). DH distributions of (C) Fe2O3, (D) ZnO and (E) Fe2O3 and ZnO.
Mentions: ZnO ENPs and iron oxide were characterized to determine surface charge, as well as primary particle and agglomerate size, prior to IV injections. The crystallite primary particle size of ZnO determined by X-ray diffraction was 20±3 nm. After dispersion in distilled water and sonication at 242 J/mL, we observed a mean agglomerate DH of 217±22.9 nm, PDI of 0.224, and zeta potential of 19.1±2.2 mV for ZnO ENPs. Fe2O3 ENPs had a primary particle size of 19.6±2.9 nm, and when dispersed and sonicated in sterile water had a DH of 163.1±49.0 nm, PDI of 0.257, and zeta potential of −28±0.3 mV. To ensure that the tracer particle Fe2O3 and ZnO ENP had the same uptake pattern by hepatic and splenic macrophages, they were mixed together at a ratio of 1:1. The combined suspensions had a DH of 518.9±36.5 nm, PDI of 0.606, and zeta potential of 3.31±0.5 mV. The interval between sonication of ENPs and rat injection was 1–2 minutes. Therefore, these agglomerate DHs were representative of what was injected IV. Transmission electron microscopy revealed the hexagonal and rod-shaped structure of Fe2O3 (Figure 1A) and ZnO ENPs (Figure 1B), respectively. Figure 1C–E displays the size distribution of Fe2O3, ZnO, and combined suspension of Fe2O3 and ZnO, respectively.

Bottom Line: We found that the liver was the major site of initial uptake of (65)ZnO ENPs.In vivo magnetometry showed a time-dependent and transient reduction in Kupffer cell phagosomal motility.Administration of ZnO ENPs transiently inhibited Kupffer cell phagosomal motility and later induced hepatocyte injury, but did not alter bacterial clearance from the blood or killing in the liver, spleen, lungs, or kidneys.

View Article: PubMed Central - PubMed

Affiliation: Center for Nanotechnology and Nanotoxicology, Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

ABSTRACT

Background: Zinc oxide engineered nanoparticles (ZnO ENPs) have potential as nanomedicines due to their inherent properties. Studies have described their pulmonary impact, but less is known about the consequences of ZnO ENP interactions with the liver. This study was designed to describe the effects of ZnO ENPs on the liver and Kupffer cells after intravenous (IV) administration.

Materials and methods: First, pharmacokinetic studies were conducted to determine the tissue distribution of neutron-activated (65)ZnO ENPs post-IV injection in Wistar Han rats. Then, a noninvasive in vivo method to assess Kupffer cell phagosomal motility was employed using ferromagnetic iron particles and magnetometry. We also examined whether prior IV injection of ZnO ENPs altered Kupffer cell bactericidal activity on circulating Pseudomonas aeruginosa. Serum and liver tissues were collected to assess liver-injury biomarkers and histological changes, respectively.

Results: We found that the liver was the major site of initial uptake of (65)ZnO ENPs. There was a time-dependent decrease in tissue levels of (65)Zn in all organs examined, refecting particle dissolution. In vivo magnetometry showed a time-dependent and transient reduction in Kupffer cell phagosomal motility. Animals challenged with P. aeruginosa 24 hours post-ZnO ENP injection showed an initial (30 minutes) delay in vascular bacterial clearance. However, by 4 hours, IV-injected bacteria were cleared from the blood, liver, spleen, lungs, and kidneys. Seven days post-ZnO ENP injection, creatine phosphokinase and aspartate aminotransferase levels in serum were significantly increased. Histological evidence of hepatocyte damage and marginated neutrophils were observed in the liver.

Conclusion: Administration of ZnO ENPs transiently inhibited Kupffer cell phagosomal motility and later induced hepatocyte injury, but did not alter bacterial clearance from the blood or killing in the liver, spleen, lungs, or kidneys. Our data show that diminished Kupffer cell organelle motion correlated with ZnO ENP-induced liver injury.

No MeSH data available.


Related in: MedlinePlus