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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

Pharmacokinetics of 65Zn post-intravenous (IV) injection of 65ZnO.Notes: (A) Total distribution of recovered 65Zn in rat tissues at 0, 7, 14, and 21 days postinjection. (B) Excretion of 65Zn post-IV injection of 65Zn ENPs. (C) Percentage of injected 65Zn dose retained in the liver diminished over time. (D) Overall organ distribution of 65Zn over time post-IV injection of 65ZnO ENPs.Abbreviation: ENPs, engineered nanoparticles.
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f2-ijn-10-4173: Pharmacokinetics of 65Zn post-intravenous (IV) injection of 65ZnO.Notes: (A) Total distribution of recovered 65Zn in rat tissues at 0, 7, 14, and 21 days postinjection. (B) Excretion of 65Zn post-IV injection of 65Zn ENPs. (C) Percentage of injected 65Zn dose retained in the liver diminished over time. (D) Overall organ distribution of 65Zn over time post-IV injection of 65ZnO ENPs.Abbreviation: ENPs, engineered nanoparticles.

Mentions: The amounts of total recovered 65Zn in rats over time are shown in Figure 2A. This shows that 82.7% of the injected dose was recovered at 30 minutes postinjection and declined to 38% over 7 days. After 21 days, the amount of 65Zn was 25% in the total rat carcass. Excretion of 65Zn through urine and feces is presented in Figure 2B. At 24 hours postinjection of 65Zn, 2.1% had been excreted in the urine and 10.5% in the feces. Cumulative urine and fecal elimination of 65Zn at 21 days was 4% and 47%, respectively. The liver was found to have the highest retention of 65Zn at 30 minutes (Figure 2C), which declined to 11% over a 24-hour period. After 7 days, the presence of ZnO ENPs in the liver diminished to 3.3%, and only 1.2% remained after 21 days. Figure 2D displays the overall tissue distribution of 65Zn at four different time points after injection of combined 65ZnO and Fe2O3. At 24 hours, we observed that 65Zn was found in the bone (14%), skin (9%), lungs (13%), blood (15%), and plasma (13%). Retained 65Zn decreased over time from the liver and other organs, most likely due to ZnO ENP dissolution and clearance of Zn through the urine and feces. However, notable accumulation of 65Zn within the bone was observed (Figure 2D).


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)

Pharmacokinetics of 65Zn post-intravenous (IV) injection of 65ZnO.Notes: (A) Total distribution of recovered 65Zn in rat tissues at 0, 7, 14, and 21 days postinjection. (B) Excretion of 65Zn post-IV injection of 65Zn ENPs. (C) Percentage of injected 65Zn dose retained in the liver diminished over time. (D) Overall organ distribution of 65Zn over time post-IV injection of 65ZnO ENPs.Abbreviation: ENPs, engineered nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492628&req=5

f2-ijn-10-4173: Pharmacokinetics of 65Zn post-intravenous (IV) injection of 65ZnO.Notes: (A) Total distribution of recovered 65Zn in rat tissues at 0, 7, 14, and 21 days postinjection. (B) Excretion of 65Zn post-IV injection of 65Zn ENPs. (C) Percentage of injected 65Zn dose retained in the liver diminished over time. (D) Overall organ distribution of 65Zn over time post-IV injection of 65ZnO ENPs.Abbreviation: ENPs, engineered nanoparticles.
Mentions: The amounts of total recovered 65Zn in rats over time are shown in Figure 2A. This shows that 82.7% of the injected dose was recovered at 30 minutes postinjection and declined to 38% over 7 days. After 21 days, the amount of 65Zn was 25% in the total rat carcass. Excretion of 65Zn through urine and feces is presented in Figure 2B. At 24 hours postinjection of 65Zn, 2.1% had been excreted in the urine and 10.5% in the feces. Cumulative urine and fecal elimination of 65Zn at 21 days was 4% and 47%, respectively. The liver was found to have the highest retention of 65Zn at 30 minutes (Figure 2C), which declined to 11% over a 24-hour period. After 7 days, the presence of ZnO ENPs in the liver diminished to 3.3%, and only 1.2% remained after 21 days. Figure 2D displays the overall tissue distribution of 65Zn at four different time points after injection of combined 65ZnO and Fe2O3. At 24 hours, we observed that 65Zn was found in the bone (14%), skin (9%), lungs (13%), blood (15%), and plasma (13%). Retained 65Zn decreased over time from the liver and other organs, most likely due to ZnO ENP dissolution and clearance of Zn through the urine and feces. However, notable accumulation of 65Zn within the bone was observed (Figure 2D).

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