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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

Effect of ZnO nanoparticles on liver histology of male Wistar Han rats.Notes: (A) Control (intravenously injected with sterile saline). (B) At 24 hours, hepatocyte swelling was evident with an intravenous dose of 5 mg/kg of ZnO engineered nanoparticles (ENPs). (C) After 7 days, granulation and necrotic regions accompanied by neutrophil infiltration were observed; the arrow on the left indicates neutrophil infiltration; the arrows on the right indicate granulation and necrotic regions. (D) At 24 hours, 10 mg/kg ZnO ENPs caused an influx of neutrophils (arrow) and binucleated hepatocytes (circled). (E) At 7 days, inflammation and liver necrosis were evident (arrow). (F) At 24 hours, 20 mg/kg ZnO ENPs induced inflammatory cell infiltration (arrow). (G) At 7 days, inflammatory cell infiltration remained (upper arrow), along with binucleated cells (circled) and some necrosis (lower arrow).
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f6-ijn-10-4173: Effect of ZnO nanoparticles on liver histology of male Wistar Han rats.Notes: (A) Control (intravenously injected with sterile saline). (B) At 24 hours, hepatocyte swelling was evident with an intravenous dose of 5 mg/kg of ZnO engineered nanoparticles (ENPs). (C) After 7 days, granulation and necrotic regions accompanied by neutrophil infiltration were observed; the arrow on the left indicates neutrophil infiltration; the arrows on the right indicate granulation and necrotic regions. (D) At 24 hours, 10 mg/kg ZnO ENPs caused an influx of neutrophils (arrow) and binucleated hepatocytes (circled). (E) At 7 days, inflammation and liver necrosis were evident (arrow). (F) At 24 hours, 20 mg/kg ZnO ENPs induced inflammatory cell infiltration (arrow). (G) At 7 days, inflammatory cell infiltration remained (upper arrow), along with binucleated cells (circled) and some necrosis (lower arrow).

Mentions: Two of eight liver-injury enzyme biomarkers that were measured showed time-dependent changes (Figure 5). We observed a significant elevation in AST (Figure 5A) at the 5 and 10 mg/kg doses after 7 days. The higher dose of 20 mg/kg incited a fivefold increase in AST after 24 hours, which decreased after 7 days. CPK levels at 5, 10, and 20 mg/kg were significantly increased at 7 days (Figure 5B). This elevation coincided with dose-dependent histopathological changes, including necrosis and infiltration of inflammatory cells (Figure 6). Normal liver-tissue structure could be seen in control (saline-administered) rats (Figure 6A). Light micrographs of representative rat liver sections taken at 24 hours post-ENP exposure of 5 mg/kg show an influx of inflammatory cells (Figure 6B). After 1 week, noticeable areas of hepatocyte granulation and nuclear condensation were evident, along with spotty necrosis (Figure 6C). In Figure 6D, the higher dose of 10 mg/kg induced a significant influx of neutrophils into the portal triad, which persisted after 7 days (Figure 6E). Figure 6F shows inflammatory cell infiltrate near the hepatic portal triad of a rat injected with 20 mg/kg of ZnO ENPs. The inflammation was observed at 7 days, along with focal regions of necrosis and binucleated cells (Figure 6G).


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)

Effect of ZnO nanoparticles on liver histology of male Wistar Han rats.Notes: (A) Control (intravenously injected with sterile saline). (B) At 24 hours, hepatocyte swelling was evident with an intravenous dose of 5 mg/kg of ZnO engineered nanoparticles (ENPs). (C) After 7 days, granulation and necrotic regions accompanied by neutrophil infiltration were observed; the arrow on the left indicates neutrophil infiltration; the arrows on the right indicate granulation and necrotic regions. (D) At 24 hours, 10 mg/kg ZnO ENPs caused an influx of neutrophils (arrow) and binucleated hepatocytes (circled). (E) At 7 days, inflammation and liver necrosis were evident (arrow). (F) At 24 hours, 20 mg/kg ZnO ENPs induced inflammatory cell infiltration (arrow). (G) At 7 days, inflammatory cell infiltration remained (upper arrow), along with binucleated cells (circled) and some necrosis (lower arrow).
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Related In: Results  -  Collection

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f6-ijn-10-4173: Effect of ZnO nanoparticles on liver histology of male Wistar Han rats.Notes: (A) Control (intravenously injected with sterile saline). (B) At 24 hours, hepatocyte swelling was evident with an intravenous dose of 5 mg/kg of ZnO engineered nanoparticles (ENPs). (C) After 7 days, granulation and necrotic regions accompanied by neutrophil infiltration were observed; the arrow on the left indicates neutrophil infiltration; the arrows on the right indicate granulation and necrotic regions. (D) At 24 hours, 10 mg/kg ZnO ENPs caused an influx of neutrophils (arrow) and binucleated hepatocytes (circled). (E) At 7 days, inflammation and liver necrosis were evident (arrow). (F) At 24 hours, 20 mg/kg ZnO ENPs induced inflammatory cell infiltration (arrow). (G) At 7 days, inflammatory cell infiltration remained (upper arrow), along with binucleated cells (circled) and some necrosis (lower arrow).
Mentions: Two of eight liver-injury enzyme biomarkers that were measured showed time-dependent changes (Figure 5). We observed a significant elevation in AST (Figure 5A) at the 5 and 10 mg/kg doses after 7 days. The higher dose of 20 mg/kg incited a fivefold increase in AST after 24 hours, which decreased after 7 days. CPK levels at 5, 10, and 20 mg/kg were significantly increased at 7 days (Figure 5B). This elevation coincided with dose-dependent histopathological changes, including necrosis and infiltration of inflammatory cells (Figure 6). Normal liver-tissue structure could be seen in control (saline-administered) rats (Figure 6A). Light micrographs of representative rat liver sections taken at 24 hours post-ENP exposure of 5 mg/kg show an influx of inflammatory cells (Figure 6B). After 1 week, noticeable areas of hepatocyte granulation and nuclear condensation were evident, along with spotty necrosis (Figure 6C). In Figure 6D, the higher dose of 10 mg/kg induced a significant influx of neutrophils into the portal triad, which persisted after 7 days (Figure 6E). Figure 6F shows inflammatory cell infiltrate near the hepatic portal triad of a rat injected with 20 mg/kg of ZnO ENPs. The inflammation was observed at 7 days, along with focal regions of necrosis and binucleated cells (Figure 6G).

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