Assessment of the Hepatotoxicity of Intratracheally Instilled Silver Nanoparticles in Hypertensive Mice

Background: Silver nanoparticles (AgNPs) are extensively used in numerous engineering and biomedical fields. Inhaled nanoparticles can induce lung inflammation and translocate into secondary organs including the liver. However, the possible impact of these nanoparticles on the liver received only scant attention, especially following intratracheal (i.t.) instillation in an animal model of hypertension. Aims and Objectives: Here, we evaluated the hepatotoxicity and mechanism of action of polyethylene glycol (PEG)-coated AgNPs in a mouse model of hypertension. Materials and Methods: Mice were made hypertensive (HT) by inserting osmotic minipump infusing angiotensin II (ANG II) or vehicle (control) normotensive (NT). Either saline (control) or PEG-AgNPs (0.5 mg/kg) were i.t. instilled on days 7, 14, 21 and 28 post-ANG II or vehicle infusion. Twenty-four hours after the last exposure (day 29), lung histopathology and several markers of liver function, inflammation, oxidative stress, DNA damage and apoptosis were evaluated in all mice. Results: In comparison with either saline-treated HT group or PEG-AgNPs-treated NT group, lung histology of PEG-AgNPs-treated HT mice showed more focal areas of widening of interalveolar septae with inflammatory cells consisting mainly in macrophages and neutrophil polymorphs. In PEG-AgNPs-treated HT mice, the activities of lactate dehydrogenase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase and alkaline phosphatase in plasma were increased, compared with either saline-treated HT or PEG-AgNPs-treated NT mice. Similarly, markers of hepatic oxidative stress (lipid peroxidation, glutathione and catalase), inflammation (interleukin [IL]-6, IL-1 β and tumour necrosis factor α), DNA damage (8-hydroxy-2′-deoxyguanosine) and apoptosis (cleaved caspase-3) were significantly increased in PEG-AgNPs-treated HT mice, compared with either saline-treated HT or PEG-AgNPs-treated NT mice. Conclusion: Our data provide novel evidence on the aggravation of liver damage following pulmonary administration of PEG-AgNPs in hypertension through mechanisms involving inflammation oxidative stress, DNA damage and apoptosis.