Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes

Large production volumes of zinc oxide nanoparticles (ZnONP) might be anticipated to pose risks, of accidental inhalation in occupational and even in consumer settings. Herein, we further investigated the pathological changes induced by ZnONP and their possible mechanism of action. Two doses of ZnON...

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Published in:	Particle and fibre toxicology 2011-09, Vol.8 (1), p.27-27, Article 27
Main Authors:	Cho, Wan-Seob, Duffin, Rodger, Howie, Sarah E M, Scotton, Chris J, Wallace, William A H, Macnee, William, Bradley, Mark, Megson, Ian L, Donaldson, Ken
Format:	Article
Language:	eng
Subjects:	Animals Apoptosis Bronchoalveolar Lavage Fluid - cytology Bronchoalveolar Lavage Fluid - immunology Cytokines - immunology Cytotoxicity Disease Progression Enzyme-Linked Immunosorbent Assay Female Free radicals Immunoglobulin A - blood Immunoglobulin A - immunology Immunoglobulin E - blood Immunoglobulin E - immunology Immunohistochemistry Inhalation Exposure Lung - drug effects Lung - immunology Lung - pathology Lung Injury - chemically induced Lung Injury - immunology Lung Injury - pathology Lungs Lysosomes - drug effects Lysosomes - immunology Lysosomes - metabolism Lysosomes - pathology Methods Mice Mice, Inbred BALB C Mice, Inbred C57BL Microscopy, Electron, Transmission Nanoparticles Nanoparticles - chemistry Nanoparticles - toxicity Particle Size Pathology Rats Rats, Wistar Rodents Severity of Illness Index Skin Solubility Surface Properties Zinc Oxide - chemistry Zinc Oxide - toxicity Zinc oxides
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Summary:	Large production volumes of zinc oxide nanoparticles (ZnONP) might be anticipated to pose risks, of accidental inhalation in occupational and even in consumer settings. Herein, we further investigated the pathological changes induced by ZnONP and their possible mechanism of action. Two doses of ZnONP (50 and 150 cm2/rat) were intratracheally instilled into the lungs of rats with assessments made at 24 h, 1 wk, and 4 wks after instillation to evaluate dose- and time-course responses. Assessments included bronchoalveolar lavage (BAL) fluid analysis, histological analysis, transmission electron microscopy, and IgE and IgA measurement in the serum and BAL fluid. To evaluate the mechanism, alternative ZnONP, ZnONP-free bronchoalveolar lavage exudate, and dissolved Zn2+ (92.5 μg/rat) were also instilled to rats. Acridine orange staining was utilized in macrophages in culture to evaluate the lysosomal membrane destabilization by NP. ZnONP induced eosinophilia, proliferation of airway epithelial cells, goblet cell hyperplasia, and pulmonary fibrosis. Bronchocentric interstitial pulmonary fibrosis at the chronic phase was associated with increased myofibroblast accumulation and transforming growth factor-β positivity. Serum IgE levels were up-regulated by ZnONP along with the eosinophilia whilst serum IgA levels were down-regulated by ZnONP. ZnONP are rapidly dissolved under acidic conditions (pH 4.5) whilst they remained intact around neutrality (pH 7.4). The instillation of dissolved Zn2+ into rat lungs showed similar pathologies (eg., eosinophilia, bronchocentric interstitial fibrosis) as were elicited by ZnONP. Lysosomal stability was decreased and cell death resulted following treatment of macrophages with ZnONP in vitro. We hypothesise that rapid, pH-dependent dissolution of ZnONP inside of phagosomes is the main cause of ZnONP-induced diverse progressive severe lung injuries.
ISSN:	1743-8977 1743-8977