Abstract
BackgroundLarge 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.MethodsTwo 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.ResultsZnONP 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.ConclusionsWe hypothesise that rapid, pH-dependent dissolution of ZnONP inside of phagosomes is the main cause of ZnONP-induced diverse progressive severe lung injuries.
Highlights
Large production volumes of zinc oxide nanoparticles (ZnONP) might be anticipated to pose risks, of accidental inhalation in occupational and even in consumer settings
We assessed the pulmonary inflammogenicity of a large panel of NP, including ZnONP and found that metal oxide NP elicited diverse patterns of inflammation with different cellular bases, at both the acute and chronic phase [10]. We extended these experiments to evaluate the mechanisms of eosinophilic inflammation and pulmonary fibrosis induced by ZnONP instillation
When ZnONP were dispersed with serum protein, they showed a “soft agglomerates” which is readily dispersed without any stresses because of the protein corona on the surface of NP
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. Methods: 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. Alternative ZnONP, ZnONP-free bronchoalveolar lavage exudate, and dissolved Zn2+ (92.5 μg/rat) were instilled to rats. Zinc oxide nanoparticles (ZnONP) are utilised in many commercial products including cosmetics, paints, textiles, food additives, and personal hygiene products. Exposure of human skin epithelial cells to ZnONP produced severe cytotoxicity accompanied by oxidative stress and genotoxicity [8]. Few studies have been reported concerning the in vivo toxicity of ZnONP intratracheal instillation of ZnONP (50 - 70 nm) in Sprague-Dawley rats induced cytotoxicity and neutrophilic inflammation at 24 h after instillation [9]
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