title: Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes.
abstract: BACKGROUND
  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.
  
  
  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. 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  We hypothesise that rapid, pH-dependent dissolution of ZnONP inside of phagosomes is the main cause of ZnONP-induced diverse progressive severe lung injuries.
authors: ELEGI Group, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors: Wan-Seob
authors: WS
authors: Cho
authors: Rodger
authors: R
authors: Duffin
authors: Sarah E M
authors: SE
authors: Howie
authors: Chris J
authors: CJ
authors: Scotton
authors: William A H
authors: WA
authors: Wallace
authors: William
authors: W
authors: Macnee
authors: Mark
authors: M
authors: Bradley
authors: Ian L
authors: IL
authors: Megson
authors: Ken
authors: K
authors: Donaldson
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007150:Immunohistochemistry; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D012995:Solubility; D013499:Surface Properties; D015034:Zinc Oxide / Q000737:chemistry / Q000633:toxicity*
chemical_list: D016207:Cytokines; D007070:Immunoglobulin A; D007073:Immunoglobulin E; D015034:Zinc Oxide