Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure

Yong Ho Kim, Farnoosh Fazlollahi, Ian M. Kennedy, Nazanin R. Yacobi, Sarah F. Hamm-Alvarez, Zea Borok, Kwang Jin Kim, Edward D. Crandall

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Rationale: Although inhalation of zinc oxide (ZnO) nanoparticles (NPs) is known to cause systemic disease (i.e., metal fume fever), little is known about mechanisms underlying injury to alveolar epithelium. Objectives: Investigate ZnO NP-induced injury to alveolar epithelium by exposing primary cultured rat alveolar epithelial cell monolayers (RAECMs) to ZnO NPs. Methods: RAECMs were exposed apically to ZnO NPs or, in some experiments, to culture fluid containing ZnCl2 or free Zn released from ZnO NPs. Transepithelial electrical resistance (RT) and equivalent short-circuit current (IEQ) were assessed as functions of concentration and time. Morphologic changes, lactate dehydrogenase release, cell membrane integrity, intracellular reactive oxygen species (ROS), and mitochondrial activity were measured. Measurements and Main Results: Apical exposure to 176 μg/ml ZnO NPs decreased RT and IEQ of RAECMs by 100% over 24 hours, whereas exposure to 11 μg/ml ZnO NPs had little effect. Changes in RT and IEQ causedby 176 μg/ml ZnO NPs were irreversible. ZnO NP effects on RT yielded half-maximal concentrations of approximately 20 μg/ml. Apical exposure for 24 hours to 176 μg/ml ZnO NPs induced decreases in mitochondrial activity and increases in lactate dehydrogenase release, permeability to fluorescein sulfonic acid, increased intracellular ROS, and translocation of ZnO NPs from apical to basolateral fluid (most likely across injured cells and/or damaged paracellular pathways). Conclusions: ZnO NPs cause severe injury to RAECMs in a dose- and time-dependent manner, mediated, at least in part, by free Zn released from ZnO NPs, mitochondrial dysfunction, and increased intracellular ROS.

Original languageEnglish (US)
Pages (from-to)1398-1409
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number11
StatePublished - Dec 1 2010


  • Epithelial monolayers
  • Mitochondrial damage
  • Plasma membrane integrity
  • Reactive oxygen species
  • Zinc toxicity

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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