Cadmium-mediated toxicity of lung epithelia is enhanced through NF-κB-mediated transcriptional activation of the human zinc transporter ZIP8

Jessica R. Napolitano, Ming Jie Liu, Shengying Bao, Melissa Crawford, Patrick Nana-Sinkam, Estelle Cormet-Boyaka, Daren L. Knoell

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Cadmium (Cd), a toxic heavy metal and carcinogen that is abundantly present in cigarette smoke, is a cause of smoking-induced lung disease. SLC39A8 (ZIP8), a zinc transporter, is a major portal for Cd uptake into cells. We have recently identified that ZIP8 expression is under the transcriptional control of the NF-κB pathway. On the basis of this, we hypothesized that cigarette-smoke induced inflammation would increase ZIP8 expression in lung epithelia, thereby enhancing Cd uptake and cell toxicity. Herein we report that ZIP8 is a central mediator of Cdmediated toxicity. TNF-α treatment of primary human lung epithelia and A549 cells induced ZIP8 expression, resulting in significantly higher cell death attributable to both apoptosis and necrosis following Cd exposure. Inhibition of the NF-κB pathway and ZIP8 expression significantly reduced cell toxicity. Zinc (Zn), a known cytoprotectant, prevented Cd-mediated cell toxicity via ZIP8 uptake. Consistent with cell culture findings, a significant increase in ZIP8 mRNA and protein expression was observed in the lung of chronic smokers compared with nonsmokers. From these studies, we conclude that ZIP8 expression is induced in lung epithelia in an NF-κB-dependent manner, thereby resulting in increased cell death in the presence of Cd. From this we contend that ZIP8 plays a critical role at the interface between micronutrient (Zn) metabolism and toxic metal exposure (Cd) in the lung microenvironment following cigarette smoke exposure. Furthermore, dietary Zn intake, or a lack thereof, may be a contributing factor in smoking-induced lung disease.

Original languageEnglish (US)
Pages (from-to)L909-L918
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number9
StatePublished - May 1 2012
Externally publishedYes


  • Chronic obstructive pulmonary disease
  • Cigarette smoke
  • Inflammation

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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