Abstract
BackgroundThe cadmium (Cd) present in air pollutants and cigarette smoke has the potential of causing multiple adverse health outcomes involving damage to pulmonary and cardiovascular tissue. Injury to pulmonary epithelium may include alterations in tight junction (TJ) integrity, resulting in impaired epithelial barrier function and enhanced penetration of chemicals and biomolecules. Herein, we investigated mechanisms involved in the disruption of TJ integrity by Cd exposure using an in vitro human air-liquid-interface (ALI) airway tissue model derived from normal primary human bronchial epithelial cells.MethodsALI cultures were exposed to noncytotoxic doses of CdCl2 basolaterally and TJ integrity was measured by Trans-Epithelial Electrical Resistance (TEER) and immunofluorescence staining with TJ markers. PCR array analysis was used to identify genes involved with TJ collapse. To explore the involvement of kinase signaling pathways, cultures were treated with CdCl2 in the presence of kinase inhibitors specific for cellular Src or Protein Kinase C (PKC).ResultsNoncytotoxic doses of CdCl2 resulted in the collapse of barrier function, as demonstrated by TEER measurements and Zonula occludens-1 (ZO-1) and occludin staining. CdCl2 exposure altered the expression of several groups of genes encoding proteins involved in TJ homeostasis. In particular, down-regulation of select junction-interacting proteins suggested that a possible mechanism for Cd toxicity involves disruption of the peripheral junctional complexes implicated in connecting membrane-bound TJ components to the actin cytoskeleton. Inhibition of kinase signaling using inhibitors specific for cellular Src or PKC preserved the integrity of TJs, possibly by preventing occludin tyrosine hyperphosphorylation, rather than reversing the down-regulation of the junction-interacting proteins.ConclusionsOur findings indicate that acute doses of Cd likely disrupt TJ integrity in human ALI airway cultures both through occludin hyperphosphorylation via kinase activation and by direct disruption of the junction-interacting complex.
Highlights
Cadmium (Cd) is a highly toxic heavy metal present in environmental pollution and tobacco smoke [1]
Given that pulmonary disease is a common outcome of Cdrelated exposures and that the human airway is exposed to Cd through, e.g., cigarette smoke, airway epithelium could be a major target for Cd-mediated tight junction (TJ) disruption
Hematoxylin and eosin (H&E) staining of the paraffin-embedded tissue sections indicated that the ALI cultures were fully differentiated into a pseudostratified mucociliary epithelium, with cells resembling goblet cells interspersed among ciliated cells along the apical side of the cultures (Figure 1A)
Summary
Cadmium (Cd) is a highly toxic heavy metal present in environmental pollution and tobacco smoke [1]. Given that pulmonary disease is a common outcome of Cdrelated exposures and that the human airway is exposed to Cd through, e.g., cigarette smoke, airway epithelium could be a major target for Cd-mediated TJ disruption. Whether or not such toxicity occurs and the underlying mechanism for this toxicity, warrants further investigation. The cadmium (Cd) present in air pollutants and cigarette smoke has the potential of causing multiple adverse health outcomes involving damage to pulmonary and cardiovascular tissue. We investigated mechanisms involved in the disruption of TJ integrity by Cd exposure using an in vitro human air-liquid-interface (ALI) airway tissue model derived from normal primary human bronchial epithelial cells
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