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1 Department of Internal Medicine, VA Medical Center-Iowa City, Iowa City, IA, USA
2 Department of Research Service, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA; Department of Radiation Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
3 Department of Radiation Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
4 Department of Internal Medicine, VA Medical Center-Iowa City, Iowa City, IA, USA; Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
5 Department of Internal Medicine, VA Medical Center-Iowa City, Iowa City, IA, USA; Department of Radiation Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: bradley-britigan{at}uiowa.edu.
Production of pyocyanin enhances Pseudomonas aeruginosa virulence. Many of pyocyanin's in vitro and in vivo cytotoxic effects on human cells appear to result from its ability to redox cycle. Pyocyanin directly accepts electrons from NADH or NADPH with subsequent electron transfer to oxygen, generating reactive oxygen species (ROS). Reduced glutathione (GSH) is an important cellular antioxidant and it contributes to the regulation of redox-sensitive signaling systems. Using the human bronchial epithelial (HBE) and the A549 human type II alveolar epithelial cell lines, we tested the hypothesis that pyocyanin can deplete airway epithelial cells of GSH. Incubation of both cell types with pyocyanin led to a concentration-dependent loss of cellular GSH (up to 50%) and an increase in oxidized GSH (GSSG) in the HBE, but not A549 cells, at 24 h. An increase in total GSH, mostly as GSSG, was detected in the culture media, suggesting export of GSH or GSSG from the pyocyanin-exposed cells. Loss of GSH could be due to pyocyanininduced H2O2 formation. However, overexpression of catalase only partially prevented the pyocyanin-mediated decline in cellular GSH. Cell-free EPR studies revealed that pyocyanin directly oxidizes GSH, forming pyocyanin free radical and superoxide. Pyocyanin oxidized other thiol-containing compounds, cysteine and N-acetyl-cysteine, but not methionine. Thus, GSH may enhance pyocyanin-induced cytotoxicity by functioning as an alternative source of reducing equivalents for pyocyanin redox cycling. Pyocyanin-mediated alterations in cellular GSH may alter epithelial cell functions by modulating redox sensitive signaling events.
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