Identification of Nrf2-dependent airway epithelial adaptive response to proinflammatory oxidant-hypochlorous acid challenge by transcription profiling.
In inflammatory diseases of the airway, a high level (estimated to be as high as 8 mM) of HOCl can be generated through a reaction catalyzed by the leukocyte granule enzyme myeloperoxidase (MPO). HOCl, a potent oxidative agent, causes extensive tissue injury through its reaction with various cellular substances, including thiols, nucleotides, and amines. In addition to its physiological source, HOCl can also be generated by chlorine gas inhalation from an accident or a potential terrorist attack. Despite the important role of HOCl-induced airway epithelial injury, the underlying molecular mechanism is largely unknown. In the present study, we found that HOCl induced dose-dependent toxicity in airway epithelial cells. By transcription profiling using GeneChip, we identified a battery of HOCl-inducible antioxidant genes, all of which have been reported previously to be regulated by nuclear factor erythroid-related factor 2 (Nrf2), a transcription factor that is critical to the lung antioxidant response. Consistent with this finding, Nrf2 was found to be activated time and dose dependently by HOCl. Although the epidermal growth factor receptor-MAPK pathway was also highly activated by HOCl, it was not involved in Nrf2 activation and Nrf2-dependent gene expression. Instead, HOCl-induced cellular oxidative stress appeared to lead directly to Nrf2 activation. To further understand the functional significance of Nrf2 activation, small interference RNA was used to knock down Nrf2 level by targeting Nrf2 or enhance nuclear accumulation of Nrf2 by targeting its endogenous inhibitor Keap1. By both methods, we conclude that Nrf2 directly protects airway epithelial cells from HOCl-induced toxicity.
D000220:Adaptation, Biological; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D006997:Hypochlorous Acid / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D006997:Hypochlorous Acid; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases