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PROINFLAMMATORY OXIDANT HYPOCHLOROUS ACID (HOCL) INDUCES DUAL SIGNALING PATHWAYS IN AIRWAY EPITHELIAL CELLS
Citation:
ZHU, L., Y. ZHAO, J. PI, M. E. ANDERSEN, A. M. JARABEK, AND Y. CHEN. PROINFLAMMATORY OXIDANT HYPOCHLOROUS ACID (HOCL) INDUCES DUAL SIGNALING PATHWAYS IN AIRWAY EPITHELIAL CELLS. Presented at American Thoracic Society Annual Meeting, San Francisco, CA, May 18 - 23, 2007.
Description:
In the airway of inflammatory diseases such as bacterial infection, cystic fibrosis and COPD, high level of HOCL (local concentration of up to 5mM) can be generated through a reaction catalyzed by leukocyte granule enzyme- Myeloperoxidase (MPO). HOCL is a very potent oxidative agent, and causes extensive tissue injury through its reaction with various cellular substances including thiols, nucleotides and amines. Besides its physiological source, HOCL can also be generated by chlorine gas inhalation resulting from either an accident or potential terrorist attack. Despite the pivotal role of HOCL in airway epithelial injury in inflammatory diseases as well as environmental exposures, underlying molecular mechanism is largely unknown. In this study, we used epithelial cell line and primary cell models to investigate HOCL induced signaling pathways in epithelial injury and repair. Using MTT assay, LC50 of HOCL was 0.99±0.04 mM for both NCIH292 cells and primary cells. HOCL induced cellular oxidative stress as demonstrated by glutathione depletion and activation of intracellular oxidant sensitive fluorescence dye. It also activated EGFR-MAPK pathway and increased nuclear accumulation of Nrf2 as well as Nrf2 inducible genes. Interestingly, Nrf2 nuclear accumulation and Nrf2 activated genes couldn¿t be blocked by pre-treatment of various antioxidants, suggesting an oxidant independent mechanism. EGFR-MAPK pathway, in contrast, appeared to be activated by oxidant mediated signaling. Further study using chemical inhibitor, RNAi as well as dominant negative construct indicated that EGFR-MAPK and Nrf2 were indeed activated by independent pathways. Detailed studies on how these two pathways affect HOCL induced epithelial injury/repair in various airway inflammation models are currently on-going. This abstract does not represent EPA policy.