PMID- 18156441
OWN - NLM
STAT- MEDLINE
DCOM- 20080509
LR  - 20200930
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 294
IP  - 3
DP  - 2008 Mar
TI  - Identification of Nrf2-dependent airway epithelial adaptive response to 
      proinflammatory oxidant-hypochlorous acid challenge by transcription profiling.
PG  - L469-77
AB  - 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.
FAU - Zhu, Lingxiang
AU  - Zhu L
AD  - Division of Translational Biology, The Hamner Institutes for Health Sciences, 6 
      Davis Dr., Research Triangle Park, NC 27709, USA.
FAU - Pi, Jingbo
AU  - Pi J
FAU - Wachi, Shinichiro
AU  - Wachi S
FAU - Andersen, Melvin E
AU  - Andersen ME
FAU - Wu, Reen
AU  - Wu R
FAU - Chen, Yin
AU  - Chen Y
LA  - eng
GR  - R01 AI-061695/AI/NIAID NIH HHS/United States
GR  - R01 HL-077902/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071221
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Oxidants)
RN  - 712K4CDC10 (Hypochlorous Acid)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Adaptation, Biological
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Epithelial Cells/drug effects/*physiology
MH  - ErbB Receptors/physiology
MH  - Gene Expression Profiling
MH  - Humans
MH  - Hypochlorous Acid/*toxicity
MH  - Mitogen-Activated Protein Kinases/physiology
MH  - NF-E2-Related Factor 2/*physiology
MH  - Oxidants/*toxicity
MH  - Oxidative Stress
EDAT- 2007/12/25 09:00
MHDA- 2008/05/10 09:00
CRDT- 2007/12/25 09:00
PHST- 2007/12/25 09:00 [pubmed]
PHST- 2008/05/10 09:00 [medline]
PHST- 2007/12/25 09:00 [entrez]
AID - 00310.2007 [pii]
AID - 10.1152/ajplung.00310.2007 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2008 Mar;294(3):L469-77. doi: 
      10.1152/ajplung.00310.2007. Epub 2007 Dec 21.