Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking. Academic Article uri icon

Overview

MeSH

  • ATP-Binding Cassette Transporters
  • Adult
  • Analysis of Variance
  • Bronchoscopy
  • Carrier Proteins
  • Epithelium
  • Female
  • Glucuronosyltransferase
  • Humans
  • Male
  • Middle Aged
  • Nuclear Proteins
  • Oligonucleotide Array Sequence Analysis
  • Oxidants
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction

MeSH Major

  • Bronchi
  • Gene Expression Regulation
  • NF-E2-Related Factor 2
  • Smoking

abstract

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oxidant-responsive transcription factor known to induce detoxifying and antioxidant genes. Cigarette smoke, with its large oxidant content, is a major stress on the cells of small airway epithelium, which are vulnerable to oxidant damage. We assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample the small airway epithelium in healthy-nonsmoker and healthy-smoker, and gene expression was assessed using microarrays. Relative to nonsmokers, Nrf2 protein in the small airway epithelium of smokers was activated and localized in the nucleus. The human homologs of 201 known murine Nrf2-modulated genes were identified, and 13 highly smoking-responsive Nrf2-modulated genes were identified. Construction of an Nrf2 index to assess the expression levels of these 13 genes in the airway epithelium of smokers showed coordinate control, an observation confirmed by quantitative PCR. This coordinate level of expression of the 13 Nrf2-modulated genes was independent of smoking history or demographic parameters. The Nrf2 index was used to identify two novel Nrf2-modulated, smoking-responsive genes, pirin (PIR) and UDP glucuronosyltransferase 1-family polypeptide A4 (UGT1A4). Both genes were demonstrated to contain functional antioxidant response elements in the promoter region. These observations suggest that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cells, and that there is variability within the human population in the Nrf2 responsiveness to oxidant burden.

publication date

  • July 2009
  • August 2009

has subject area

  • ATP-Binding Cassette Transporters
  • Adult
  • Analysis of Variance
  • Bronchi
  • Bronchoscopy
  • Carrier Proteins
  • Epithelium
  • Female
  • Gene Expression Regulation
  • Glucuronosyltransferase
  • Humans
  • Male
  • Middle Aged
  • NF-E2-Related Factor 2
  • Nuclear Proteins
  • Oligonucleotide Array Sequence Analysis
  • Oxidants
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smoking

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2707520

Digital Object Identifier (DOI)

  • 10.2119/molmed.2008.00130

PubMed ID

  • 19593404

Additional Document Info

start page

  • 203

end page

  • 219

volume

  • 15

number

  • 7-8