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

Ralf Harto Hübner, Jamie D. Schwartz, Bishnu P. De, Barbara Ferris, Larsson Omberg, Jason G. Mezey, Neil R. Hackett, Ronald Crystal

Research output: Contribution to journalArticle

54 Citations (Scopus)

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 healthysmoker, 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.

Original languageEnglish
Pages (from-to)203-219
Number of pages17
JournalMolecular Medicine
Volume15
Issue number7-8
DOIs
Publication statusPublished - 1 Jul 2009
Externally publishedYes

Fingerprint

Epithelium
Smoking
Oxidants
Genes
Smoke
Tobacco Products
Antioxidant Response Elements
Glucuronosyltransferase
Bronchoscopy
Genetic Promoter Regions
Transcription Factors
Antioxidants
History
Observation
Demography
Gene Expression
Polymerase Chain Reaction
Peptides
Population
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking. / Hübner, Ralf Harto; Schwartz, Jamie D.; De, Bishnu P.; Ferris, Barbara; Omberg, Larsson; Mezey, Jason G.; Hackett, Neil R.; Crystal, Ronald.

In: Molecular Medicine, Vol. 15, No. 7-8, 01.07.2009, p. 203-219.

Research output: Contribution to journalArticle

Hübner, Ralf Harto ; Schwartz, Jamie D. ; De, Bishnu P. ; Ferris, Barbara ; Omberg, Larsson ; Mezey, Jason G. ; Hackett, Neil R. ; Crystal, Ronald. / Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking. In: Molecular Medicine. 2009 ; Vol. 15, No. 7-8. pp. 203-219.
@article{62a055a8cca14d77a5ed4dacaf94310d,
title = "Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette 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 healthysmoker, 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.",
author = "H{\"u}bner, {Ralf Harto} and Schwartz, {Jamie D.} and De, {Bishnu P.} and Barbara Ferris and Larsson Omberg and Mezey, {Jason G.} and Hackett, {Neil R.} and Ronald Crystal",
year = "2009",
month = "7",
day = "1",
doi = "10.2119/molmed.2008.00130",
language = "English",
volume = "15",
pages = "203--219",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",
number = "7-8",

}

TY - JOUR

T1 - Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking

AU - Hübner, Ralf Harto

AU - Schwartz, Jamie D.

AU - De, Bishnu P.

AU - Ferris, Barbara

AU - Omberg, Larsson

AU - Mezey, Jason G.

AU - Hackett, Neil R.

AU - Crystal, Ronald

PY - 2009/7/1

Y1 - 2009/7/1

N2 - 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 healthysmoker, 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.

AB - 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 healthysmoker, 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.

UR - http://www.scopus.com/inward/record.url?scp=67650354551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650354551&partnerID=8YFLogxK

U2 - 10.2119/molmed.2008.00130

DO - 10.2119/molmed.2008.00130

M3 - Article

C2 - 19593404

AN - SCOPUS:67650354551

VL - 15

SP - 203

EP - 219

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

IS - 7-8

ER -