Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation

David J. Blake, Anju Singh, Ponvijay Kombairaju, Deepti Malhotra, Thomas J. Mariani, Rubin M. Tuder, Edward Gabrielson, Shyam Biswal

Research output: Contribution to journalArticle

Abstract

Exposure to cigarette smoke (CS) is the primary factor associated with the development of chronic obstructive pulmonary disease (COPD). CS increases the level of oxidants in the lungs, resulting in a depletion of antioxidants, which promotes oxidative stress and the destruction of alveolar tissue. In response to CS, pulmonary epithelial cells counteract increased levels of oxidants by activating Nrf2-dependent pathways to augment the expression of detoxification and antioxidant enzymes, thereby protecting the lung from injury. We hypothesize that increasing the pathways activated by Nrf2 will afford protection against CS-induced lung damage. To this end we have developed a novel mouse model in which the cytosolic inhibitor of Nrf2, Keap1, is genetically deleted in Clara cells, which predominate in the upper airways in mice. Deletion of Keap1 in Clara cells resulted in increased expression of Nrf2-dependent genes, such as Nqo1 and Gclm, as determined by microarray analysis and quantitative PCR. Deletion of Keap1 in airway epithelium decreased Keap1 protein levels and significantly increased the total level of glutathione in the lungs. Increased Nrf2 activation protected Clara cells against oxidative stress ex vivo and attenuated oxidative stress and CS-induced inflammation in vivo. Expression of KEAP1 was also decreased in human epithelial cells through siRNA transfection, which increased the expression of Nrf2-dependent genes and attenuated oxidative stress. In conclusion, activating Nrf2 pathways in tissue-specific Keap1 knockout mice represents an important genetic approach against oxidant-induced lung damage.

Original languageEnglish (US)
Pages (from-to)524-536
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume42
Issue number5
DOIs
StatePublished - May 1 2010

Keywords

  • Cigarette smoke
  • Inflammation
  • Keap1
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation'. Together they form a unique fingerprint.

  • Cite this