Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury

Am J Respir Cell Mol Biol. 1996 Jun;14(6):556-68. doi: 10.1165/ajrcmb.14.6.8652184.


Using hyperoxia as a model of oxidant-induced lung injury in the rat, we explored the regulation of heme oxygenase-1 (HO-1) expression in vivo and in vitro. We demonstrate marked increase of HO-1 messenger ribonucleic acid (mRNA) levels in rat lungs after hyperoxia. Increased HO-1 mRNA expression correlated with increased HO-1 protein and enzyme activity. Immunohistochemical studies of the rat lung after hyperoxia showed increased HO-1 expression in a variety of cell types, including the bronchoalveolar epithelium and interstitial and inflammatory cells. We then examined the regulation of HO-1 expression in vitro after hyperoxia and observed increased HO-1 gene expression in various cultured cells including epithelial cells, fibroblasts, macrophages, and smooth muscle cells. Increased HO-1 mRNA expression correlated with increased HO-1 protein in vitro, and resulted from increased gene transcription and not from increased mRNA stability. We show that transcriptional activation of the HO-1 gene by hyperoxia requires cooperation between the HO-1 promoter and an enhancer fragment located 4 kb upstream from its transcription site. Increased HO-1 gene transcription was associated with increased activator protein-1 (AP-1) binding activity and supershift of the AP-1 complex by antibodies to c-Fos and c-Jun after hyperoxia. Taken together, our data suggest that AP-1 activation may represent one mechanism mediating hyperoxia-induced HO-1 gene transcription.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cells, Cultured / chemistry
  • Cells, Cultured / physiology
  • Dose-Response Relationship, Drug
  • Epithelial Cells
  • Epithelium / chemistry
  • Epithelium / physiology
  • Fibroblasts / chemistry
  • Fibroblasts / physiology
  • Gene Expression Regulation, Enzymologic / physiology
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase (Decyclizing) / metabolism
  • Humans
  • Hyperoxia / physiopathology*
  • Immunohistochemistry
  • Kinetics
  • Lung Diseases / chemically induced
  • Macrophages, Alveolar / chemistry
  • Macrophages, Alveolar / physiology
  • Macrophages, Peritoneal / chemistry
  • Macrophages, Peritoneal / physiology
  • Mice
  • Molecular Sequence Data
  • Oxygen / adverse effects
  • Protein Binding / physiology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Specific Pathogen-Free Organisms
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic / physiology


  • RNA, Messenger
  • Transcription Factor AP-1
  • Heme Oxygenase (Decyclizing)
  • Oxygen