Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway

Hum Gene Ther. 2002 Nov 1;13(16):1945-60. doi: 10.1089/10430340260355356.


Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 confers protection against many types of cell and tissue damage by modulating apoptotic cell death or cytokine expression profiles, we hypothesized that adenovirus-mediated transfer of HO-1 cDNA and subsequent overexpression of the protein in lung would provide therapeutic benefit in a murine model of bleomycin-induced pulmonary fibrosis. In C57BL/6 mice, HO-1 overexpression clearly suppressed the development of fibrotic changes and was associated with enhanced interferon gamma production in lung and reduced numbers of respiratory epithelial cells with damaged DNA. However, HO-1 overexpression did not prevent pulmonary fibrosis induced by agonistic anti-Fas antibody inhalation in C57BL/6 or ICR mice, a strain known to develop pulmonary fibrosis via the Fas-Fas ligand (FasL) pathway. Consistent with the concept that HO-1 overexpression prevents fibrosis via a pathway independent of Fas-FasL interaction, Ad.HO-1 administration prevented bleomycin-induced pulmonary fibrosis in gld/gld mice, which express nonfunctional FasL. These observations suggest that using HO-1 overexpression strategies to treat idiopathic pulmonary fibrosis, or fibrotic disorders of other target organs, by attenuating apoptotic cell death likely would be effective in clinical situations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Apoptosis
  • Bleomycin / pharmacology*
  • Blotting, Western
  • Bronchoalveolar Lavage Fluid
  • DNA / metabolism
  • DNA, Complementary / metabolism
  • Fas Ligand Protein
  • Fibrosis
  • Gene Transfer Techniques*
  • Genetic Vectors*
  • Heme Oxygenase (Decyclizing) / biosynthesis*
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase-1
  • Hydroxyproline / metabolism
  • In Situ Nick-End Labeling
  • Ligands
  • Lung / drug effects
  • Lung / pathology
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Signal Transduction
  • Time Factors


  • DNA, Complementary
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins
  • Bleomycin
  • DNA
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Hydroxyproline