Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection

Sei Ichiro Tsuchihashi, Masha Livhits, Yuan Zhai, Ronald W. Busuttil, Jesus A. Araujo, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Heme oxygenase-1 (HO-1) overexpression protects against tissue injury in many inflammatory processes, including ischemia/reperfusion injury (IRI). This study evaluated whether genetically decreased HO-1 levels affected susceptibility to liver IRI. Partial warm ischemia was produced in hepatic lobes for 90 min followed by 6 h of reperfusion in heterozygous HO-1 knockout (HO-1+/-) and HO-1+/+ wild-type (WT) mice. HO-1 +/- mice demonstrated reduced HO-1 mRNA/protein levels at baseline and postreperfusion. This corresponded with increased hepatocellular damage in HO-1+/- mice, compared with WT. HO-1+/- mice revealed enhanced neutrophil infiltration and proinflammatory cytokine (TNF-α, IL-6, and IFN-γ) induction, as well as an increase of intrahepatic apoptotic TUNEL+ cells with enhanced expression of proapoptotic genes (Bax/cleaved caspase-3). We used cobalt protoporphyrin (CoPP) treatment to evaluate the effect of increased baseline HO-1 levels in both WT and HO-1 +/- mice. CoPP treatment increased HO-1 expression in both animal groups, which correlated with a lower degree of hepatic damage. However, HO-1 mRNA/protein levels were still lower in HO-1+/- mice, which failed to achieve the degree of antioxidant hepatoprotection seen in CoPP-treated WT. Although the baseline and postreperfusion HO-1 levels correlated with the degree of protection, the HO-1 fold induction correlated instead with the degree of damage. Thus, basal HO-1 levels are more critical than the ability to up-regulate HO-1 in response to the IRI and may also predict the success of pharmacologically induced cytoprotection. This model provides an opportunity to further our understanding of HO-1 in stress defense mechanisms and design new regimens to prevent IRI.

Original languageEnglish (US)
Pages (from-to)4749-4757
Number of pages9
JournalJournal of Immunology
Issue number7
StatePublished - Oct 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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