Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice

Heme oxygenase–1 (HO–1), a stress–responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin, and iron, has previously been shown to protect grafts from ischemia/reperfusion injury and rejection. Here we investigated the protective potential of HO–1 in 5 models of immune–mediated liver injury. We found that up–regulation of endogenous HO–1 by cobalt–protoporphyrin–IX (CoPP) protected mice from apoptotic liver damage induced by anti–CD95 antibody (Ab) or D–galactosamine in combination with either anti–CD3 Ab, lipopolysaccharide (LPS), or tumor necrosis factor α (TNF–α). HO–1 induction prevented apoptotic liver injury, measured by inhibition of caspase 3 activation, although it did not protect mice from caspase–3—independent necrotic liver damage caused by concanavalin A (Con A) administration. In addition, overexpression of HO–1 by adenoviral gene transfer resulted in protection from apoptotic liver injury, whereas inhibition of HO–1 enzymatic activity by tin–protoporphyrin–IX (SnPP) abrogated the protective effect. HO–1—mediated protection seems to target parenchymal liver cells directly because CoPP treatment protected isolated primary hepatocytes from anti–CD95—induced apoptosis in vitro. Furthermore, depletion of Kupffer cells (KCs) did not interfere with the protective effect in vivo. Exogenous CO administration or treatment with the CO–releasing agent methylene chloride mimicked the protective effect of HO–1, whereas treatment with exogenous biliverdin or overexpression of ferritin by recombinant adenoviral gene transfer did not. In conclusion, HO–1 is a potent protective factor for cytokine– and CD95–mediated apoptotic liver damage. Induction of HO–1 might be of a therapeutic modality for inflammatory liver diseases. (Hepatology 2003;38:909-918).