| 14512878 |
Sass G, Soares MC, Yamashita K, Seyfried S, Zimmermann WH, Eschenhagen T, Kaczmarek E, Ritter T, Volk HD, Tiegs G: Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. Hepatology. 2003 Oct;38(4):909-18.
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 alpha (TNF-alpha). 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. |
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