Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice
✍ Scribed by Gabriele Sass; Miguel Che Parreira Soares; Kenichiro Yamashita; Stefan Seyfried; Wolfram-Hubertus Zimmermann; Thomas Eschenhagen; Elzbieta Kaczmarek; Thomas Ritter; Hans-Dieter Volk; Gisa Tiegs
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 1016 KB
- Volume
- 38
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Heme oxygenase-1 (HO-l), 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 &om apoptotic liver damage induced by anti-CD95 antibody (Ab) or D-gahctosamhe in combination with either anti-CD3 Ab, lipopolysaccharide (LPS), or tumor necrosis factor a (TNF-a). HO-1 induction prevented apoptotic liver injury, measured by inhibition of caspase 3 activation, although it did not protect mice &.om caspase-Sindependent necrotic liver damage caused by concanavalin A (Con A) administration. In addition, overexpression of HO-1 by adenoviral gene transfer resulted in protection &.om apoptotic liver injury, whereas inhibition of HO-1 enzymatic activity by tin-protoporphyrin-M (SnPP) abrogated the protective 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 Kupfir cells (KCS) did not interfere with the protective effect in uivo. Ekogenous CO administration or treatment with the CO-releasing agent methyiene chloride mimicked the protective effka 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 &or for cytokine-and CD95mediated apoptotic liver damage. Induction of HO-1 might be of a therapeutic modality for inflammatory liver diseases. (HEPATOLOGY 2003;38:909-918.