Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

Abstract

Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of results in the production of carbon monoxide (CO), free iron, and biliverdin (BV). HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells. 5 In vivo, HO-1 induction has been shown previously to protect mice from apoptotic liver damage 5 and to protect rats from liver graft rejection as well as from ischemia/reperfusion injury. 6 -8 To investigate mechanisms of cytokine-dependent liver injury, mice can be sensitized with the hepatocytespecific transcriptional inhibitor D-galactosamine (GalN) in combination with the macrophage activator lipopolysaccharide (LPS). 9 In this GalN/LPS model, mice develop severe liver injury, which is dependent on tumor necrosis factor (TNF) 10,11 and interferon ␥ (IFN-␥) 12 induction, while interleukin (IL) 10 prevents injury. 13 In the present study we show that HO-1, induced by CoPP, protects mice from GalN/LPS-induced liver injury, prolongs survival, and reduces cytokine expression. Protection from liver damage could also be achieved by pretreatment with the HO products CO and BV, but not by ferritin. Prolongation of survival and cytokine reduction was only detectable in mice pretreated with a combination of both hepatoprotective products CO and BV. Materials and MethodsAnimals. BALB/c-mice (6-8 weeks old; weight range, 18-22 g) were obtained from the animal facilities of the

Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

“…Activation of NF-κB, probably due to oxidative stress, could lead to expression of TNF-α. An inhibition of proinflammatory cytokine production as a result of HO-1 overexpression, as reported for several other liver injury models [73][74][75] , could not be demonstrated in the present study. In addition, we have shown that activation of NF-κB and expression of TNF-α and TGF-β were increased by cholestasis and that these effects were not blocked by HO-1 overexpression (Figure 9).…”

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

“…The quantity of CO produced per mole of inhaled DCM in rats was about 0.7 to 0.8 mol (Andersen et al, 1994). The half-life of DCM in vivo is about 3 h, and CO released from DCM has a half-life of about 13 h (Wirkner et al, 1997;Sass et al, 2004).…”

Lucidone Suppresses Hepatitis C Virus Replication by Nrf2-Mediated Heme Oxygenase-1 Induction

“…Its reaction products including biliverdin, carbon monoxide, and ferrous iron are regarded as potential cytoprotectants (9). Among the various intracellular molecules capable of inducing HO-1, BTB and CNC homolog 1 (Bach1) and nuclear factor erythroid-derived 2 related factor 2 (Nrf2) play crucial roles in the regulation of HO-1 expression for the maintenance of cellular redox homeostasis (10).…”