Bilirubin rinse: A simple protectant against the rat liver graft injury mimicking heme oxygenase-1 preconditioning

Kato, Yutaro; Shimazu, Motohide; Kondo, Masayuki; Uchida, Koji; Kumamoto, Yusuke; Wakabayashi, Go; Kitajima, Masaki; Suematsu, Makoto

doi:10.1053/jhep.2003.50300

Cited by 94 publications

(79 citation statements)

References 35 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5,18 Our previous study in rats suggested that another HO-derived product bilirubin but not CO has the ability to improve bile acid-dependent bile output of the post-cold ischemic liver grafts through its antioxidative action. 32 However, such an effect of bilirubin appears to be distinct from the stimulatory action of CO on biliary fluid excretion indicated in the current study. CO has been shown to exert diverse actions on biliary function through multiple mechanisms: First, stress-inducible levels of CO have the ability to elongate the intervals of bile canalicular contraction, which helps increase the stroke volume for promoting bile excretion; this process appears to involve mechanisms mediated by modulation of cytochrome P450 epoxygenases and intra- cellular Ca 2ϩ mobilization.…”

Section: Discussioncontrasting

confidence: 59%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

View full text Add to dashboard Cite

Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine ␤-synthase (CBS) that rate-limits transsulfuration pathway and H 2 S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H 2 S to stimulate HCO 3 ؊ -dependent choleresis: these responses were attenuated by blocking HO C arbon monoxide (CO) is generated from inducible heme oxygenase 1 (HO-1) and constitutive heme oxygenase 2 (HO-2), respectively, and has the ability to regulate neurovascular functions, 1,2 apoptotic responses, 3,4 and metabolism of xenobiotics and toxicants. 5,6 This gas is overproduced through increased delivery of heme as a substrate and the HO-1 induction on exposure to stressors such as hypoxia and oxidative stress. Mechanisms by which CO regulates cell functions appear to involve an activation of soluble guanylate cyclase (sGC), the enzyme that allows the gas to bind to the prosthetic heme to synthesize cyclic guanosine monophosphate as a second messenger. 1 Distinct from nitric oxide (NO) that forms 5-coordinated NO-Fe(II) complex to trigger full activation of the enzyme, CO activates this enzyme only modestly because the gas binding stabilizes 6-coordinated CO-Fe(II)-histidine complex. 7 Mitogen-activated protein kinase has also been shown to serve as a CO-responsive signal transducer. 8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. 7-9 However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.Because this gas has the ability to inhibit ferrous form of the prosthetic heme of enzymes, tryptophan 2,3-dioxygenase or cytochromes P450 have been considered puta-

show abstract

Section: Discussioncontrasting

confidence: 59%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

View full text Add to dashboard Cite

show abstract

“…21 Recently it has been shown that BV therapy blocked hepatic acetaminophen-induced injury in rats by protecting the liver against reactive oxygen and nitrogen intermediates. 22 Kato et al 23 have shown that BR rinse of livers decreased the oxidative stress and hepatobiliary dysfunction, mimicking the effects of HO-1-mediated preconditioning. In this report, BR used to rinse the grafts at a dose of 50 mol/L resulted in a mortality rate of 100%.…”

Section: Discussionmentioning

confidence: 95%

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

et al. 2004

View full text Add to dashboard Cite

Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1␤, tumor necrosis factor ␣, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs. (HEPATOLOGY 2004;40:1333-1341 I schemia and reperfusion injury (IRI), an antigen-independent component of the insult to the liver during "harvesting," represents an important problem affecting liver transplantation. IRI causes up to 10% of early liver failures and can lead to a higher incidence of acute and chronic rejection. 1 Moreover, with the increasing donor shortage, more functionally "suboptimal" or "marginal" livers are being used. Such livers are more susceptible to the damage caused by IRI compared with normal livers. 2 Indeed, minimizing the adverse effects of IRI could significantly increase the number of patients that successfully undergo liver transplantation.Liver IRI is mediated by several processes that lead to hepatocellular damage, which is triggered when the liver is transiently deprived of oxygen during the organ procurement for transplantation, and later reoxygenated during reperfusion. The structural changes promoted by cold ischemia and reperfusion become more prominent with increased storage time. 3 The sinusoidal endothelial cells are very sensitive to IRI, thus affecting the delicate balance that maintains homeostasis in the microcirculation with

show abstract

“…70 Bilirubin had a protective effect on the transplanted liver grafts via inhibition of lipid peroxidation in hepatocytes. 71 Although reduced iron (Fe 2 þ ) released by HO-1 from the core of the heme molecule is a potent prooxidant, the potential catalysis of oxidative reactions by this compound is limited through its chelation by iron-sequestering protein ferritin as well as via its active removal from the cell by the specific Fe-ATPase pump. 72 Moreover, ferritin production and biological activity of Fe-ATPase pump are potentiated by increased free iron in the intracellular pool due to enhanced HO-1 expression.…”

Section: Expression Of Il-6 After To Administration and Its Possible mentioning

confidence: 99%

Upregulation of heme oxygenase-1 gene by turpentine oil-induced localized inflammation: involvement of interleukin-6

Tron¹,

Novosyadlyy²,

Dudás³

et al. 2005

Laboratory Investigation

View full text Add to dashboard Cite

Heme oxygenase-1 (HO-1) is the inducible isoform of an enzyme family responsible for heme degradation and was suggested to be involved in the acute phase response in the liver. However, the mechanisms of the HO-1 regulation under inflammatory conditions are poorly understood. Therefore, the purpose of the current work was to study the expression of HO-1 in the liver and other organs of rats with a localized inflammation after intramuscular injection of turpentine oil (TO). Since interleukin-6 (IL-6) is known to be a principal mediator of inflammation, the levels of this cytokine were also estimated in the animal model used. HO-1 and IL-6 expression was evaluated by Northern blot, in situ hybridization, Western blot, immunohistochemistry and enzyme-linked immunosorbent assay. In the liver and injured muscle, the HO-1 mRNA levels were dramatically increased 4-6 h after TO administration. HO-1 protein levels in the liver were elevated starting from 6-12 h after the treatment. In other internal organs such as the heart, kidney and large intestine, only a slight induction of HO-1 mRNA was observed. IL-6-specific transcripts appeared only in the injured muscle and were in accordance with serum levels of IL-6. In turn, temporal expression of IL-6 in the muscle and circulatory IL-6 levels correlated well with HO-1 expression in the liver and injured muscle. In the liver of control rats HO-1 protein was detected in Kupffer cells, while in TO-injected rats also hepatocytes became strongly HO-1 positive. Conversely, in the injured muscle, HO-1 immunoreactivity was attributed only to macrophages. Our data demonstrate that during localized inflammation HO-1 expression was rapidly and strongly induced in macrophages of injured muscle and in hepatocytes, and IL-6 derived from injured muscle seems to be responsible for the HO-1 induction in the liver.

show abstract

Bilirubin rinse: A simple protectant against the rat liver graft injury mimicking heme oxygenase-1 preconditioning

Cited by 94 publications

References 35 publications

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

Upregulation of heme oxygenase-1 gene by turpentine oil-induced localized inflammation: involvement of interleukin-6

Contact Info

Product

Resources

About