A novel strategy against ischemia and reperfusion injury: cytoprotection with heme oxygenase system

Katori, Masamichi; Anselmo, Dean M.; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.

doi:10.1016/s0966-3274(02)00043-6

Cited by 78 publications

(49 citation statements)

References 46 publications

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“…Induction of HO-1 affords important cytoprotective functions in hepatic IRI 6,8,9,11,[15][16][17] ; however, the role of BV-one of the key products of HO-1-and its potential use in preventing IRI have not been explored. We have demonstrated that BV treatment exerts striking cytoprotection in rat liver models of hepatic cold ischemia followed by ex vivo reperfusion or syngeneic OLT.…”

Section: Discussionmentioning

confidence: 99%

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Biliverdin therapy protects rat livers from ischemia and reperfusion injury

et al. 2004

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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

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Section: Discussionmentioning

confidence: 99%

“…Because activation of HO-1 affords a cytoprotective function, its use as a novel strategy to prevent IRI has been extensively studied. 6 In the clinical setting, however, upregulating HO-1 may be a suboptimal approach for many reasons. First, no known reagents specifically induce HO activity.…”

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confidence: 99%

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

et al. 2004

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“…PDTC is one of the most effective inducers of heme oxygenase-1 (HO-1), which also confers cytoprotection against oxidative stress [16] . HO is the rate-limiting enzyme in the conversion of heme into carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (Fe 2+ ) [17] . Three isoforms of HO have so far been identified: inducible HO-1; constitutively expressed HO-2; and HO-3 which is related to HO-2, but is less well characterized [17] .…”

Section: Introductionmentioning

confidence: 99%

“…HO is the rate-limiting enzyme in the conversion of heme into carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (Fe 2+ ) [17] . Three isoforms of HO have so far been identified: inducible HO-1; constitutively expressed HO-2; and HO-3 which is related to HO-2, but is less well characterized [17] . The HO system is thought to play a pivotal role in the maintenance of antioxidant and oxidant homeostasis during cellular injury.…”

Section: Introductionmentioning

confidence: 99%

“…The HO system is thought to play a pivotal role in the maintenance of antioxidant and oxidant homeostasis during cellular injury. The HO system exerts four major beneficial effects broadly: (a) antioxidant function; (b) maintenance of the microcirculation; (c) anti-apoptosis; and (d) anti-inflammatory function [17] . The antioxidant function relies on heme degradation, production of bilirubin [18] , and the formation of ferritin via Fe 2+ [19] .…”

Section: Introductionmentioning

confidence: 99%

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Pyrrolidine dithiocarbamate reduces ischemia-reperfusion injury of the small intestine

Mallick

Yang²,

Winslet³

et al. 2005

WJG

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AIM:To evaluate whether pyrrolidine dithiocarbamate (PDTC), an enhancer of HO production, attenuates intestinal IR injury.METHODS: E i g h t e e n m a l e ra t s w e r e ra n d o m l y allocated into three groups: (a) sham; (b) IR, consisting of 30 min of intestinal ischemia, followed by 2-h period of reperfusion; and (c) PDTC treatment before IR. Intestinal microvascular perfusion (IMP) was monitored continuously by laser Doppler flowmetry. At the end of the reperfusion, serum samples for lactate dehydrogenase (LDH) levels and biopsies of ileum were obtained. HO activity in the ileum was assessed at the end of the reperfusion period. RESULTS:At the end of the reperfusion in the IR group, IMP recovered partially to 42.5% of baseline (P <0.05 vs sham), whereas PDTC improved IMP to 67.3% of baseline (P <0.01 vs IR). There was a twofold increase in HO activity in PDTC group (2 062.66±106.11) as compared to IR (842.3±85.12) (P <0.001). LDH was significantly reduced (P<0.001) in PDTC group (585.6±102.4) as compared to IR group (1 973.8±306.5). Histological e x a m i n a t i o n s h o w e d t h a t t h e i l e a l m u c o s a wa s significantly less injured in PDTC group as compared with IR group. CONCLUSION:

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Heme oxygenase‐1: a new drug target in oxidative tissue injuries in critically ill conditions

Takahashi

Shimizu

Akagi

et al. 2006

Drug Development Research

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Oxidative stresses associated with ischemia/reperfusion, neutrophil activation, and anesthesia with certain volatile agents, etc., are thought to play an important role in the development of acute organ failure in critical illnesses, such as acute lung injury, acute coronary artery insufficiency, acute liver failure, acute renal failure, and multiple organ dysfunction syndrome. Such oxidative stressors provoke a set of cellular responses, particularly those that participate in the defense against tissue injuries. Free heme, which can be rapidly released from hemeproteins, may constitute a major threat in the oxidant stress because it catalyzes the formation of reactive oxygen species. To counteract such insults, cells respond by inducing the 33-kDa heat shock protein, heme oxygenase (HO)-1, the rate-limiting enzyme in heme degradation. Induced HO-1 as such removes free heme by an enzymatic process. In addition, HO-1 induction itself confers protection to tissues from further oxidative injuries. In contrast, the abrogation of HO-1 induction, or chemical ablation of HO activity abolishes the beneficial effect of HO-1, and results in the aggravation of tissue injuries. In this article, we review recent advances in the essential role of HO-1 in tissue protection in various models of experimental oxidative tissue injuries as well as in human disorders, which is related to critically ill conditions, with special emphasis on the role of its induction in tissue defense and its potential therapeutic implications. Drug Dev. Res. 67:130-153, 2006.

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A novel strategy against ischemia and reperfusion injury: cytoprotection with heme oxygenase system

Cited by 78 publications

References 46 publications

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

Pyrrolidine dithiocarbamate reduces ischemia-reperfusion injury of the small intestine

Heme oxygenase‐1: a new drug target in oxidative tissue injuries in critically ill conditions

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