Hypoxia inducible factor-1α accumulation in steatotic liver preservation: Role of nitric oxide

Open-Acces journal.-- et al.[Aim]: To examine the relevance of hypoxia inducible factor (HIF-1) and nitric oxide (NO) on the preservation of fatty liver against cold ischemia-reperfusion injury (IRI). Methods]: We used an isolated perfused rat liver model and we evaluated HIF-1α in steatotic and non-steatotic livers preserved for 24 h at 4°C in University of Wisconsin and IGL-1 solutions, and then subjected to 2 h of normothermic reperfusion. After normoxic reperfusion, liver enzymes, bile production, bromosulfophthalein clearance, as well as HIF-1α and NO [endothelial NO synthase (eNOS) activity and nitrites/nitrates] were also measured. Other factors associated with the higher susceptibility of steatotic livers to IRI, such as mitochondrial damage and vascular resistance were evaluated. [Results]: A significant increase in HIF-1α was found in steatotic and non-steatotic livers preserved in IGL-1 after cold storage. Livers preserved in IGL-1 showed a significant attenuation of liver injury and improvement in liver function parameters. These benefits were enhanced by the addition of trimetazidine (an antiischemic drug), which induces NO and eNOS activation, to IGL-1 solution. In normoxic reperfusion, the presence of NO favors HIF-1α accumulation, promoting also the activation of other cytoprotective genes, such as hemeoxygenase- 1. [Concluison]: We found evidence for the role of the HIF-1α/NO system in fatty liver preservation, especially when IGL-1 solution is used. © 2010 Baishideng.Supported by The Ministerio de de Sanidad y Consumo (PI 081988), CIBER-EHD, Instituto Carlos III, Madrid and Ministerio de Asuntos Exteriores y de Cooperación Internacionales (A/020255/08 and A/02987/09), MadridPeer Reviewe

Hypoxia inducible factor-1α accumulation in steatotic liver preservation: role of nitric oxide

AIM: To examine the relevance of hypoxia inducible factor (HIF-1) and nitric oxide (NO) on the preservation of fatty liver against cold ischemia-reperfusion injury (IRI). METHODS: We used an isolated perfused rat liver model and we evaluated HIF-1α in steatotic and non-steatotic livers preserved for 24 h at 4°C in University of Wisconsin and IGL-1 solutions, and then subjected to 2 h of normothermic reperfusion. After normoxic reperfusion, liver enzymes, bile production, bromosulfophthalein clearance, as well as HIF-1α and NO [endothelial NO synthase (eNOS) activity and nitrites/nitrates] were also measured. Other factors associated with the higher susceptibility of steatotic livers to IRI, such as mitochondrial damage and vascular resistance were evaluated. RESULTS: A significant increase in HIF-1α was found in steatotic and non-steatotic livers preserved in IGL-1 after cold storage. Livers preserved in IGL-1 showed a significant attenuation of liver injury and improvement in liver function parameters. These benefits were enhanced by the addition of trimetazidine (an anti-ischemic drug), which induces NO and eNOS activation, to IGL-1 solution. In normoxic reperfusion, the presence of NO favors HIF-1α accumulation, promoting also the activation of other cytoprotective genes, such as heme-oxygenase-1. CONCLUSION: We found evidence for the role of the HIF-1α/NO system in fatty liver preservation, especially when IGL-1 solution is used

Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion

During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH + I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH + I/R. © 2010 Macmillan Publishers Limited.This work was supported by the Ministerio de Educación y Ciencia (project grant SAF 2005-00385; project grant manager BFU2009-07410) (Madrid, Spain) and the Ministerio de Sanidad y Consumo (project grant PIO60021) (Madrid, Spain). Centro de Investigaciones Biomédicas Esther Koplowitz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is supported by the Instituto de Salud Carlos III (Spain).Peer Reviewe

Solución acuosa para la preservación de tejidos y órganos

Solución acuosa para la preservación de tejidos y órganos. Se proporciona una solución acuosa mejorada para la preservación de tejidos y órganos que comprende carvedilol, tacrolimus y trimetazidina. Se observa un efecto sinérgico para esta solución de preservación que es especialmente efectiva en órganos marginales como los hígados esteatósicos.Peer reviewedUniversidad de Barcelona, Institut d’Investigacions Biomédiques August Pi i Sunyer, Consejo Superior de Investigaciones Científicas (España)200801560B1 Patente sin examen previ

New insights into fatty liver preservation using Institute Georges Lopez preservation solution

El pdf es la versión post-print.-- et al.Institute Georges Lopez preservation solution (IGL-1) has been demonstrated to be useful for fatty liver preservation. The mechanisms responsible for this effective graft protection against ischemia-reperfusion injury are pivotal actions on generation of nitric oxide a diffusible molecule with vasodilator properties, that facilitates the up-regulation of other well-known cytoprotective genes, such as hypoxia-inducible factor-1 alpha (HIF-1α) and heme-oxygenase 1 (HO-1). During normoxic reperfusion, the presence of nitric oxide permits HIF-1α accumulation to inhibit prolyl-hydoxylases, thus promoting an additional overexpression of the HO-1 in steatotic and nonsteatotic graft livers preserved in IGL-1. © 2010.This study was supported by the Ministerio de Sanidad y Consumo (PI081988), Ministerio de Asuntos Exteriores y de Cooperación Internacional/AECI (project grants A/020255/08 and A/029087/09).Peer Reviewe

Trimetazidine: Is it a promising drug for use in steatotic grafts?

Aim: Chronic organ-donor shortage has led to the acceptance of steatotic livers for transplantation, despite the higher risk of graft dysfunction or nonfunction associated with the ischemic preservation period of these organs. The present study evaluates the effects of trimetazidine (TMZ) on an isolated perfused liver model. Methods: Steatotic and non-steatotic livers were preserved for 24 h in the University of Wisconsin (UW) solution with or without TMZ. Hepatic injury and function (transaminases, bile production and sulfobromophthalein (BSP) clearance) and factors potentially involved in the susceptibility of steatotic livers to ischemia-reperfusion (I/R) injury, including oxidative stress, mitochondrial damage, microcirculatory diseases, and ATP depletion were evaluated. Results: Steatotic livers preserved in UW solution showed higher transaminase levels, lower bile production and BSP clearance compared with non-steatotic livers. Alterations in perfusion flow rate and vascular resistance, mitochondrial damage, and reduced ATP content were more evident in steatotic livers. TMZ addition to UW solution reduced hepatic injury and ameliorated hepatic functionality in both types of the liver and protected against the mechanisms potentially responsible for the poor tolerance of steatotic livers to I/R. Conclusion: TMZ may constitute a useful approach in fatty liver surgery, limiting the inherent risk of steatotic liver failure following transplantation. © 2006 The WJG Press. All rights reserved.Supported by the Ministerio de Ciencia y Tecnología (project grants HP 2003-0051, BFI 2002-00704 and BFI 2003-00912) and the Agencia Española de Cooperación Internacional (AECI, project grant 25/03/P) (Madrid, Spain)Peer Reviewe

Trimetazidine and liver preservation against ischaemia-reperfusion injury

Trimetazidine is an anti-ischaemic drug used for angina pectoris treatment. Recently, it has been shown that trimetazidine protects against hepatic ischaemia reperfusion injury. Several hypotheses have been proposed to explain the exact hepatoprotective mechanisms but they still remain unclear. This review assesses the possible mechanisms responsible for the increase of the liver's tolerance against ischaemia-reperfusion injury with special emphasis on: (1) the prevention of oxidative stress and protection of mitochondrial function; (2) the generation of vasoactive mediators such as nitric oxide and endothelins; and finally (3) the preservation of liver energy metabolism. Copyright © 2007 Termedia & Banach.This work was supported by the Ministerio de Educación y Ciencia (project grant SAF 2005-00385), Ministerio de Sanidad y Consumo (project grant PIO60021) and Ministerio de Asuntos Exteriores y de Cooperación Internacional/Agencia Española De Cooperación Internacional.Peer Reviewe

Relevance of epidermal growth factor to improve steatotic liver preservation in IGL-1 solution

Aim Static preservation solution is critical for liver graft outcomes, especially when steatosis is present. Institut Georges Lopez (IGL)-1 solution protects fatty livers effectively against cold ischemia reperfusion injury. Its benefits are mediated by nitric oxide and prevention of oxidative stress. The supplementation of IGL-1 with epidermal growth factor (EGF) enhances steatotic graft preservation by increasing adenosine triphosphate content, thereby mitigating oxidative stress and mitochondrial damage. Methods After steatotic livers were preserved for 24 hours in IGL-1 solution with or without EGF supplements, they were perfused ex vivo for 2 hours at 37°C. The benefits of EGF were assessed by evidences of hepatic damage and functiontransaminases, bile production, and flow rateas well as by other factors presumably associated with the poor tolerance of fatty livers toward cold ischemia-reperfusion injury (IRI)energy metabolism, mitochondrial damage, oxidative stress, eNOS activity and proinflammatory interleukin (IL) beta content. Results Steatotic livers preserved in IGL-1 solutions supplemented with EGF (10 μg/L) showed lower transaminase levels, greater bile production, and ameliorated flow rates when compared to IGL-1 alone. In addition, energy metabolism deterioration, mitochondrial damage, oxidative stress, and cytokine IL-1 beta release were prevented. Conclusion EGF addition to IGL-1 increased fatty liver graft preservation, thereby reducing steatotic liver damage against cold IRI. © 2010 Elsevier Inc.This study was supported by the Ministerio de de Sanidad y Consumo (PI 081988), CIBER-ehd, Instituto Carlos III, Madrid and Ministerio de Asuntos Exteriores y de Cooperación Internacionales (A/020255/08 and A/02987/09), Madrid. Mohamed Amine Zaouali is fellowship-holder from the Societat Catalana de Trasplantament.Peer Reviewe

Improved rat steatotic and nonsteatotic liver preservation by the addition of epidermal growth factor and insulin-like growth factor-I to University of Wisconsin solution

This study examined the effects of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) supplementation to University of Wisconsin solution (UW) in steatotic and nonsteatotic livers during cold storage. Hepatic injury and function were evaluated in livers preserved for 24 hours at 4°C in UW and in UW with EGF and IGF-I (separately or in combination) and then perfused ex vivo for 2 hours at 37°C. AKT was inhibited pharmacologically. In addition, hepatic injury and survival were evaluated in recipients who underwent transplantation with steatotic and nonsteatotic livers preserved for 6 hours in UW and UW with EGF and IGF-I (separately or in combination). The results, based on isolated perfused liver, indicated that the addition of EGF and IGF-I (separately or in combination) to UW reduced hepatic injury and improved function in both liver types. A combination of EGF and IGF-I resulted in hepatic injury and function parameters in both liver types similar to those obtained by EGF and IGF-I separately. EGF increased IGF-I, and both additives up-regulated AKT in both liver types. This was associated with glycogen synthase kinase-3β (GSK3β) inhibition in nonsteatotic livers and PPARγ overexpression in steatotic livers. When AKT was inhibited, the effects of EGF and IGF-I on GSK3β, PPARγ, hepatic injury and function disappeared. The benefits of EGF and IGF-I as additives in UW solution were also clearly seen in the liver transplantation model, because the presence of EGF and IGF-I (separately or in combination) in UW solution reduced hepatic injury and improved survival in recipients who underwent transplantation with steatotic and nonsteatotic liver grafts. In conclusion, EGF and IGF-I may constitute new additives to UW solution in steatotic and nonsteatotic liver preservation, whereas a combination of both seems unnecessary. © 2010 AASLD.Supported by the Ministerio de Sanidad y Consumo (project grant PIO60021) and the Ministerio de Ciencia e Innovación (project grant BFU2009-07410) (both in Madrid, Spain). The Centro de Investigaciones Biomédicas Esther Koplowitz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), is supported by the Instituto de Salud Carlos III (Spain).Peer Reviewe