Hepatocellular ultrastructure after ischemia/reperfusion injury in human orthotopic liver transplantation

Nadig, Satish N.; Periyasamy, Basker; Shafizadeh, Stephen; Polito, Carmen; Fiorini, Ryan N.; Rodwell, David W.; Evans, Zachary; Cheng, Gang; Dunkelberger, Dana G.; Schmidt, Michael G.; Self, Sally; Chavin, Kenneth D.

doi:10.1016/j.gassur.2004.04.002

Cited by 11 publications

(9 citation statements)

References 11 publications

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“…In general, transplantation centers reject severely steatotic grafts for transplantation since steatosis markedly increases the risk of primary graft non-function [3–5, 35]. Hepatic steatosis is often associated with obesity; therefore, high body mass index is used as an indicator for rejection of potential donors for living liver donation [36].…”

Section: Discussionmentioning

confidence: 99%

“…Hepatic steatosis is highly prevalent in liver donors, and steatotic liver grafts represent the most common “extended criteria” organ. However, use of steatotic livers for transplantation remains problematic because these livers have higher graft nonfunction [3–5]. Therefore, approaches to prevent steatosis-induced primary graft failure are important for expansion of the usable donor pool and for improving liver transplantation safety.…”

Section: Introductionmentioning

confidence: 99%

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Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers

Liu

Rehman

Krishnasamy

et al. 2012

Free Radical Biology and Medicine

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This study investigated the role of inducible nitric oxide synthase (iNOS) in failure of ethanol-induced fatty liver grafts. Rat livers were explanted 20 h after gavaging with ethanol (5 g/kg) and storing in UW solution for 24 h before implantation. Hepatic Oil-Red-O staining-positive areas increased from ~2% to ~33% after ethanol treatment, indicating steatosis. iNOS expression increased ~8-fold after transplantation of lean grafts (LG) and 25-fold in fatty grafts (FG). Alanine aminotransferase release, total bilirubin, hepatic necrosis, TUNEL-positive cells and cleaved caspase-3 were higher in FG than LG. A specific iNOS inhibitor 1400W (5 μM in the cold-storage solution) blunted these alterations by >42% and increased survival of fatty grafts from 25% to 88%. Serum nitrite/nitrate and hepatic nitrotyrosine adducts increased to a greater extent after transplantation of FG than LG, indicating reactive nitrogen species (RNS) overproduction. Phospho-c-Jun and phospho-c-Jun N-terminal kinase-1/2 (JNK1/2) were higher in FG than in LG, indicating more JNK activation in fatty grafts. RNS formation and JNK activation were blunted by 1400W. Mitochondrial polarization and cell death were visualized by intravital multiphoton microscopy of rhodamine 123 and propidium iodide, respectively. After implantation, viable cells with depolarized mitochondria were 3-fold higher in FG than in LG and 1400W decreased mitochondrial depolarization in FG to the levels of LG. Taken together, iNOS is upregulated after transplantation of FG, leading to excessive RNS formation, JNK activation, mitochondrial dysfunction, and severe graft injury. The iNOS inhibitor 1400W could be an effective therapy for primary non-function of fatty liver grafts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers

Liu

Rehman

Krishnasamy

et al. 2012

Free Radical Biology and Medicine

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“…1,2 Marginal livers have an increased susceptibility to cold and warm ischemia reperfusion (I/R) injury resulting in poor graft outcomes. 3–5 Cholestasis is a major risk factor for oxidative stress and complications of I/R injury. Recent studies have clearly established a critical role for neutrophils in the mechanism of hepatocyte injury during cholestasis.…”

Section: Introductionmentioning

confidence: 99%

Cyclopamine Attenuates Acute Warm Ischemia Reperfusion Injury in Cholestatic Rat Liver: Hope for Marginal Livers

et al. 2011

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Cholestasis is a significant risk factor for immediate hepatic failure due to ischemia reperfusion (I/R) injury in patients undergoing liver surgery or transplantation. We recently demonstrated that inhibition of Hedgehog (Hh) signaling with cyclopamine (CYA) before I/R prevents liver injury. In this study we hypothesized that Hedgehog (Hh) signaling may modulate I/R injury in cholestatic rat liver. Cholestasis was induced by bile duct ligation (BDL). Seven days after BDL, rats were exposed to either CYA or vehicle for 7 d daily before subjecting them to 30 min of ischemia and 4 h of reperfusion. Expression of Hh ligands (sonic hedgehog, Patched-1 and Glioblastoma-1), assessment of liver injury, neutrophil infiltration, cytokines, lipid peroxidation, cell proliferation and apoptosis were determined. Significant upregulation of Hh ligands was seen in vehicle treated BDL rats. I/R injury superimposed on these animals resulted in markedly elevated serum alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin accompanied with increased neutrophil recruitment and lipid peroxidation. Preconditioning with CYA reduced the histological damage and serum liver injury markers. CYA also reduced neutrophil infiltration, proinflammatory cytokines such as TNF-α and IL-1β expression of α-smooth muscle actin and Type 1 collagen resulting in reduced fibrosis. Furthermore CYA treated animals showed reduced cholangiocyte proliferation, and apoptosis. Hepatoprotection by CYA was conferred by reduced activation of protein kinase B (Akt) and extracellular signal regulated kinase (ERK). Endogenous Hh signaling in cholestasis exacerbates inflammatory injury during liver I/R. Blockade of Hh pathway represents a clinically relevant novel approach to limit I/R injury in cholestatic marginal liver.

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“…In Western countries, up to one third of the general population is affected by hepatic steatosis [1], [2], [3], and is now the most common cause of chronic liver disease in children and adolescents [4]. Hepatic steatosis has been associated with increased sensitivity of the liver to other injuries, such as insulin resistance [2] and ischemia/reperfusion (I/R) during transplantation [5]. A substantial number of patients with hepatic steatosis may finally develop cirrhosis [3], [6].…”

Section: Introductionmentioning

confidence: 99%

Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

et al. 2013

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Fatty liver or hepatic steatosis is a common health problem associated with abnormal liver function and increased susceptibility to ischemia/reperfusion injury. The objective of this study was to investigate the effect of the fatty acid synthase inhibitor cerulenin on hepatic function in steatotic ob/ob mice. Different dosages of cerulenin were administered intraperitoneally to ob/ob mice for 2 to 7 days. Body weight, serum AST/ALT, hepatic energy state, and gene expression patterns in ob/ob mice were examined. We found that cerulenin treatment markedly improved hepatic function in ob/ob mice. Serum AST/ALT levels were significantly decreased and hepatic ATP levels increased in treated obese mice compared to obese controls, accompanied by fat depletion in the hepatocyte. Expression of peroxisome proliferator-activated receptors α and γ and uncoupling protein 2 were suppressed with cerulenin treatment and paralleled changes in AST/ALT levels. Hepatic glutathione content were increased in some cases and apoptotic activity in the steatotic livers was minimally changed with cerulenin treatment. In conclusion, these results demonstrate that fatty acid synthase blockade constitutes a novel therapeutic strategy for altering hepatic steatosis at non-stressed states in obese livers.

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Hepatocellular ultrastructure after ischemia/reperfusion injury in human orthotopic liver transplantation

Cited by 11 publications

References 11 publications

Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers

Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers

Cyclopamine Attenuates Acute Warm Ischemia Reperfusion Injury in Cholestatic Rat Liver: Hope for Marginal Livers

Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

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