Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review

Vardanian, Andrew J.; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.

doi:10.2119/2007-00134.vardanian

Cited by 138 publications

(92 citation statements)

References 121 publications

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“…I/R injury induces an inflammatory response and cytokine release from non-parenchymal cells and passenger leucocytes in the liver (Fondevila et al 2003;Montalvo-Jave et al 2008;Teoh and Farrell 2003). The distal cascade of the inflammatory response following I/R which leads to organ damage has been studied extensively (Clavien et al 2001;Jaeschke 2003;Jaeschke and Lemasters 2003;Vardanian et al 2008).…”

Section: Introductionmentioning

confidence: 99%

HMGB1 in ischemic and non-ischemic liver after selective warm ischemia/reperfusion in rat

Liu

Dirsch

Fang

et al. 2011

Histochem Cell Biol

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High mobility group box 1 (HMGB1) acts as an early mediator in inflammation and organ injury. Ischemia reperfusion (I/R) injury induces HMGB1 translocation and expression in ischemic areas. However, it is unknown whether selective warm liver I/R injury also induces the expression of HMGB1 in non-ischemic lobes. The present study aimed to test the hypothesis that selective liver I/R injury also causes HMGB1 translocation and up-regulates its expression in non-ischemic liver areas. In the present study, selective I/R injury was induced by clamping the median and left lateral liver lobes for 90 min followed by 0.5, 6 and 24 h reperfusion. We used male inbred Lewis rats; six animals for each point in time and six animals for the normal control group. Selective hepatic I/R injury induced morphological changes not only in ischemic lobes but also in non-ischemic lobes. HMGB1 translocation and expression was increased in a time-dependent manner in the ischemic lobes, and increased in with delayed onset in the non-ischemic lobes. Serum HMGB1 levels were increased after reperfusion. Furthermore, liver I/R injury up-regulated the expression of HMGB1 receptors (Toll-like receptor 4 and receptor for advanced glycation end products and pro-inflammatory cytokines (Tumor necrosis factor-alpha and interleukin-6) in both ischemic lobes, however, the up-regulation of these cytokines was more prominent in the ischemic lobes. In conclusion, selective warm I/R induces a substantial "sympathetic/bystander" effect on the non-ischemic lobes in terms of HMGB1 translocation and local cytokine production.

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Section: Introductionmentioning

confidence: 99%

HMGB1 in ischemic and non-ischemic liver after selective warm ischemia/reperfusion in rat

Liu

Dirsch

Fang

et al. 2011

Histochem Cell Biol

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“…The liver exhibits both direct cellular damage as the result of the ischemic insult as well as further dysfunction and damage resulting from activation of inflammatory pathways (10). We have previously shown that hepatocytes actively release HMGB1 in response to oxidative stress, suggesting that these parenchymal cells can provide danger signals to neighboring immune cells in the liver to promote inflammation and organ damage (11).…”

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confidence: 99%

High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity

Evankovich¹,

Cho²,

Zhang

et al. 2010

Journal of Biological Chemistry

213

212

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The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1. High Mobility Group Box Protein 1 (HMGB1)3 is a ubiquitously expressed nuclear molecule that functions as a structural protein of chromatin (1). In addition to its nuclear role, HMGB1 also functions as an inflammatory cytokine when released from necrotic cells or actively secreted from stressed cells. Its proinflammatory properties were first highlighted in experiments showing that HMGB1 is actively secreted by activated macrophages, serving as a late mediator of lethality in sepsis (2). Whereas HMGB1 is involved in the late systemic inflammatory response to sepsis, our laboratory demonstrated that HMGB1 is a central and necessary mediator of organ damage following acute, sterile organ injury (3, 4). HMGB1 is rapidly mobilized and released by hepatocytes in the setting of hepatic ischemia and reperfusion injury. Extracellular HMGB1 functions as a damage-associated molecular pattern (DAMP) molecule and activates proinflammatory signaling pathways by activating pattern recognition receptors including Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) (5, 6). Mounting evidence suggests HMGB1 may also function to facilitate the recognition of other immune co-activators such as LPS, DNA, and IL-1 through avid binding to these molecules (7-9).Thoro...

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“…Activation of Kupffer cells with production of reactive oxygen species, upregulation of the inducible nitric oxide synthase and proinflammatory cytokines, and neutrophil accumulation contribute to inflammation-associated liver damage. [1][2][3][4] One may therefore speculate whether a reduction in leukocyte adhesion and transmigration into the interstitium may reduce the incidence and severity of I/R-induced complications. FTY720 (2-amino-2-[4-octylphenyl]-1,3-propaneldiol hydrochloride), a synthetic structural analogon of sphingosine related to myriocin, is considered to be a possible drug targeting this problem.…”

mentioning

confidence: 99%

Protective Effects of Early CD4+ T Cell Reduction in Hepatic Ischemia/Reperfusion Injury

Martin

Mory

Prescher

et al. 2010

Journal of Gastrointestinal Surgery

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Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review

Cited by 138 publications

References 121 publications

HMGB1 in ischemic and non-ischemic liver after selective warm ischemia/reperfusion in rat

HMGB1 in ischemic and non-ischemic liver after selective warm ischemia/reperfusion in rat

High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity

Protective Effects of Early CD4+ T Cell Reduction in Hepatic Ischemia/Reperfusion Injury

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