Mitochondrial dysfunction during anoxia/reoxygenation injury of liver sinusoidal endothelial cells

Fujii, Yuichi; Johnson, Michael E.; Gores, Gregory J.

doi:10.1002/hep.1840200127

Cited by 32 publications

(32 citation statements)

References 49 publications

(30 reference statements)

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“…The mitochondrial membrane potential in KMCH cells was measured by using a fluorescence unquenching assay as previously described in detail by us [28] . This assay is based on the concept of resonance energy transfer between the mitochondrial membrane potential-sensitive dyes tetramethylrhodamine ethyl ester and mitotracker green.…”

Section: Quantification Of Mitochondrial Membrane Potentialmentioning

confidence: 99%

Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells

Üstündağ

Bronk

Gores³

2007

WJG

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Section: Quantification Of Mitochondrial Membrane Potentialmentioning

confidence: 99%

Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells

Üstündağ

Bronk

Gores³

2007

WJG

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Section: -11mentioning

confidence: 99%

“…2 For example, we have pro-employing multiparameter digitized video microscopy, the hepatoposed that phospholipase-mediated calpain activation contri-cytes were cultured on collagen-coated glass coverslips. [13][14][15] butes to hepatocellular death during anoxia.2 Another potenDetermination of Cell Viability and ATP. In cells suspensions, cell tial signaling mechanism for hepatocellular death maybe the viability was determined by propidium iodide fluorometry.…”

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confidence: 99%

Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat

et al. 1997

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known to induce hepatocellular injury. 5,6 Although ceramides Although ceramide signaling pathways have been imare well known to cause cell death by inducing apoptosis, plicated in cell death, neither their role in hepatocellular they can also cause cell death by necrosis. [3][4][5]7 Based on these death nor the cellular mechanisms mediating ceramidedata, we generated the hypothesis that the ceramide signalinduced cell death are known. The mitochondrial meming pathway induces cell death in hepatocytes, either by causbrane permeability transition (MMPT) has been proing apoptosis or necrosis. posed as a common final pathway in cell death. Thus the Induction of the mitochondrial membrane permeability aims of our study were to determine if ceramides cause transition (MMPT), an abrupt increase in the permeability of hepatocellular death by inducing the MMPT. Ceramides the inner mitochondrial membrane to small molecular weight induce hepatocellular death by necrosis and not solutes, has been implicated as a final common pathway causapoptosis as confirmed by morphology and the absence ing hepatocellular injury. 1,[8][9][10] The MMPT is characterized by of internucleosomal DNA cleavage. Ceramide-mediated mitochondrial depolarization, failure of oxidative phosphoryhepatocyte necrosis was acyl chain-length, concentralation with ATP depletion, and ultimately cell death. 1 The tion, and time-dependent. Ceramide induced cell necroincreased permeability of the inner mitochondrial membrane sis was associated with adenosine triphosphate (ATP) is thought to be facilitated by a specific proteinaceous ''megadepletion and mitochondrial depolarization suggesting pore'' located on the inner mitochondrial membrane. The that ceramides caused mitochondrial dysfunction. In opening of this pore is partially inhibited by cyclosporine A isolated mitochondria, ceramides induced the cycloplus trifluoperazine (CyA/TFP). 8-11sporine A-sensitive MMPT in an acyl chain-length and The overall objective of our study was to determine if ceraconcentration dependent manner. Ceramide toxicity mide causes hepatocyte necrosis by inducing the MMPT. Our was specific as the less potent dihydro form did not inspecific aims were to answer the following questions: 1) Do duce cell necrosis, significant ATP depletion, mitochonceramides induce cell death, and if so, does cell death occur by drial depolarization nor the MMPT. 1 However, we have suggested that signaling ley rats (200-300 g) as previously described.12 For those experiments cascades may induce cell death. 2 For example, we have pro-employing multiparameter digitized video microscopy, the hepatoposed that phospholipase-mediated calpain activation contri-cytes were cultured on collagen-coated glass coverslips. [13][14][15] butes to hepatocellular death during anoxia.2 Another potenDetermination of Cell Viability and ATP. In cells suspensions, cell tial signaling mechanism for hepatocellular death maybe the viability was determined by propidium iodide fluorometry.12 ATP was quantified using the luciferin...

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“…A recent short-term study of sinusoidal endothelial cells in culture, using a perifusion system, showed that mitochondrial dysfunction occurred during hypoxia and following hypoxia-reoxygenation. 16 There do not, however, appear to be other data pertinent to the operation of oxidative stress and the mechanism of hypoxia-reoxygenation injury in cultured hepatic sinusoidal endothelial cells.Endogenous levels of reduced glutathione (GSH) are critically important in protection against injury from ROS during ischemia-reperfusion injury in the intact liver 17,18 as well as in other tissues. 19,20 Using production of oxidized glutathione (GSSG) as a marker of oxidative stress, Jaeschke noted substantial increases in plasma GSSG with minimal-toinsignificant increases in hepatic tissue and biliary GSSG 4 ; this constellation of changes was indicative of significant oxidative stress in the intravascular, but not in the intracellular, compartment.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells

2000

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To characterize the role of oxidative stress in cultured rat sinusoidal endothelial cells, we studied the production of superoxide after reoxygenation, the relationship of reduced glutathione (GSH) levels to cell injury, and the protective efficacy of antioxidants. Hypoxia (pO 2 1-2 mm Hg) was achieved by culturing cells under 95% N 2 5% CO 2 for 4 hours. Reoxygenation was then reestablished, and viability was determined at 24 hours by trypan blue exclusion; putative protective agents were added at the time of reoxygenation (4 hours). As previously reported, reoxygenation after 4 hours hypoxia accentuated sinusoidal cell death fourfold compared with hypoxic or normoxic controls (P F .0001). Superoxide was not produced on reoxygenation, and superoxide dismutase provided no protection against reoxygenation injury. Cellular levels of GSH fell to 37 ؎ 4% of normoxic controls (P F .0001) following reoxygenation. These changes were essentially abrogated by Trolox (Aldrich Chemical Co., Milwaukee, WI) and dimethyl sulfoxide, both of which also completely protected against reoxygenation injury. When cellular GSH levels were lowered by addition of diethylmaleate (which conjugates GSH), this reduced the viability of endothelial cells cultured under normoxic conditions and greatly augmented reoxygenation injury. Conversely, addition of exogenous GSH partially protected endothelial cells against hypoxia-reoxygenation injury. Desferrioxamine also protected against reoxygenation injury, but catalase was only partly protective. It is concluded that sinusoidal endothelial cells undergo significant intracellular oxidative stress following reoxygenation, and their viability is critically dependent on GSH levels. Reactive oxygen species are likely mediators of oxidative stress in hepatic sinusoidal endothelial cells. (HEPATOLOGY 2000;31:160-165.)In the intact liver, oxidative stress appears to be part of the mechanism for ischemia-reperfusion injury and is related to the generation of reactive oxygen species (ROS) 1-4 and possibly nitric oxide. 5 However, the role of individual cell types in the production of these potentially cytotoxic mediators remains uncertain. Conversely, sinusoidal endothelial cells appear to be a major target of ischemia-reperfusion (or hypoxia-reoxygenation) injury. [6][7][8] The resultant endothelial injury disrupts the microcirculation, reducing blood flow and enhancing further tissue necrosis. Neutrophils adhere to damaged endothelial cells and their resultant activation is likely to be one source of ROS. In the present studies, we have explored the possibility that sinusoidal endothelial cells could themselves generate oxidative stress.Earlier in vitro studies on the effects of hypoxia-reoxygenation on endothelial cells have usually been performed on cultures of endothelial cells derived from large blood vessels, such as the pulmonary artery and umbilical vein. 9,10 From this work, it is apparent that nonhepatic endothelial cells are susceptible to hypoxia-reoxygenation injury through the generation of...

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Mitochondrial dysfunction during anoxia/reoxygenation injury of liver sinusoidal endothelial cells

Cited by 32 publications

References 49 publications

Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells

Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells

Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat

Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells

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