Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation

Gao, Wenshi; Bentley, Rex C.; Madden, John F.; Clavien, Pierre‐Alain

doi:10.1002/hep.510270626

Cited by 304 publications

(232 citation statements)

References 66 publications

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“…39 The extent of apoptosis after 1 hour of reperfusion was directly related to the duration of cold preservation, indicating that key events leading to apoptosis occur in the cold. A practical consequence of these studies is that there are now new rationales for the prevention of cold preservation injury based on proven events that occur in the cold.…”

Section: Discussionmentioning

confidence: 97%

Evidence that actin disassembly is a requirement for matrix metalloproteinase secretion by sinusoidal endothelial cells during cold preservation in the rat

Upadhya

Strasberg

1999

Hepatology

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Cold preservation induces the secretion of matrix metalloproteinases (MMPs) by hepatic sinusoidal endothelial cells (SECs). These enzymes are important mediators of cold preservation injury. The purpose of this study was to determine if low temperature caused actin disassembly in SECs and whether actin disassembly was required for secretion of MMPs under these conditions. To establish the basis of interpreting the effect of low temperature, isolated SECs were exposed to cytochalasin B with or without pretreatment with phalloidin. Cytochalasin B produced actin disassembly and resulted in the secretion of MMPs. Both were retarded by phalloidin pretreatment. Low temperature (4ЊC) also induced actin disassembly and MMP secretion and pretreatment with phalloidin again retarded actin disassembly and MMP secretion. Cycloheximide had no effect on these results. Actin disassembly began with 30 minutes of exposure of isolated SECs to cold and reached a final state at 8 hours, at which time no actin stress fibers were visible, and the normally fusiform SECs were fully rounded. Increased MMP activity in the supernatant was also present at 30 minutes and continued to rise sharply in the first hour; thereafter the rate of rise diminished. The study shows that secretion of MMPs during cold preservation is dependent on the induction of actin disassembly by low temperature. The rapid appearance of increased MMP activity after exposure to cold and the studies using cycloheximide indicate that the MMPs originate from preformed MMPs rather than newly synthesized MMPs. (HEPA-TOLOGY 1999;30:169-176.)Preservation injury leads to hepatic failure and the loss of about 8% of transplanted livers in the United States. [1][2][3] Preservation injury also restricts strategies to increase the use of donor organs, for instance, by splitting 1 liver for use in 2 adults. Livers are damaged during low temperature (4°C) preservation by a well-documented injury to the hepatic sinusoidal endothelial cells, 4,5 while hepatocytes are relatively spared. 4 During cold preservation, SECs partially detach from the connective tissue matrix of the sinusoidal wall and become rounded in shape, apparently connected to the matrix only by isolated cords of cytoplasm. 4,6 After preservation, at the moment of reperfusion, recipient leukocytes, platelets, and clotting factors come into contact with the exposed donor connective tissue matrix and hepatocytes, as well as the altered sinusoidal endothelial cells (SECs), in the hepatic sinusoid. This leads to adherence and activation of the platelets 7 and leukocytes 8,9 as well as thrombosis 10 with resultant damage to the allograft. The degree to which these events occur on reperfusion is directly related to the duration of cold preservation in every model.Recently, we offered an explanation for the detachment and rounding of SECs based on pathological activity of matrix metalloproteinases (MMPs). 11 We found that MMPs are present in liver effluents after cold preservation in both man and in the rat and that their acti...

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Section: Discussionmentioning

confidence: 97%

Evidence that actin disassembly is a requirement for matrix metalloproteinase secretion by sinusoidal endothelial cells during cold preservation in the rat

Upadhya

Strasberg

1999

Hepatology

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“…45,46 Kupffer cells also can contribute to IR injury through their ability to produce cytokines and reactive oxygen species (ROS) which contributes to SEC apoptosis. 47,48 A confounding factor in the IR injury response is the existence of hepatic zonation. A recent study demonstrated that SEC apoptosis was significantly enhanced in the presence of Kupffer cells, and that this was blocked by inhibition of ROS and inhibitors of caspase 3 and caspase 9, suggesting that Kupffer cell-derived ROS contributes to SEC apoptosis.…”

Section: Ischemia and Reperfusion Injurymentioning

confidence: 99%

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

2008

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Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Vascular Cell Signaling Mediated by NO. Endothelial cells (ECs) produce NO through the enzyme endothelial NO synthase (eNOS). NO then regulates important vascular functions, such as vascular tone, angiogenesis, and arterial remodeling. 1 eNOS is regulated in a multiprotein complex (Fig. 1), which includes the activating kinase, Akt1 and putative negative regulator caveolin-1 (Cav-1). Although eNOS Ϫ/Ϫ mice evidence impaired angiogenesis, overexpression of a constitutively active allele of eNOS that mimics the phosphorylated and active state rescues these angiogenic defects. 2 Because eNOS is an EC-specific Akt substrate, ECs from mice lacking the Akt1 isoform also have defects in eNOS phosphorylation, NO production, and angiogenesis which are correspondingly rescued by Akt1 overexpression. 3 One key mechanism by which the Akt-eNOS axis promotes angiogenesis in vivo is through mobilization of endothelial progenitor cells and EC migration to sites of vascular injury. In contradistinction to AKT, Cav-1 is a negative regulator of eNOS. Mice deficient in Cav-1 have defective mechanotransduction, calcium signaling, prostacyclin production, and elevated NO production indicating that endothelial Cav-1 also importantly regulates vascular function by regulating eNOS and other signaling pathways. 4 Upon its generation in ECs, NO also acts on adjacent vascular effector cells to modulate vascular tone, cellular proliferation, apoptosis, migration, and synthesis of extracellular matrix (Fig. 2). NO acts in part by stimulating soluble guanylate cyclase (sGC) to produce intracellular Abbreviations: Cav-

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“…Detection of apoptosis with the TUNEL-assay was performed as previously described by Gao et al 22 Briefly, 4, 12, and 24 h after 1 min of exposure to hypotonic stress cells were fixed in freshly prepared 4% paraformaldehyde in PBS (pH 7.2) for 30 min. The cells were treated with terminal deoxynucleotidyl transferase from calf thymus (Kit Boehringer) in the presence of fluorescein-dUTP and d-NTP.…”

Section: Tunel Assaymentioning

confidence: 99%

Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding

Selzner

Graf

et al. 2004

Cell Death Differ

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Although exposure of cells to extreme hypotonic stress appears to be a purely experimental set up, it has found an application in clinical routine. For years, surgeons have washed the abdominal cavity with distilled water to lyse isolated cancer cells left after surgery. No data are available supporting this practice or evaluating the potential mechanisms of cell injury under these circumstances. Recent evidence indicates that increases in cell volume stimulate release of adenosine triphosphate and autocrine stimulation of purinergic (P2) receptors in the plasma membrane of certain epithelial cell types. Under physiological conditions, purigenic stimulation can contribute to cell volume recovery through activation of solute efflux. In addition, adenosine triphosphate-P2 receptor binding might trigger other mechanisms affecting cell viability after profound hypotonic stress. This study demonstrates a novel pathway of cell death by apoptosis in human colon cancer cells following a short hypotonic stress. This pathway is induced by transitory cell swelling which leads to extracellular release of adenosine triphosphate (ATP) and specific binding of ATP to P2 receptors (probably P2X7). Extracellular ATP induced activation of caspases 3 and 8, annexin V, release of cytochrome c, and eventually cell death. The effect of ATP can be blocked by addition of (i) apyrase to hydrolyse extracellular ATP and (ii) suramin, a P2 receptor antagonist. Finally, (iii) gadolinium pretreatment, a blocker of ATP release, reduces sensitivity of the cells to hypotonic stress. The adenosine triphosphate-P2 receptor cell death pathway suggests that autocrine/paracrine signaling may contribute to regulation of viability in certain cancer cells disclosed with this pathway.

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Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation

Cited by 304 publications

References 66 publications

Evidence that actin disassembly is a requirement for matrix metalloproteinase secretion by sinusoidal endothelial cells during cold preservation in the rat

Evidence that actin disassembly is a requirement for matrix metalloproteinase secretion by sinusoidal endothelial cells during cold preservation in the rat

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding

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