Endothelial Cell and Hepatocyte Deaths Occur by Apoptosis After Ischemia-Reperfusion Injury in the Rat Liver1,2

Kohli, Vivek; Selzner, Markus; Madden, John F.; Bentley, Rex C.; Clavien, Pierre‐Alain

doi:10.1097/00007890-199904270-00003

Cited by 322 publications

(251 citation statements)

References 32 publications

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“…While this model is not designed to mimic the precise sequence of pathogenetic events linked to specific thromboinflammatory diseases, it nonetheless provides important insights into the molecular processes by which dying endothelial cells promote leukocyte trafficking in vivo. The disruption of membrane phospholipid asymmetry in endothelial cells leading to PS exposure is a characteristic feature of dying cells regardless of the cause 44,45 , as in the antiphospholipid syndrome 46 , in response to immunomodulatory and chemotherapeutic regimens containing agents such as thalidomide 47 and arsenic 48 , and after ischaemia reperfusion [49][50][51] . Therefore, our observations related to PS-positive endothelial cells after needle injury may have relevance to disease processes.…”

Section: Discussionmentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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“…In addition, ischemia reperfusion directly causes dysregulation of endothelial function via accelerated endothelial cell apoptosis. This may contribute to the increased microvascular permeability and impairment in barrier function (Kohli et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

et al. 2006

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Background Revascularization of a limb following prolonged ischemia results in substantial skeletal muscle injury. Statins play a well-understood role in the treatment of hypercholesterolemia but are also known to have anti-inflammatory properties. The purpose of this study was to examine the effects of pravastatin pre-treatment in the setting of skeletal muscle ischemia reperfusion injury (IRI).Methods Adult male Sprague Dawley rats (n = 27) were randomized into 3 groups: control group, I/R group, IR group pre-treated with pravastatin. Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanters for 2.5 h. Treatment groups received normal saline in equal volumes prior to tourniquet release. Following 12 h reperfusion, the tibialis anterior muscle was dissected and muscle function assessed electrophysiologically by electrical field stimulation. The animals were then killed and skeletal muscle harvested for evaluation.Results We found that pre-treatment with pravastatin reduces the tissue oxidative damage and edema associated with skeletal muscle reperfusion injury. Skeletal muscle injury, measured by edema, leucosequestration and electrical properties were significantly lower with pravastatin pre-treatment compared to the non-treated group.Interpretation We feel that pravastatin pre-treatment may be a potential therapeutic intervention for skeletal muscle ischemia reperfusion injury in the clinical setting.

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“…6 -9 Extensive damage to the hepatic vasculature in these settings by accumulation and entrapment of neutrophils, platelets, and mononuclear phagocytes may augment endothelial injury and a "no-reflow" phenomenon, thereby sustaining hepatocyte injury. 10,11 The precise method of death of hepatocytes, endothelial cells, and inflammatory cells in the injured liver remains not fully clarified, but seems to include components of both apoptotic and necrotic pathways. 12,13 Regardless of the method of death, it is established that I/R injury in the liver may overwhelm innate regenerative programs.…”

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confidence: 99%

Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice

et al. 2004

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Hepatic ischemia/reperfusion (I/R) injury associated with liver transplantation and hepatic resection is characterized by hepatocellular damage and a deleterious inflammatory response. In this study, we examined whether receptor for advanced glycation end product (RAGE) activation is linked to mechanisms accentuating inflammation on I/R in a murine model of total hepatic ischemia. Animals treated with soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE, displayed increased survival after total hepatic I/R compared with vehicle treatment. TUNEL assay and histologic analysis revealed that blockade of RAGE was highly protective against hepatocellular death and necrosis on I/R; in parallel, proliferating cell nuclear antigen was enhanced in livers of mice treated with sRAGE. Rapid activation of p38, p44/42, stress-activated protein kinase and c-Jun N-terminal kinase mitogen-activated protein kinases, signal transducer and activator of transcription-3, and nuclear translocation of activator protein-1 was evident at early times on I/R. In the remnants of sRAGE-treated livers, however, activation of each of these signaling and transcription factor pathways was strikingly decreased. sRAGE-treated remnants displayed enhanced activation of nuclear factor B, in parallel with increased transcripts for the proregenerative cytokine, tumor necrosis factor-␣. In conclusion, these data suggest that RAGE modulates hepatic I/R injury, at least in part by activation of key signaling pathways linked to proinflammatory and cell death-promoting responses. We propose that blockade of this pathway may represent a novel strategy to attenuate injury in hepatic I/R and to facilitate regeneration. (HEPATOLOGY 2004;39:422-432.)

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Endothelial Cell and Hepatocyte Deaths Occur by Apoptosis After Ischemia-Reperfusion Injury in the Rat Liver1,2

Abstract: These results suggest that apoptosis of endothelial cells followed by hepatocytes is an important mechanism of cell death after ischemia/reperfusion injury in the liver.

Cited by 322 publications

References 32 publications

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice

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