Graft protein C entrapment is associated with reduced phagocyte activation during reperfusion in human liver transplantation

Ilmakunnas, Minna; Pesonen, Eero; Höckerstedt, Krister; Mäkisalo, Heikki; Fernández, José A.; Griffin, John H.; Repo, Heikki; Siitonen, Sanna; Petäjä, Jari

doi:10.1097/01.ccm.0000198108.38349.28

Cited by 9 publications

(8 citation statements)

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“…Although we could not obtain blood samples across the hepatic circulation postoper- atively to investigate hepatic HMGB1 release, HMGB1 levels in systemic circulation declined rapidly after reperfusion, and postoperatively, HMGB1 was undetectable in most patients. This suggests that, despite inducing intense momentary hepatic phagocyte activation and sequestration, 33,35 reperfusion does not lead to extensive delayed hepatic HMGB1 release into systemic circulation.…”

Section: Discussionmentioning

confidence: 95%

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

et al. 2008

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High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor ␣ (TNF-␣), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P Ͻ 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-␣ or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P ϭ 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r ϭ 0.497, P ϭ 0.03) and peak postoperative alanine aminotransferase levels (r ϭ 0.588, P ϭ 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14: 1517Transpl 14: -1525Transpl 14: , 2008

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Section: Discussionmentioning

confidence: 95%

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

et al. 2008

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“…EPCR-GPI cell painting would be well suited for ex vivo cell therapies aimed at improving survival and engraftment of transplants. Both APC and liposomal thrombomodulin improved the outcome of pancreatic islets transplantation for type I diabetes (50)(51)(52)(53), and APC's cytoprotective effects have been shown to reduce graft-related injury (54,55). Furthermore, overexpression of EPCR on murine transplant tissue protected against transplantation-related thrombotic and inflammatory injury (56).…”

Section: Discussionmentioning

confidence: 99%

Cell painting with an engineered EPCR to augment the protein C system

Bouwens¹,

Stavenuiter²,

Mosnier³

2015

Thromb Haemost

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The protein C (PC) system conveys beneficial anticoagulant and cytoprotective effects in numerous in vivo disease models. The endothelial protein C receptor (EPCR) plays a central role in these pathways as cofactor for PC activation and by enhancing activated protein C (APC)-mediated protease-activated receptor (PAR) activation. During inflammatory disease, expression of EPCR on cell membranes is often diminished thereby limiting PC activation and APC’s effects on cells. Here a caveolae-targeting glycosylphosphatidylinositol (GPI)-anchored EPCR (EPCR-GPI) was engineered to restore EPCR’s bioavailability via “cell painting.” The painting efficiency of EPCR-GPI on EPCR-depleted endothelial cells was time- and dose-dependent. The EPCR-GPI bioavailability after painting was long lasting since EPCR surface levels reached 400% of wild-type cells after 2 hours and remained >200% for 24 hours. EPCR-GPI painting conveyed APC binding to EPCR-depleted endothelial cells where EPCR was lost due to shedding or shRNA. EPCR painting normalized PC activation on EPCR-depleted cells indicating that EPCR-GPI is functional active on painted cells. Caveolin-1 lipid rafts were enriched in EPCR after painting due to the GPI-anchor targeting caveolae. Accordingly, EPCR painting supported PAR1 and PAR3 cleavage by APC and augmented PAR1-dependent Akt phosphorylation by APC. Thus, EPCR-GPI painting achieved physiological relevant surface levels on endothelial cells, restored APC binding to EPCR-depleted cells, supported PC activation, and enhanced APC-mediated PAR cleavage and cytoprotective signaling. Therefore, EPCR-GPI provides a novel tool to restore the bioavailability and functionality of EPCR on EPCR-depleted and deficient cells.

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“…Although we could not obtain blood samples across the hepatic circulation postoperatively to investigate hepatic HMGB1 release, HMGB1 levels in systemic circulation declined rapidly after reperfusion, and postoperatively, HMGB1 was undetectable in most patients. This suggests that, despite inducing intense momentary hepatic phagocyte activation and sequestration,33, 35 reperfusion does not lead to extensive delayed hepatic HMGB1 release into systemic circulation.…”

Section: Discussionmentioning

confidence: 95%

Banking 101: Mobile-izing Financial Inclusion in an Emerging India

Kumar

Mathur²,

Lal

2013

Bell Labs Tech. J.

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The market for mobile financial services in India is growing steadily. With 41 percent of India's adults financially excluded, however, promoting financial literacy requires serious attention. We present Banking 101—a contextually relevant, mobile storytelling tool that, if integrated with mobile financial offerings, can offer a holistic solution to financial exclusion. © 2013 Alcatel‐Lucent.

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Graft protein C entrapment is associated with reduced phagocyte activation during reperfusion in human liver transplantation

Cited by 9 publications

References 50 publications

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

Cell painting with an engineered EPCR to augment the protein C system

Banking 101: Mobile-izing Financial Inclusion in an Emerging India

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