scholarly journals Endogenous Interleukin-33 Acts as an Alarmin in Liver Ischemia-Reperfusion and Is Associated With Injury After Human Liver Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Louise Barbier ◽  
Aurélie Robin ◽  
Rémy Sindayigaya ◽  
Héloïse Ducousso ◽  
Fanny Dujardin ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Renal Failure ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Human Liver ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Dysfunction ◽  
Hepatic Ischemia ◽  
Transplant Patients

Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33–deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.

scholarly journals Disulfide High‐Mobility Group Box 1 Drives Ischemia‐Reperfusion Injury in Human Liver Transplantation

Hepatology ◽  
2020 ◽  
Author(s):  
Rebecca A. Sosa ◽  
Allyson Q. Terry ◽  
Fady M. Kaldas ◽  
Yi‐Ping Jin ◽  
Maura Rossetti ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Human Liver ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Mobility ◽  
High Mobility Group

scholarly journals Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

2020 ◽  
Author(s):  
Alberto Calleri ◽  
Dorotea Roggio ◽  
Victor Navarro-Tableros ◽  
Nicola De Stefano ◽  
Chiara Pasquino ◽  
...  
Keyword(s):  
Stem Cell ◽  
Reperfusion Injury ◽  
Extracellular Vesicles ◽  
Human Liver ◽  
Imaging System ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

AbstractHepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 × 109 particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-α, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 × 109 particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 × 109 HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.

scholarly journals MicroRNA-141-3p Attenuates Oxidative Stress-induced Hepatic Ischemia Reperfusion Injury via Keap1/Nrf2 Pathway

2021 ◽  
Author(s):  
Tingting Li ◽  
Qingsong Chen ◽  
Jiangwen Dai ◽  
Zuotian Huang ◽  
Yunhai Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Abstract Hepatic ischemia reperfusion injury (IRI) is a major factor affecting the prognosis of liver transplantation through a series of severe cell death and inflammatory responses. MicroRNA-141-3p (miR-141-3p) has been reported to be associated with hepatic steatosis and other liver diseases. However, the potential role of miR-141-3p in hepatic IRI is currently unknown. In the present study, we found that miR-141-3p levels were negatively correlated with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) in liver transplantation patients. The results demonstrated that miR-141-3p was decreased in mouse liver tissue after hepatic IRI in mice and in hepatocytes after hypoxia/reoxygenation (H/R). Overexpression of miR-141-3p directly decreased Kelch-like ECH-associated protein 1 (Keap1) levels and attenuated cell apoptosis in vivo and in vitro, while inhibition of miR-141-3p facilitated apoptosis. Further experiments revealed that overexpression of miR-141-3p also attenuated oxidative stress-induced damage in hepatocytes under H/R conditions. Taken together, our results indicate that miR-141-3p plays a major role in hepatic IRI through the Keap1 signaling pathway, and the present study suggests that miR-141-3p might have a protective effect on hepatic IRI to some extent.

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