The Evolving Role of Neutrophils in Liver Transplant Ischemia-Reperfusion Injury

Nakamura, Kojiro; Kageyama, Shoichi; Kupiec‐Weglinski, Jerzy W.

doi:10.1007/s40472-019-0230-4

Cited by 41 publications

(47 citation statements)

References 122 publications

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“…Intravital microscopy was used in mice hepatic I/R injury model to show massive recruitment of neutrophils to the site of hepatic injury [51]. Accumulated Neutrophils in the hepatic parenchyma release ROS and proteases, which results in hepatocytes damage and hepatic sinusoids destruction [52]. Thereby, several studies emphasized the strategies of inhibiting neutrophils recruitment to reduce I/Rinduced liver injury [53,54].…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Ginkgo Biloba Dropping Pills Against Liver Ischemia/reperfusion Injury in Mice

Wang

Zhang

Wang³

et al. 2020

Preprint

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Background: Liver ischemia-reperfusion (I/R) injury is an inevitable pathological phenomenon in various clinical conditions, such as liver transplantation, resection surgery, or shock, which is the major cause of morbidity and mortality after operation. Ginkgo Biloba Dropping Pill (GBDP) is a unique Chinese Ginkgo Biloba leaf extract preparation that exhibits a variety of beneficial biological activities. The aim of this study is to investigate the protective effects of GBDP on the liver I/R injury both in vitro and in vivo. Methods: Hypoxia/reoxygenation (H/R) experiments were performed in AML-12 cells and primary hepatocytes, which were pretreated with GBDP (60 or 120 μg/mL) followed by incubation in a hypoxia chamber. Cell viability and cell apoptosis were detected by MTT assay and annexin V staining respectively. C57BL/6 mice were used to establish liver I/R injury model, and were pretreated with GBDP (100 or 200 mg/kg/day, i.g.) for two weeks. Liver damage was detected by plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Liver necrosis and neutrophil infiltration were determined by H&E and myeloperoxidase immunohistochemistry staining. Finally, TUNEL staining and western blot analysis of apoptosis-related proteins were used to investigate the anti-apoptotic effect of GBDP. Results: In the in vitro study, GBDP pretreatment improved the cell viability of AML-12 cells in H/R injury model. Similarly, the same result was found in the primary hepatocytes isolated from C57BL/6 mice. Moreover, GBDP decreased the number of apoptotic cells induced by H/R. In the in vivo study, oral administration of GBDP ameliorated liver injury evidenced by a significant decline in the levels of ALT and AST. Furthermore, the result of H&E staining showed that GBDP reduced the size of necrosis area. In addition, the decreased infiltration of neutrophils indicated that GBDP may play an anti-inflammatory effect. More importantly, GBDP reduced TUNEL-positive cells and the expression of Bax and caspase-3 in liver indicating GBDP has anti-apoptotic effects.Conclusion: Our findings elucidated that GBDP has potential effects for protecting against liver I/R injury characterized by its anti-apoptotic, anti-necrotic, and anti-inflammatory properties, which would promisingly make a contribution to the exploration of therapeutic strategies in the liver I/R injury.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Ginkgo Biloba Dropping Pills Against Liver Ischemia/reperfusion Injury in Mice

Wang

Zhang

Wang³

et al. 2020

Preprint

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“…Hepatic CC1 ablation enhances IR-inflammatory phenotype in mouse OLT. Since the release of DAMPs, such as HMGB1, from damaged cells triggers a cascade of inflammatory cytokine/ chemokine events, which further aggravate organ damage (17), we aimed to evaluate the impact of graft CC1 deficiency on the release of HMGB1 and accompanied innate-immune response in our model. At 6 hours after reperfusion, CC1-KO liver grafts (CC1-KO → WT) showed higher serum HMGB1 levels ( Figure 1F) and increased frequency of intragraft infiltration by CD11b-positive (macrophage)/Ly6G-positive (neutrophil) cells (Figure 1, D and G), along with elevated serum MCP1 ( Figure 1F) and hepatic mRNA levels coding for MCP1, CXCL1, CXCL2, and CXCL10 ( Figure 1H), as compared with controls (WT → WT).…”

Section: Hepatic Ceacam1 Expression Indicates Donor Liver Quality Andmentioning

confidence: 99%

“…Hepatic CC1 deletion augments cell damage by enhancing reactive oxygen species (ROS) and HMGB1 translocation during liver cold storage. Although restoration of blood flow at reperfusion is the principal cause of liver IRI (17), cold storage itself can also trigger hepatocellular damage (8). Having demonstrated the importance of graft CC1 expression on HMGB1 release in OLT ( Figure 1F), we next asked whether CEACAM1 may affect graft injury and HMGB1 signaling during ex vivo cold storage (before revascularization).…”

Section: Hepatic Ceacam1 Expression Indicates Donor Liver Quality Andmentioning

confidence: 99%

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Nakamura¹,

Kageyama²,

Kaldas³

et al. 2020

Journal of Clinical Investigation

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“…Intravital microscopy was used in mice hepatic I/R injury model to show massive recruitment of neutrophils to the site of hepatic injury [54]. Accumulated neutrophils in the hepatic parenchyma release ROS, proteases, and inflammatory factors, which results in hepatocytes damage and hepatic sinusoids destruction [55]. Thereby, several studies emphasized the strategies of inhibiting neutrophils recruitment to reduce I/R-induced liver injury [56,57].…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Ginkgo Biloba Dropping Pills against liver ischemia/reperfusion injury in mice

et al. 2020

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Background Liver ischemia/reperfusion (I/R) injury is an inevitable pathological phenomenon in various clinical conditions, such as liver transplantation, resection surgery, or shock, which is the major cause of morbidity and mortality after operation. Ginkgo Biloba Dropping Pill (GBDP) is a unique Chinese Ginkgo Biloba leaf extract preparation that exhibits a variety of beneficial biological activities. The aim of this study is to investigate the protective effects of GBDP on the liver I/R injury both in the in vitro and in vivo. Methods Hypoxia/reoxygenation (H/R) experiments were performed in alpha mouse liver 12 (AML-12) cells and primary hepatocytes, which were pretreated with GBDP (60 or 120 µg/mL) followed by incubation in a hypoxia chamber. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) assay. Annexin V staining as well as western blot analysis of apoptosis-related proteins was performed to detect the protective effect of GBDP on cell apoptosis induced by H/R injury. C57BL/6 mice were used to establish the liver I/R injury model, and were pretreated with GBDP (100 or 200 mg/kg/day, i.g.) for two weeks. The liver damage was evaluated by detection of plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as histopathological examinations. Liver inflammation was determined by detecting the secretion of pro-inflammatory cytokines and neutrophil infiltration through enzyme-linked immunosorbent assay (ELISA) and myeloperoxidase (MPO) immunohistochemistry staining. Finally, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick and labeling (TUNEL) staining and western blot analysis of apoptosis-related proteins were used to investigate the anti-apoptotic effect of GBDP in mice. Results In the in vitro study, GBDP pretreatment improved the cell viability of AML-12 cells in the H/R injury model. Similarly, the same result was found in the primary hepatocytes isolated from C57BL/6 mice. Moreover, GBDP decreased the number of apoptotic cells and reduced the expression of apoptosis-related proteins induced by H/R injury. In the in vivo study, oral administration of GBDP ameliorated liver injury evidenced by a significant decline in the levels of ALT and AST. Furthermore, the result of hematoxylin and eosin (H&E) staining showed that GBDP reduced the size of necrosis area in the liver tissue. In addition, the decreased infiltration of neutrophils and secretion of pro-inflammatory cytokines indicated that GBDP may play an anti-inflammatory effect. More importantly, GBDP reduced TUNEL-positive cells and the expression of apoptosis-related proteins in the liver indicating GBDP has anti-apoptotic effects. Conclusions Our findings elucidated that GBDP has potential effects for protecting against liver I/R injury characterized by its anti-apoptotic, anti-necrotic, and anti-inflammatory properties, which would promisingly make contributions to the exploration of therapeutic strategies in the liver I/R injury.

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The Evolving Role of Neutrophils in Liver Transplant Ischemia-Reperfusion Injury

Cited by 41 publications

References 122 publications

Protective Effects of Ginkgo Biloba Dropping Pills Against Liver Ischemia/reperfusion Injury in Mice

Protective Effects of Ginkgo Biloba Dropping Pills Against Liver Ischemia/reperfusion Injury in Mice

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Protective effects of Ginkgo Biloba Dropping Pills against liver ischemia/reperfusion injury in mice

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