The impact of sterile inflammation in acute liver injury

Abstract Background Acetaminophen (APAP) overdose causes hepatotoxicity and even acute liver failure. Recent studies indicate that sterile inflammation and innate immune cells may play important roles in damage-induced hepatocytes regeneration and liver repair. The scavenger receptor CD36 has its crucial functions in sterile inflammation. However, the roles of CD36 in APAP induced acute liver injury remain unclear and warrant further investigation. Methods WT C57BL/6 J and CD36−/− mice were intraperitoneally injected with APAP (300 mg/kg) after fasting for 16 h. Liver injury was evaluated by serum alanine aminotransferase (ALT) level and liver tissue hematoxylin and eosin (H&E) staining. Liver inflammatory factor expression was determined by real-time polymerase chain reaction (PCR). The protein adducts forming from the metabolite of APAP and the metabolism enzyme cytochrome P450 2E1 (CYP2E1) levels were measured by Western blot. Liver infiltrating macrophages and neutrophils were characterized by flow cytometry. RNA sequencing and Western blot were used to evaluate the effect of damage-associated molecular patterns (DAMP) molecule high mobility group B1 (HMGB1) on WT and CD36−/− macrophages. Moreover, PP2, a Src kinase inhibitor, blocking CD36 signaling, was applied in APAP model. Results The expression of CD36 was increased in the liver of mice after APAP treatment. Compared with WT mice, APAP treated CD36−/− mice show less liver injury. There was no significant difference in APAP protein adducts and CYP2E1 expression between these two strains. However, reduced pro-inflammatory factor mRNA expression and serum IL-1β level were observed in APAP treated CD36−/− mice as well as infiltrating macrophages and neutrophils. Moreover, CD36 deficiency impaired the activation of c-Jun N-terminal kinase (JNK) caused by APAP. Interestingly, the lack of CD36 reduced the activation of extracellular regulated protein kinases (Erk) and v-akt murine thymoma viral oncogene homolog (Akt) induced by HMGB1. RNA transcription sequencing data indicated that HMGB1 has a different effect on WT and CD36−/− macrophages. Furthermore, treatment with PP2 attenuated APAP induced mouse liver injury. Conclusion Our data demonstrated that CD36 deficiency ameliorated APAP-induced acute liver injury and inflammatory responses by decreasing JNK activation. CD36 might serve as a new target to reduce acute liver injury.

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Manipulation of nitric oxide in an animal model of acute liver injury. The impact on liver and intestinal function

Libyan Journal of Medicine ◽

10.3402/ljm.v2i2.4699 ◽

2007 ◽

Vol 2 (2) ◽

pp. 73-81

Author(s):

Diya Adawi ◽

F Behzad Kasravi ◽

Göran Molin

Keyword(s):

Nitric Oxide ◽

Animal Model ◽

Liver Injury ◽

Acute Liver Injury ◽

Intestinal Function ◽

The Impact

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Prevalence of acute liver injury and hypertransaminemia in patients with COVID-19: a protocol for a systematic review

BMJ Open ◽

10.1136/bmjopen-2020-040517 ◽

2020 ◽

Vol 10 (7) ◽

pp. e040517

Author(s):

Gang Li ◽

Yongxing Xu ◽

Yi Tian Yang ◽

Peng Fei Liu

Keyword(s):

Systematic Review ◽

Liver Injury ◽

Acute Liver Injury ◽

Epidemiological Data ◽

Risk Of Bias ◽

Published Data ◽

Language Restriction ◽

Ethical Approval ◽

Meta Analyses ◽

The Impact

IntroductionCOVID-19 has spread rapidly in China and around the world. Published studies have revealed that some patients with COVID-19 had abnormal liver function in laboratory tests. However, the results were inconsistent and the analysis of epidemiological data stratified by the severity of COVID-19 was not available in previous meta-analyses. Furthermore, these meta-analyses were suspected of overestimating the incidence of liver injury in patients with COVID-19 because some studies considered transaminase elevation as liver injury, which might partially result from cardiac and muscle injury. This systematic review aims to enrol published literatures related to COVID-19 without language restriction, analyse the data based on the severity of the COVID-19 and explore the impact of varied definitions of liver injury on the incidence of liver injury.Methods and analysisWe have conducted a preliminary search on PubMed and Excerpta Medica Database on 13 April 2020, for the studies published after December 2019 on the prevalence of acute liver injury and hypertransaminemia in patients with COVID-19. Two reviewers will independently screen studies, extract data and assess the risk of bias. We will estimate the pooled incidence of hypertransaminemia and acute liver injury in patients with COVID-19 by using the random-effects model. The I² test will be used to identify the extent of heterogeneity. Publication bias will be assessed by funnel plot and performing the Begg’s and Egger’s test if adequate studies are available. We will perform a risk of bias assessment using the Joanna Briggs Institute’s critical appraisal checklist.Ethics and disseminationSince this study will be based on the published data, it does not require ethical approval. The final results of this study will be published in a peer-reviewed journal.PROSPERO registration numberCRD42020179462.

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Endoplasmic Reticulum Stress Increases Multidrug-resistance Protein 2 Expression and Mitigates Acute Liver Injury

Current Molecular Medicine ◽

10.2174/1566524020666200124102411 ◽

2020 ◽

Vol 20 (7) ◽

pp. 548-557

Author(s):

Wen-Ge Huang ◽

Jun Wang ◽

Yu-Juan Liu ◽

Hong-Xia Wang ◽

Si-Zhen Zhou ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Multidrug Resistance ◽

Liver Injury ◽

Protein Expression ◽

Er Stress ◽

Acute Liver Injury ◽

Multidrug Resistance Protein ◽

Functional Involvement ◽

Resistance Protein ◽

The Impact

Background: Multidrug-resistance protein (MRP) 2 is a key membrane transporter that is expressed on hepatocytes and regulated by nuclear factor kappa B (NF-κB). Interestingly, endoplasmic reticulum (ER) stress is closely associated with liver injury and the activation of NF-κB signaling. Objective: Here, we investigated the impact of ER stress on MRP2 expression and the functional involvement of MRP2 in acute liver injury. Methods: ER stress, MRP2 expression, and hepatocyte injury were analyzed in a carbon tetrachloride (CCl4)-induced mouse model of acute liver injury and in a thapsigargin (TG)-induced model of ER stress. Results: CCl4 and TG induced significant ER stress, MRP2 protein expression and NF- κB activation in mice and LO2 cells (P < 0.05). Pretreatment with ER stress inhibitor 4- phenyl butyric acid (PBA) significantly mitigated CCl4 and TG-induced ER stress and MRP2 protein expression (P < 0.05). Moreover, pretreatment with pyrrolidine dithiocarbamic acid (PDTC; NF-κB inhibitor) significantly inhibited CCl4-induced NF-κB activation and reduced MRP2 protein expression (1±0.097 vs. 0.623±0.054; P < 0.05). Furthermore, hepatic downregulation of MRP2 expression significantly increased CCl4- induced ER stress, apoptosis, and liver injury. Conclusion: ER stress enhances intrahepatic MRP2 protein expression by activating NF-κB. This increase in MRP2 expression mitigates ER stress and acute liver injury.

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Sterile inflammation in acute liver injury: myth or mystery?

Expert Review of Gastroenterology & Hepatology ◽

10.1586/17474124.2015.1060855 ◽

2015 ◽

Vol 9 (8) ◽

pp. 1027-1029 ◽

Cited By ~ 19

Author(s):

Benjamin L Woolbright ◽

Hartmut Jaeschke

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Sterile Inflammation

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Hepatoprotective Effects of Different Extracts From Triphala Against CCl4-Induced Acute Liver Injury in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.664607 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xichuan Wei ◽

Chuanhong Luo ◽

Yanan He ◽

Haozhou Huang ◽

Fei Ran ◽

...

Keyword(s):

Liver Injury ◽

Mouse Model ◽

Protein Expression ◽

Acute Liver Injury ◽

Quinone Oxidoreductase ◽

Tnf Α ◽

Gene And Protein Expression ◽

Wide Range ◽

Hepatoprotective Effects ◽

The Impact

Background:Triphala is a traditional polyherbal formula used in Indian Ayurvedic and Chinese Tibetan medicine. A wide range of biological activities have been attributed to Triphala, but the impact of various extraction methods on efficacy has not been determined.Purpose: The study aimed to evaluate Triphala extracts obtained by various methods for their hepatoprotective effects and molecular mechanisms in a mouse model of carbon tetrachloride (CCl4)-induced liver injury.Methods: HPLC fingerprinting was used to characterize the chemical characteristics of Triphala extracts obtained by (a) 0.5 h ultrasonication, (b) 2 h reflux, and (c) 4 h reflux. Hepatoprotective efficacy was evaluated in a mouse model of CCl4-induced liver damage. Serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured, as well as the liver antioxidant and inflammatory markers malondialdehyde superoxide dismutase glutathione peroxidase (GSH-Px), TNF-α, and IL-6. Gene and protein expression of Nrf-2 signaling components Nrf-2, heme oxygenase (HO-1), and NADPH Quinone oxidoreductase (NQO-1) in liver tissue were evaluated by real-time PCR and western blotting.Results: Chemical analysis showed a clear difference in content between extracts produced by ultrasonic and reflux methods. The pharmacological analysis showed that all three Triphala extracts reduced ALT, AST, MDA, TNF-α, and IL-6 levels and increased SOD and GSH-Px. Triphala extracts also induced transcript and protein expression of Nrf-2, HO-1, and NQO-1.Conclusion: Triphala extract prevents CCl4-induced acute liver injury. The ultrasonic extract of Triphala was most effective, suggesting that hepatoprotection may be related to the larger tannins via activation of Nrf-2 signaling.

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Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model

BioMed Research International ◽

10.1155/2021/8717565 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Mei-Ying Huang ◽

Dian-Wei Wan ◽

Jie Deng ◽

Wen-Jie Guo ◽

Yue Huang ◽

...

Keyword(s):

Liver Injury ◽

Er Stress ◽

Acute Liver Injury ◽

Recovery Process ◽

Regulatory Relationship ◽

Negative Feedback Regulation ◽

Injury Model ◽

The Impact

Background. Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model. Methods. In vivo and in vitro experiments were carried out. LO2 cells were treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with carbon tetrachloride (CCl4, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined. Results. TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression ( p < 0.05 ) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress ( p < 0.05 ). Similar results were observed in CCl4 or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl4-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers ( p < 0.05 ). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress. Conclusions. Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.

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MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Gut ◽

10.1136/gutjnl-2016-313615 ◽

2017 ◽

Vol 67 (2) ◽

pp. 333-347 ◽

Cited By ~ 42

Author(s):

Evangelos Triantafyllou ◽

Oltin T Pop ◽

Lucia A Possamai ◽

Annika Wilhelm ◽

Evaggelia Liaskou ◽

...

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Acute Liver Injury ◽

Myeloid Cells ◽

Confocal Imaging ◽

Macrophage Phenotype ◽

Hla Dr ◽

The Impact

ObjectiveAcute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.DesignFlow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.ResultsWe demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance.ConclusionsWe identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.

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