• cellular metabolism
• diclofenac
• drug-induced liver injury
• genomics
• hepatitis
• histopathology
• immunohistochemistry
• liver clock
• liver pathology
• transcriptional networks

Purpose: Neutrophils and cytokines play a major role in the pathogenesis of acute-on-chronic liver failure (ACLF). We aimed to determine whether chemokine (CXC) ligand 1 (CXCL1), a key marker of neutrophil recruitment and activation, could predict the severity and prognosis of hepatitis B virus–related ACLF (HBV-ACLF).

Methods: Hospitalized patients with HBV-ACLF were enrolled in a prospective study and stratified as survivors (alive at 28 days) and nonsurvivors (deceased at 28 days). Serum CXCL1 levels were measured in healthy controls, patients with chronic HBV, patients with HBV-related compensated cirrhosis, and patients with HBV-ACLF. Univariate and multivariable logistic analyses, Pearson correlation analysis, area under the receiver operating characteristic curve (AUROC), and Z tests were used to evaluate the performance of CXCL1 as a marker in HBV-ACLF.

Results: Patients with HBV-ACLF had significantly higher serum levels of CXCL1 and neutrophil count than healthy controls and patients with chronic HBV or HBV-related compensated cirrhosis (P < 0.01, respectively). Among patients with HBV-ACLF, survivors had lower serum CXCL1 levels and neutrophil count than those of nonsurvivors (P < 0.001, P < 0.05, respectively). Serum CXCL1 level was positively correlated with neutrophil count (r = 0.256, P = 0.001), ACLF grade (r = 0.295, P < 0.001) and organ failure, including coagulation (r = 0.21, P = 0.005) and brain failure (r = 0.198, P = 0.008). Multivariable logistic analyses showed serum CXCL1 [OR (95% CI) = 1.017 (1.009–1.025), P < 0.001] was an independent risk factor for 28-day mortality in HBV-ACLF. Meanwhile, the AUROC analysis demonstrated that serum CXCL1 [0.741 (0.669–0.804)] might be a reliable prognostic biomarker for patients with HBV-ACLF.

Conclusions: Overall, serum CXCL1 can serve as a biomarker indicating the severity of disease and prognosis for patients with HBV-ACLF. CXCL1 might also be a therapeutic target in this disease.

• CXCL1
• HBV-ACLF
• chemokine
• inflammation
• neutrophils

• Echinococcus granulosus
• anthelmintic drugs
• hydatidosis
• liver
• nitric oxide

• Kawasaki disease
• chemokines
• cytokines
• mast cells
• preeclampsia

• COVID-19/immunology
• COVID-19/pathology
• Cytokines/immunology
• Humans
• Mucocutaneous Lymph Node Syndrome/immunology
• Mucocutaneous Lymph Node Syndrome/pathology
• Mucocutaneous Lymph Node Syndrome/virology
• Pulmonary Alveoli/immunology
• Pulmonary Alveoli/pathology
• Pulmonary Alveoli/virology
• SARS-CoV-2/immunology
• Signal Transduction/immunology
• Thrombosis/immunology
• Thrombosis/pathology
• Thrombosis/virology
• Vascular System Injuries/immunology
• Vascular System Injuries/pathology
• Vascular System Injuries/virology

• R01 AI145829 NIAID NIH HHS
• R01 HD111146 NICHD NIH HHS
• UL1 TR001863 NCATS NIH HHS
• National Science Foundation

Innate immune disarray is a key component in the development and progression of acute on chronic liver failure (ACLF) and predisposition to infections. We evaluated the neutrophil dysfunction and its impact on outcomes in patients with ACLF.

Forty patients with acute decompensation of cirrhosis (10 each of grades 0, 1, 2, and 3 ACLF) and 10 healthy controls were prospectively evaluated for neutrophil immunophenotype (NP), neutrophil phagocytic capacity (NPC), and oxidative burst (OB) in both resting and stimulated conditions. The patients were followed up for 90 days or until death or transplant, whichever was earlier.

NP was normal (in %) and NPC (in mean fluorescence intensity [MFI]) was better in controls compared to patients with ACLF (83.74 ± 12.38 vs 63.84 ± 22.98; P = 0.007 and 98.33 ± 130.60 vs 18.73 ± 17.88, P = 0.001, respectively). Resting OB was higher in patients with ACLF compared to controls (97 ± 4.9% vs 91 ± 9%; P = 0.034), but it failed to increase further after stimulation, suggesting an immune exhaustion. NP was normal (in %) and NPC (in MFI) was better in 90‐day survivors compared to nonsurvivors (78 ± 11.9 vs 62.2 ± 24.11, P = 0.02 and 33.3 ± 22.7 vs 16.36 ± 13.3; P = 0.004, respectively). Phenotypically normal neutrophils >71.7% had 78.6% sensitivity and 65.4% specificity with an area under receiver operating curve (AUROC) of 0.70 (95% confidence interval [CI]: 0.55–0.90); P = 0.017, and NPC >17.32. MFI had 71.4% sensitivity and 69.6% specificity with an AUROC of 0.73 (95% CI: 0.54–0.86), P = 0.035, in predicting 90‐day survival.

Neutrophils have impaired bactericidal function in patients with ACLF compared to healthy adults. Neutrophil phenotype and phagocytic capacity may be used to predict 90‐day survival in patients with ACLF.

• acute decompensation
• acute on chronic liver failure
• cirrhosis
• immune dysfunction
• neutrophil dysfunction

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. It is a complex process, including a broad spectrum of hepatic lesions from fibrosis to cirrhosis. Our previous study suggested that astaxanthin (AST) could alleviate the hepatic inflammation and lipid dysmetabolism induced by ethanol administration. In this study, a total of 48 male C57BL/6J mice were divided into 4 groups: a Con group (fed with a Lieber–DeCarli liquid diet), an AST group (fed with a Lieber–DeCarli liquid diet and AST), an Et group (fed with an ethanol-containing Lieber–DeCarli liquid diet), and a EtAST group (fed with an ethanol-containing Lieber–DeCarli liquid diet and AST). Then, comparative hepatic transcriptome analysis among the groups was performed by Illumina RNA sequencing. Gene enrichment analysis was conducted to identify pathways affected by the differentially expressed genes. Changes of the top genes were verified by quantitative real-time PCR (qRT-PCR) and Western blot. A total of 514.95 ± 6.89, 546.02 ± 15.93, 576.06 ± 21.01, and 690.85 ± 54.14 million clean reads were obtained for the Con, AST, Et, and EtAST groups, respectively. Compared with the Et group, 1892 differentially expressed genes (DEGs) (including 351 upregulated and 1541 downregulated genes) were identified in the AST group, 1724 differentially expressed genes (including 233 upregulated and 1491 downregulated genes) were identified in the Con group, and 1718 DEGs (including 1380 upregulated and 338 downregulated genes) were identified in the EtAST group. The enrichment analyses revealed that the chemokine signaling, the antigen processing and presentation, the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling, and the Toll-like receptor signaling pathways enriched the most differentially expressed genes. The findings of this study provide insights for the development of nutrition-related therapeutics for ALD.

• alcoholic liver disease
• astaxanthin
• bioinformatic analysis
• comparative transcriptome analyses

Substantial evidence supports the view that inflammatory processes contribute to brain alterations in HIV infection. Mechanisms recently proposed to underlie neuropathology in Alcohol Use Disorder (AUD) include elevations in peripheral cytokines that sensitize the brain to the damaging effects of alcohol. This study included 4 groups: healthy controls, individuals with AUD (abstinent from alcohol at examination), those infected with HIV, and those comorbid for HIV and AUD. The aim was to determine whether inflammatory cytokines are elevated in AUD as they are in HIV infection. Cytokines showing group differences included interferon gamma-induced protein 10 (IP-10) and tumor necrosis factor α (TNFα). Follow-up t-tests revealed that TNFα and IP-10 were higher in AUD than controls but only in AUD patients who were seropositive for Hepatitis C virus (HCV). Specificity of TNFα and IP-10 elevations to HCV infection status was provided by correlations between cytokine levels and HCV viral load and indices of liver integrity including albumin/globulin ratio, fibrosis scores, and AST/platelet count ratio. Because TNFα levels were mediated by HCV infection, this study provides no evidence for elevations in peripheral cytokines in "uncomplicated", abstinent alcoholics, independent of liver disease or HCV infection. Nonetheless, these results corroborate evidence for elevations in IP-10 and TNFα in HIV and for IP-10 levels in HIV+HCV co-infection.

• Aged
• Alcoholism/blood
• Female
• Hepatitis B virus/isolation & purification
• Hepatitis C/blood
• Hepatitis C/virology
• Humans
• Male
• Middle Aged
• Substance Withdrawal Syndrome
• Tumor Necrosis Factor-alpha/blood
• Viral Load

• U01 AA017347 NIAAA NIH HHS
• U01 AA013521 NIH HHS
• K05 AA017168 NIAAA NIH HHS
• R01 AA005965 NIH HHS
• R01 AA010723 NIAAA NIH HHS
• R01 AA005965 NIAAA NIH HHS
• U01 AA013521 NIAAA NIH HHS
• R37 AA005965 NIAAA NIH HHS
• K05 AA017168 NIH HHS
• R37 AA010723 NIAAA NIH HHS
• U01 AA017347 NIH HHS
• R37 AA010723 NIH HHS
• National Institute on Alcohol Abuse and Alcoholism (US)
• National Institute on Alcohol Abuse and Alcoholism

Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6C^hi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6C^hi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14⁺ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA-seq-based transcriptome profiling of neutrophils from Ly6C^hi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p ≤ 0.05). In the absence of Ly6C^hi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6C^hi monocytes differentiated into ephemeral Ly6C^lo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6C^hi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6C^hi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance.

• drug-induced liver injury
• liver immunology
• macrophages
• monocytes
• neutrophils

• Animals
• Disease Models, Animal
• Fatty Liver, Alcoholic/etiology
• Fatty Liver, Alcoholic/pathology
• Hepatitis, Alcoholic/etiology
• Hepatitis, Alcoholic/pathology
• Humans

The endometrial regenerative cell (ERC) is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl₄)–induced acute liver injury (ALI).

An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl₄. Transplanted ERCs were intravenously injected (1 million/mouse) into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl₄ induction.

ERC treatment effectively decreased the CCl₄-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G) was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA) was increased after ERC treatment. Furthermore, the frequency of CD4⁺ and CD8⁺ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs) was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver.

Human ERCs protect the liver from acute injury in mice through hepatocyte proliferation promotion, as well as through anti-inflammatory and immunoregulatory effects.

• Acute liver injury
• Anti-inflammatory
• Endometrial regenerative cells
• Immunoregulation

• CCR2
• fah-deficient mice
• immune injury
• liver failure
• neutrophils

• Animals
• Bilirubin/blood
• Body Weight
• Cyclohexanones/pharmacology
• Disease Models, Animal
• Hepatocytes/enzymology
• Hydrolases/deficiency
• Hydrolases/genetics
• Inflammation/physiopathology
• Interleukins/metabolism
• Liver/physiopathology
• Liver Failure/genetics
• Liver Failure/immunology
• Male
• Mice
• Mice, Knockout
• Neutrophils/cytology
• Neutrophils/metabolism
• Nitrobenzoates/pharmacology
• Receptors, CCR2/genetics
• Tyrosine/metabolism
• Interleukin-22

Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale) against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP) and inflammatory cytokines (MIP-2, IL-6 and TNF-α) were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2) indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti-inflammatory phytomedicine against hepatic inflammation induced by antibiotic mediated endotoxemia. These results thus suggest that zingerone treatment can be used as a co-therapy with antibiotics to reduced endotoxin induced inflammation during treatment of severe P.aeruginosa infections.

• Animals
• Anti-Bacterial Agents/adverse effects
• Disease Models, Animal
• Endotoxemia/chemically induced
• Endotoxemia/complications
• Endotoxemia/pathology
• Endotoxins/biosynthesis
• Endotoxins/toxicity
• Gene Expression Regulation/drug effects
• Guaiacol/administration & dosage
• Guaiacol/analogs & derivatives
• Humans
• Inflammation/chemically induced
• Inflammation/complications
• Inflammation/drug therapy
• Inflammation/microbiology
• Inflammation/pathology
• Liver/drug effects
• Liver/microbiology
• Liver/pathology
• Mice
• Peritonitis/genetics
• Peritonitis/microbiology
• Peritonitis/pathology
• Pseudomonas aeruginosa/drug effects
• Pseudomonas aeruginosa/genetics
• Pseudomonas aeruginosa/pathogenicity
• RNA, Messenger/biosynthesis

• nlrp3
• inflammation
• liver fibrosis
• pyroptosis
• hepatocyte

• Animals
• Antirheumatic Agents/pharmacology
• Apoptosis/immunology
• Carrier Proteins/genetics
• Carrier Proteins/immunology
• Disease Models, Animal
• Growth Disorders/genetics
• Growth Disorders/immunology
• Hepatic Stellate Cells/immunology
• Hepatic Stellate Cells/pathology
• Hepatitis/drug therapy
• Hepatitis/immunology
• Hepatitis/pathology
• Hepatocytes/immunology
• Humans
• Inflammasomes/drug effects
• Inflammasomes/genetics
• Inflammasomes/immunology
• Interleukin 1 Receptor Antagonist Protein/pharmacology
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/immunology
• Liver Cirrhosis/pathology
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neutrophils/immunology
• Neutrophils/pathology
• Point Mutation
• Receptors, Interleukin-1/antagonists & inhibitors
• Receptors, Interleukin-1/immunology
• Receptors, Interleukin-1/metabolism

• R01 AI052430 NIAID NIH HHS
• DK076852 NIDDK NIH HHS
• R01 DK076852 NIDDK NIH HHS
• AI52430 NIAID NIH HHS
• DK082451 NIDDK NIH HHS
• R01 DK082451 NIDDK NIH HHS

• Acetaminophen
• Hepatotoxicity
• Inflammation
• Innate immunity
• Neutrophils
• Regeneration

• adhesion molecules
• alcoholic liver injury
• inflammation

• Alanine Transaminase/blood
• Animals
• Cytochrome P-450 CYP2E1/genetics
• E-Selectin/genetics
• E-Selectin/physiology
• Humans
• Intercellular Adhesion Molecule-1/analysis
• Interleukin-1beta/physiology
• Liver/pathology
• Liver Diseases, Alcoholic/etiology
• Mice
• Mice, Inbred C57BL
• Neutrophil Infiltration
• Tumor Necrosis Factor-alpha/physiology
• Vascular Cell Adhesion Molecule-1/analysis

• Z99 AA999999 Intramural NIH HHS
• ZIA AA000369 Intramural NIH HHS
• ZIA AA000369-11 Intramural NIH HHS

• amiodarone
• hemostatic system
• hypochlorous acid.
• idiosyncratic drug-induced liver injury
• neutrophils

• T-cell immunoglobulin domain and mucin-domain-containing molecule-3
• hepatitis B virus infection
• inducible nitric oxide synthase
• macrophage inflammatory protein 2
• neutrophil gelatinase-associated lipocalin

Background. Transplantation of ethanol-induced steatotic livers causes increased graft injury. We hypothesized that upregulation of hepatic ICAM-1 after ethanol produces increased leukocyte adherence, resulting in increased generation of reactive oxygen species (ROS) and injury after liver transplantation (LT). Methods. C57BL/6 wildtype (WT) and ICAM-1 knockout (KO) mice were gavaged with ethanol (6 g/kg) or water. LT was then performed into WT recipients. Necrosis and apoptosis, 4-hydroxynonenal (4-HNE) immunostaining, and sinusoidal leukocyte movement by intravital microscopy were assessed. Results. Ethanol gavage of WT mice increased hepatic triglycerides 10-fold compared to water treatment (P < 0.05). ICAM-1 also increased, but ALT was normal. At 8 h after LT of WT grafts, ALT increased 2-fold more with ethanol than water treatment (P < 0.05). Compared to ethanol-treated WT grafts, ALT from ethanol-treated KO grafts was 78% less (P < 0.05). Apoptosis also decreased by 75% (P < 0.05), and 4-HNE staining after LT was also decreased in ethanol-treated KO grafts compared to WT. Intravital microscopy demonstrated a 2-fold decrease in leukocyte adhesion in KO grafts compared to WT grafts. Conclusions. Increased ICAM-1 expression in ethanol-treated fatty livers predisposes to leukocyte adherence after LT, which leads to a disturbed microcirculation, oxidative stress and graft injury.

• Animals
• Hepatitis/immunology
• Humans
• Inflammation/immunology
• Liver/blood supply
• Liver/immunology
• Liver/pathology
• Microvessels/immunology
• Neutrophil Infiltration/immunology
• Neutrophils/immunology

• Canadian Institutes of Health Research

To study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl₄)-induced acute hepatotoxicity in the mouse model.

Mice were intraperitoneally injected with CCl₄ (50 μl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity.

SAMC reduced CCl₄-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl₄ enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl₄. SAMC played an essential antioxidative role during CCl₄-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl₄ via inhibiting the activity of NF-κB subunits p50 and p65, thus reducing the expressions of pro-inflammatory cytokines, mediators, and chemokines, as well as promoting pro-regenerative factors at both transcriptional and translational levels.

Our results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl₄-induced acute hepatotoxicity mouse model through regulation of NF-κB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage.

• Animals
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/metabolism
• Chromatography, Liquid
• Disease Models, Animal
• Ethanol/adverse effects
• Fatty Liver, Alcoholic/blood
• Fatty Liver, Alcoholic/etiology
• Fatty Liver, Alcoholic/metabolism
• Humans
• Lipid Metabolism
• Lipids/blood
• Liver/chemistry
• Liver/injuries
• Liver/metabolism
• Liver Neoplasms/blood
• Liver Neoplasms/metabolism
• Male
• Mass Spectrometry
• Metabolomics
• Mice
• Mice, Nude
• Xenograft Model Antitumor Assays

• drug hepatotoxicity
• acetaminophen
• innate immunity
• neutrophils
• integrins
• oxidant stress
• inflammation

• animal models
• acute and chronic alcohol abuse
• immune defects
• organ damage

• Alcoholic Intoxication/immunology
• Alcoholism/immunology
• Alcoholism/pathology
• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Routes
• Drug Administration Schedule
• Ethanol/administration & dosage
• Ethanol/pharmacology
• Humans
• Immunity/drug effects

• R01 AA013168 NIAAA NIH HHS
• R01 AA013168-04 NIAAA NIH HHS
• R01 AA012034 NIAAA NIH HHS
• R01 AA007293 NIAAA NIH HHS
• K05 AA017149 NIAAA NIH HHS
• R01 AA07293 NIAAA NIH HHS

• mrna translation initiation
• alcohol
• eukaryotic initiation factor 2b
• eukaryotic initiation factor 2

• Alcohol Drinking/metabolism
• Alcohol-Induced Disorders/metabolism
• Alcoholism/metabolism
• Female
• Humans
• Liver/metabolism
• Male
• Protein Biosynthesis

• 5R21 AA-15349-2 NIAAA NIH HHS