• Amydrium sinense
• Stat3
• carbon tetrachloride
• hepatic fibrosis
• α-SMA

• ACLF
• DAMPs
• PAMPs
• animal model
• hepatotoxic reagents

• fibrotic diseases
• liver cirrhosis
• mesenchymal stem cells
• myofibroblasts
• pulmonary fibrosis

• FFAR1 agonist
• bornyl derivatives
• carbon tetrachloride
• hepatoprotective effect
• liver injury

• Carbon tetrachloride (CCL(4))
• Ovarian fibrosis
• Oxidative stress
• Proinflammatory cytokines

• Animals
• Antioxidants/metabolism
• Carbon Tetrachloride/metabolism
• Carbon Tetrachloride/toxicity
• Chemical and Drug Induced Liver Injury/metabolism
• Cytokines/metabolism
• Fibrosis
• Liver
• Mice
• Oxidative Stress

• Hepatic fibrosis
• Igf2bp2
• Mouse hepatic stellate cells (mHSCs)
• PI3K/Akt pathway
• Tgfbr1

Liver tissue transcriptomics of liver cirrhosis (LC)–based acute-on-chronic liver failure (ACLF) rats reveal immune-metabolism disorder as the core mechanism underlying ACLF development and prognosis.

Acute-on-chronic liver failure (ACLF) is clinical syndrome with high mortality rate. This study aimed to perform detailed transcriptomic analysis in liver cirrhosis–based ACLF rats to elucidate ACLF pathogenesis. ACLF was induced by combined porcine serum with D-galactosamine and lipopolysaccharide. Gene expression profile of liver tissues from ACLF rats was generated by transcriptome sequencing to reveal the molecular mechanism. ACLF rats successfully developed with typical characteristics. Total of 2,354/3,576 differentially expressed genes were identified when ACLF was compared to liver cirrhosis and normal control, separately. The functional synergy analysis revealed prominent immune dysregulation at ACLF stage, whereas metabolic disruption was significantly down-regulated. Relative proportions of innate immune–related cells showed significant elevation of monocytes and macrophages, whereas adaptive immune–related cells were reduced. The seven differentially expressed genes underlying the ACLF molecular mechanisms were externally validated, among them THBS1, IL-10, and NR4A3 expressions were confirmed in rats, patient transcriptomics, and liver biopsies, verifying their potential value in the ACLF pathogenesis. This study indicates immune-metabolism disorder in ACLF rats, which may provide clinicians new targets for improving intervention strategies.

• HNF4α
• fibrosis
• gender differences
• liver inflammation
• steatohepatitis

• Animals
• Diet, Western
• Disease Models, Animal
• Ethanol/administration & dosage
• Fatty Liver, Alcoholic/pathology
• Female
• Fibrosis
• Hepatocyte Nuclear Factor 4/metabolism
• Liver/immunology
• Liver/metabolism
• Liver/pathology
• Male
• Mice, Inbred C57BL
• Mice

• AA012863 NIAAA NIH HHS
• AA027586 NIAAA NIH HHS
• I01 BX004694 BLRD VA
• R01 AA027586 NIAAA NIH HHS
• R01 AA012863 NIAAA NIH HHS
• U54 HD090216 NICHD NIH HHS

• IRAK3
• Liver fibrosis
• Lumican
• Murine liver fibrosis model
• Polyhexamethylene guanidine phosphate (PHMG-p)

• bile duct ligation
• chorionic-plate-derived mesenchymal stem cells
• liver regeneration
• phosphatase of regenerating liver-1

• Animals
• Bile Ducts/metabolism
• Cell Proliferation/physiology
• Female
• Hepatocytes/metabolism
• Humans
• Liver/metabolism
• Liver Regeneration/physiology
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Placenta/cytology
• Placenta/metabolism
• Pregnancy
• Rats

• Salvia reflexa
• cattle
• diterpenoids
• hepatotoxicity
• lance-leaf sage
• sage mint

Excess alcohol (ethanol, EtOH) consumption is a significant cause of chronic liver disease, accounting for nearly half of the cirrhosis‐associated deaths in the United States. EtOH‐induced liver toxicity is linked to EtOH metabolism and its associated increase in proinflammatory cytokines, oxidative stress, and the subsequent activation of Kupffer cells. Dihydromyricetin (DHM), a bioflavonoid isolated from Hovenia dulcis, can reduce EtOH intoxication and potentially protect against chemical‐induced liver injuries. But there remains a paucity of information regarding the effects of DHM on EtOH metabolism and liver protection. As such, the current study tests the hypothesis that DHM supplementation enhances EtOH metabolism and reduces EtOH‐mediated lipid dysregulation, thus promoting hepatocellular health.

The hepatoprotective effect of DHM (5 and 10 mg/kg; intraperitoneal injection) was evaluated using male C57BL/6J mice and a forced drinking ad libitum EtOH feeding model and HepG2/VL‐17A hepatoblastoma cell models. EtOH‐mediated lipid accumulation and DHM effects against lipid deposits were determined via H&E stains, triglyceride measurements, and intracellular lipid dyes. Protein expression of phosphorylated/total proteins and serum and hepatic cytokines was determined via Western blot and protein array. Total NAD⁺/NADH Assay of liver homogenates was used to detect NAD + levels.

DHM reduced liver steatosis, liver triglycerides, and liver injury markers in mice chronically fed EtOH. DHM treatment resulted in increased activation of AMPK and downstream targets, carnitine palmitoyltransferase (CPT)‐1a, and acetyl CoA carboxylase (ACC)‐1. DHM induced expression of EtOH‐metabolizing enzymes and reduced EtOH and acetaldehyde concentrations, effects that may be partly explained by changes in NAD⁺. Furthermore, DHM reduced the expression of proinflammatory cytokines and chemokines in sera and cell models.

In total, these findings support the utility of DHM as a dietary supplement to reduce EtOH‐induced liver injury via changes in lipid metabolism, enhancement of EtOH metabolism, and suppressing inflammation responses to promote liver health.

• Alcohol Liver Damage
• Dihydromyricetin
• Ethanol
• Steatosis

• Adipose tissue
• Angiotensin converting enzyme 2 (ACE2)
• Mas receptor
• Metabolism
• Renin-angiotensin system

• Adipokines/metabolism
• Adipose Tissue/metabolism
• Angiotensin I/metabolism
• Animals
• Humans
• Inflammation/metabolism
• Peptide Fragments/metabolism
• Proto-Oncogene Mas

Iron is implicated in the pathogenesis of a number of human liver diseases. Hereditary hemochromatosis is the classical example of a liver disease caused by iron, but iron is commonly believed to contribute to the progression of other forms of chronic liver disease such as hepatitis C infection and nonalcoholic fatty liver disease. In this review, we present data from cell culture experiments, animal models, and clinical studies that address the hepatotoxicity of iron. These data demonstrate that iron overload is only weakly fibrogenic in animal models and rarely causes serious liver damage in humans, calling into question the concept that iron overload is an important cause of hepatotoxicity. In situations where iron is pathogenic, iron-induced liver damage may be potentiated by coexisting inflammation, with the resulting hepatocyte necrosis an important factor driving the fibrogenic response. Based on the foregoing evidence that iron is less hepatotoxic than is generally assumed, claims that assign a causal role to iron in liver injury in either animal models or human liver disease should be carefully evaluated.

• chelation
• cirrhosis
• hemochromatosis
• iron
• liver injury
• phlebotomy

• Carbon tetrachloride
• Liver fibrosis
• Mitogen-activated protein kinase
• Nuclear factor kappa B
• Sasa veitchii

• Animal model
• BDL
• CCl(4)
• Cirrhosis
• HFD
• Liver disease
• MCD
• NASH
• NCPH
• PPVL
• Portal hypertension
• TAA

• Coll
• JNK
• endoplasmic reticulum stress
• fatty liver fibrosis
• total saponins of Panax japonicus

• Chromatin immunoprecipitation
• ELISA
• Electrophoretic mobility shift assay
• Immunohistochemistry
• Immunoprecipitation
• In situ hybridization
• RT-PCR

Human hepatitis B virus (HBV) infection is an important public health issue in the Asia-Pacific region and is associated with chronic hepatitis, liver fibrosis, cirrhosis and even liver cancer. However, the underlying mechanisms of HBV-associated liver fibrosis remain incompletely understood.

In the present study, proteomic and transcriptomic approaches as well as biological network analyses were performed to investigate the differentially expressed molecular signature and key regulatory networks that were associated with HBV-mediated liver fibrosis. RNA sequencing and 2DE-MALDI-TOF/TOF were performed on liver tissue samples obtained from HBV-infected C57BL/6 mouse generated via AAV8-HBV virus. The results showed that 322 genes and 173 proteins were differentially expressed, and 28 HBV-specific proteins were identified by comprehensive proteomic and transcriptomic analysis. GO analysis indicated that the differentially expressed proteins were predominantly involved in oxidative stress, which plays a key role in HBV-related liver fibrosis. Importantly, CAT, PRDX1, GSTP1, NXN and BLVRB were shown to be associated with oxidative stress among the differentially expressed proteins. The most striking results were validated by Western blot and RT-qPCR. The RIG-I like receptor signaling pathway was found to be the major signal pathway that changed during HBV-related fibrosis.

This study provides novel insights into HBV-associated liver fibrosis and reveals the significant role of oxidative stress in liver fibrosis. Furthermore, CAT, BLVRB, NXN, PRDX1, and IDH1 may be candidates for detection of liver fibrosis or therapeutic targets for the treatment of liver fibrosis.

The online version of this article (doi:10.1186/s12864-017-3984-z) contains supplementary material, which is available to authorized users.

• HBV
• Liver fibrosis
• Proteomics
• Transcriptomics

TSA markedly reduced the CCl₄-induced liver injury in mice.

Oxidative stress induces the activation of liver fibrogenic cells (myofibroblasts), thus promoting the expression of fibrosis-related genes, leading to hepatic fibrogenesis. MicroRNAs (miRNAs) are a new class of small RNAs ~18–25 nucleotides in length involved in post-transcriptional regulation of gene expression. Wound-healing and remodeling processes in liver fibrosis have been associated with changes in hepatic miRNA expression. However, the role of miR-706 in liver fibrogenesis is currently unknown. In the present study, we show that miR-706 is abundantly expressed in hepatocytes. Moreover, oxidative stress leads to a significant downregulation of miR-706, and the further reintroduction of miR-706 inhibits oxidative stress-induced expression of fibrosis-related markers such as α-SMA. Subsequent studies revealed that miR-706 directly inhibits PKCα and TAOK1 expression via binding to the 3′-untranslated region, preventing epithelial mesenchymal transition. In vivo studies showed that intravenous injection of miR-706 agomir successfully increases hepatic miR-706 and decreases α-SMA, PKCα, and TAOK1 protein levels in livers of carbon tetrachloride (CCl₄)-treated mice. In summary, this study reveals a protective role for miR-706 by blocking the oxidative stress-induced activation of PKCα/TAOK1. Our results further identify a major implication for miR-706 in preventing hepatic fibrogenesis and suggest that miR-706 may be a suitable molecular target for anti-fibrosis therapy.

• Liver fibrosis
• NF-κB
• TGF-β/Smad
• liver inflammation
• trillin

• Carbon tetrachloride
• Epithelial–mesenchymal transition
• Glutamine
• Liver fibrosis
• Oxidative stress
• Transforming growth factor-β

Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests.

• Liver cirrhosis
• Drug metabolism
• Transport
• Breath tests
• Lipid metabolism
• Glucose metabolism

• Animals
• Biological Transport, Active
• Breath Tests
• Cytochrome P-450 Enzyme System/metabolism
• Glucose/metabolism
• Glucuronosyltransferase/metabolism
• Humans
• Lipid Metabolism
• Liver/metabolism
• Liver Cirrhosis/metabolism
• Liver Cirrhosis, Experimental/metabolism
• Liver Function Tests
• Sulfotransferases/metabolism

This review analyzes current studies of the therapeutic effects of Phoenix dactylifera, or date palm fruit, on the physiologic system. Specifically, we sought to summarize the effects of its application in preventing cell damage, improving cancer therapeutics and reducing damage caused by conventional chemotherapy. Phoenix dactylifera exhibits potent anti-oxidative properties both in vitro and in vivo. This allows the fruit to prevent depletion of intrinsic protection from oxidative cell damage and assist these defense systems in reducing cell damage. Macroscopically, this mechanism may be relevant to the prevention of various adverse drug events common to chemotherapy including hepatotoxicity, nephrotoxicity, gastrotoxicity, and peripheral neuropathy. While such effects have only been studied in small animal systems, research suggests a potential application to more complex mammalian systems and perhaps a solution to some problems of chemotherapy in hepato-compromised and nephro-compromised patients.

• chemotherapy-induced adverse events
• hepatotoxicity
• mucositis
• nephrotoxicity
• peripheral neuropathy

• Animals
• Cytoprotection/drug effects
• Humans
• Islam
• Medicine, Traditional
• Neoplasms/drug therapy
• Oxidative Stress/drug effects
• Phoeniceae/chemistry
• Polyphenols/pharmacology
• Polyphenols/therapeutic use

Hepatocellular carcinoma (HCC) is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR) is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase–, v-akt murine thymoma viral oncogene homolog 1–, or signal-transducer and activator of transcription–signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor β, vascular endothelial growth factor, and glucose-regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC.

• angiogenesis
• glucose-regulated protein 78 kDa
• hepatocarcinogenesis
• molecular targets
• vascular endothelial growth factor

Liver cirrhosis and hepatocellular carcinomas are major health problems of chronic hepatitis B virus (HBV) infection. To date, rare model has reproduced liver fibrosis associated with long-term HBV infection which in turn has hindered both the understanding of HBV biology and the development of new treatment options. Here, using adeno-associated virus serotype 8 (AAV8) mediated delivery of a 1.2-kb HBV genome, we successfully generated a chronic HBV infectious mouse model that presents the associated liver fibrosis observed following human infection. After AAV8/HBV1.2 vector administration, mice demonstrated effective HBV replication and transcription which resulted in HBV antigen expression and viremia over 6 months. Although no obvious acute inflammatory response was noted, these mice still developed chronic liver disease and hepatic fibrogenesis as demonstrated by increased ground glass-like hepatocytes, an increasing trend of collagen deposition and upregulated fibrosis markers, including type I collagen, type III collagen, tissue inhibitor of metalloproteinase (TIMP), and transforming growth factor-β1(TGF-β1). Taken together, AAV-mediated HBV gene delivery to the mouse liver, induced HBV persistent infection accompanied by liver fibrosis which can serve as a model for investigating the precise mechanisms underlying liver fibrosis following chronic HBV infection as well as for the potential development of novel therapeutics.

• Animals
• Blotting, Northern
• Blotting, Southern
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/virology
• Cells, Cultured
• Dependovirus/genetics
• Disease Models, Animal
• Drug Delivery Systems
• Enzyme-Linked Immunosorbent Assay
• Genetic Vectors/administration & dosage
• Genome, Viral
• HEK293 Cells
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/genetics
• Hepatitis B, Chronic/virology
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/virology
• Liver Neoplasms/genetics
• Liver Neoplasms/virology
• Mice
• Mice, Inbred C57BL
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Viremia/genetics
• Viremia/virology
• Virus Replication

• Rosa laevigata Michx
• liver fibrosis
• protective effect
• total saponins

• Actins/metabolism
• Alanine Transaminase/metabolism
• Animals
• Aspartate Aminotransferases/metabolism
• Carbon Tetrachloride/toxicity
• Collagen/metabolism
• Down-Regulation
• Fibronectins/metabolism
• Fruit/chemistry
• Glutathione/metabolism
• Hydroxyproline/metabolism
• Liver/drug effects
• Liver/metabolism
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/drug therapy
• Male
• Malondialdehyde/metabolism
• Matrix Metalloproteinases/genetics
• Matrix Metalloproteinases/metabolism
• Oxidative Stress/drug effects
• Rats
• Rats, Sprague-Dawley
• Rosa/chemistry
• Saponins/pharmacology
• Signal Transduction
• Superoxide Dismutase/metabolism

• Animal models
• CTGF
• PDGF-β
• TGF-β
• chemotoxins
• liver fibrosis

• Animals
• Carbon Tetrachloride/toxicity
• Connective Tissue Growth Factor/metabolism
• Dimethylnitrosamine/toxicity
• Disease Models, Animal
• Immunohistochemistry
• Lipid Peroxidation/drug effects
• Liver Cirrhosis, Experimental/chemically induced
• Liver Cirrhosis, Experimental/physiopathology
• Male
• Platelet-Derived Growth Factor/metabolism
• Rats
• Rats, Sprague-Dawley
• Thioacetamide/toxicity
• Transforming Growth Factor beta/metabolism

• Angiogenesis
• Fibrogenesis
• Inflammation
• Liver fibrosis
• Pituitary tumor transforming factor
• Thioacetamide

• Hepatocellular carcinoma
• Liver cirrhosis
• Liver disease
• Telomerase
• Telomeres

• Animals
• Humans
• Liver Diseases/genetics
• Liver Diseases/pathology
• Telomerase/metabolism
• Telomere/physiology

• Animal models
• Cell tracking
• Fibrosis
• Hepatic stellate cell
• Liver

• ALT, aminotransferase
• ANOVA, analysis of variance
• AST, aspartate aminotransferase
• NorUDCA, norursodeoxycholic acid
• SEM, standard error of the mean
• TAA, thioacetamide
• TIMP-1, tissue inhibitor of metalloproteinase-1
• UDCA, ursodeoxycholic acid
• fibrosis
• liver
• norursodeoxycholic acid
• thioacetamide
• ursodeoxycholic acid

Cirrhosis is a long-term consequence of chronic hepatic injury with fibrosis. No effective therapy is currently available for decompensated cirrhosis except liver transplantation. Hence, we investigated the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model.

The BM-MSCs were injected directly into the right liver lobe twice, at 6 and 8 weeks during the 12-week TAA administration, in thioacetamide (TAA)-induced cirrhotic rats model, and hepatic fibrosis was evaluated. At 12 weeks, the effect of BM-MSCs on hepatic fibrosis was analyzed histomorphologically using the Laennec fibrosis scoring system, and the collagen proportionate area was quantified. Cirrhosis-related factors, such as transforming growth factor β1 (TGF-β1), type 1 collagen (collagen-1), α-smooth muscle actin (α-SMA), and P-Smad3/Smad3 expression levels, were evaluated using real-time polymerase chain reaction and western blot assays.

According to the Laennec fibrosis scoring system, histological improvement was observed in hepatic fibrosis after BM-MSC treatment (P <0.01). The percentage of the collagen proportionate area decreased from 16.72 ± 5.51 to 5.06 ± 1.27 after BM-MSC treatment (P <0.01). The content of hepatic hydroxyproline was significantly lower in the BM-MSC treated group (46.25 ± 13.19) compared to the untreated cirrhotic group (85.81 ± 17.62; P <0.01). BM-MSC administration significantly decreased TGF-β1, collagen-1, and α-SMA expression in TAA-induced cirrhotic rats (P <0.01). We also confirmed P-Smad3/Smad3, downstream effectors of the TGF-β1 signaling pathway, and found that MSC transplantation inhibited Smad3 phosphorylation.

BM-MSC treatment attenuated hepatic fibrosis in rats with TAA-induced cirrhosis, raising the possibility of the clinical use of BM-MSCs in the treatment of cirrhosis.

The online version of this article (doi:10.1186/s12876-014-0198-6) contains supplementary material, which is available to authorized users.

This study investigated the anti-inflammatory effects of DEC on the CCl₄-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl₄ 0.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg) was administered by gavage for 12 days before finishing the CCl₄ induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, and αSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβ expressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.

• retinol
• retinaldehyde
• retinoic acid
• 4-methylpyrazole
• interferon-gamma

• Antioxidants
• Carbon tetrachloride
• Hepatoprotective
• Oxidative stress
• Phoenix dactylifera seeds

• Administration, Oral
• Animals
• Antioxidants/isolation & purification
• Antioxidants/pharmacology
• Carbon Tetrachloride/toxicity
• Chemical and Drug Induced Liver Injury/physiopathology
• Chemical and Drug Induced Liver Injury/prevention & control
• DNA Damage/drug effects
• Disease Models, Animal
• Egypt
• Free Radical Scavengers/isolation & purification
• Free Radical Scavengers/pharmacology
• Liver Diseases/physiopathology
• Liver Diseases/prevention & control
• Male
• Medicine, Traditional
• Nitric Oxide/metabolism
• Oxidative Stress/drug effects
• Phoeniceae/chemistry
• Plant Extracts/pharmacology
• Rats
• Rats, Wistar
• Seeds
• Thiobarbituric Acid Reactive Substances/metabolism

• CELL SIGNALLING
• CHOLESTATIC LIVER DISEASES
• DRUG INDUCED HEPATOTOXICITY
• FIBROGENESIS
• INFLAMMATION

• Animals
• Apoptosis
• Biomarkers/metabolism
• Bone Marrow Transplantation
• Cell Transdifferentiation
• Chronic Disease
• Down-Regulation
• Hepatic Stellate Cells/enzymology
• Hepatocytes/enzymology
• Humans
• Liver Cirrhosis/enzymology
• Liver Cirrhosis/etiology
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 8/deficiency
• Mitogen-Activated Protein Kinase 8/metabolism
• Up-Regulation

Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl₄). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl₄-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl₄-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis.

• cirrhosis
• computer simulation
• elastography
• hepatocyte
• inflammation