• beta-blockers
• hepatic circulation
• liver cirrhosis
• pharmacological treatments
• portal hypertension

• BNW-1-157/N/4/K Medical University of Silesia

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.

• cardiotonic steroids
• exosomes
• hepatic fibrosis
• miRNA
• oxidative stress

• Cell recruitment
• HSCs
• Inflammatory responses
• KCs

Liver resection is an effective treatment for benign and malignant liver tumors. However, a method for preoperative evaluation of hepatic reserve has not yet been established. Previously reported assessments of preoperative hepatic reserve focused only on liver failure in the early postoperative period and did not consider the long-term recovery of hepatic reserve. When determining eligibility for hepatectomy, the underlying pathophysiology needs to be considered to determine if the functional hepatic reserve can withstand both surgery and any postoperative therapy.

To identify pre-hepatectomy factors associated with both early postoperative liver failure and long-term postoperative liver function recovery.

This study was a retrospective cohort study. We retrospectively investigated 215 patients who underwent hepatectomy at our hospital between May 2013 and December 2016. Early post-hepatectomy liver failure (PHLF) was defined using the International Study Group of Liver Surgery’s definition of PHLF. Long-term postoperative recovery of liver function was defined as the time taken for serum total bilirubin and albumin levels to return to levels of < 2 mg/dL and > 2.8 g/dL, respectively, and the time taken for Child-Pugh score to return to Child-Pugh class A.

Preoperative type IV collagen 7S was identified as a significant independent factor associated with both PHLF and postoperative long-term recovery of liver function. Further analysis revealed that the time taken for the recovery of Child-Pugh scores and serum total bilirubin and albumin levels was significantly shorter in patients with type IV collagen 7S ≤ 6 ng/mL than in those with type IV collagen 7S > 6 ng/mL. In additional analyses, similar results were observed in patients without chronic viral hepatitis associated with fibrosis.

Preoperative type IV collagen 7S is a preoperative predictor of PHLF and long-term postoperative liver function recovery. It can also be used in patients without chronic hepatitis virus.

• Hepatectomy
• Liver failure
• Type IV collagen 7S
• Liver fibrosis
• Postoperative complications
• Long-term postoperative liver function recovery

• Adult
• Aged
• Aged, 80 and over
• Bilirubin/blood
• Collagen Type IV/blood
• Female
• Hepatectomy/adverse effects
• Humans
• Liver/physiopathology
• Liver Failure/etiology
• Liver Function Tests/methods
• Liver Function Tests/statistics & numerical data
• Liver Neoplasms/blood
• Liver Neoplasms/surgery
• Male
• Middle Aged
• Postoperative Complications/etiology
• Predictive Value of Tests
• Preoperative Period
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Treatment Outcome
• Young Adult

Liver fibrosis is a significant health problem which represents the liver’s scarring process and response to injury through deposition of collagen and extracellular matrix, and ultimately leads to cirrhosis. Resveratrol is a naturally occurring phytoalexin found predominantly in grapes. This study aimed to investigate the antifibrotic role of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were divided into four groups and treated for three weeks; control, resveratrol administered orally (20 mg/kg daily), DMN intraperitoneally injected (10 mg/kg 3 days/week), and the last group was pre-treated daily with resveratrol then injected with DMN, 3 days/week. DMN administration induced severe liver pathological alterations. However, oral administration of resveratrol before DMN significantly prevented the induced loss in body weight, as well as the increase in liver weight which arise from DMN administration. Resveratrol has also inhibited the elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin levels. Furthermore, resveratrol significantly increased hepatic reduced glutathione (GSH) levels and reduced the levels of malondialdehyde (MDA) due to its antioxidants effect as well as increased serum protein levels. In addition, DMN induced elevation in hydroxyproline content. On the other hand, hydroxyproline level was significantly reduced in the resveratrol pretreated rats. Resveratrol has also remarkably maintained the normal liver lobular architecture. Moreover, resveratrol had displayed potent potentials to prevent collagen deposition, lymphocytic infiltration, necrosis, steatosis, vascular damage, blood hypertention, cholangiocyte proliferation. It can be concluded that resveratrol has a marked protective role on DMN-induced liver fibrosis in rats, and can be considered as antiproliferative, antihypertensive, as well as antifibrotic agent and may be used to block the development of liver fibrosis.

• Antifibrotic role
• Dimethylnitrosamine
• Liver fibrosis
• Rats
• Resveratrol

Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulation-like response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny.

• Inflammation
• Non-alcoholic fatty liver disease
• Hepatic steatosis
• Extraembryonic functions
• Fibrosis
• Portal hypertension

Collagen produced during the process of liver fibrosis can induce a hepatocellular protective response through ERK1 signalling. However, the influence of T cells and associated cytokine production on this protection is unknown. In addition, athymic mice are frequently used in hepatocellular carcinoma xenograft experiments but current methods limit our ability to study the impact of liver fibrosis in this setting due to high mortality. Therefore, a mouse model of liver fibrosis lacking T cells was developed using Foxn1 nu/nu mice and progressive oral administration of thioacetamide (TAA) [0.01–0.02%] in drinking water. Fibrosis developed over a period of 16 weeks (alpha-SMA positive area: 20.0 ± 2.2%, preCol1a1 mRNA expression: 11.7 ± 4.1 fold changes, hydroxyproline content: 1041.2 ± 77μg/g of liver) at levels comparable to that of BALB/c mice that received intraperitoneal TAA injections [200 μg/g of body weight (bw)] (alpha-SMA positive area: 20.9 ± 2.9%, preCol1a1 mRNA expression: 13.1 ± 2.3 fold changes, hydroxyproline content: 931.6 ± 14.8μg/g of liver). No mortality was observed. Athymic mice showed phosphorylation of ERK1/2 during fibrogenesis (control 0.03 ± 0.01 vs 16 weeks 0.22 ± 0.06AU; P<0.05). The fibrosis-induced hepatoprotection against cytotoxic agents, as assessed histologically and by serum AST levels, was not affected by the absence of circulating T cells (anti-Fas JO2 [0.5μg/g bw] for 6h (fibrotic 4665 ± 2596 vs non-fibrotic 13953 ± 2260 U/L; P<0.05), APAP [750 mg/kg bw] for 6 hours (fibrotic 292 ± 66 U/L vs non-fibrotic 4086 ± 2205; P<0.01) and CCl₄ [0.5mL/Kg bw] for 24h (fibrotic 888 ± 268 vs non-fibrotic 15673 ± 2782 U/L; P<0.001)). In conclusion, liver fibrosis can be induced in athymic Foxn1 nu/nu mice without early mortality. Liver fibrosis leads to ERK1/2 phosphorylation. Finally, circulating T lymphocytes and associated cytokines are not involved in the hepatocellular protection afforded by liver fibrosis.

• Animals
• Blotting, Western
• Carcinogens/pharmacology
• Chemical and Drug Induced Liver Injury/prevention & control
• Disease Models, Animal
• Fluorescent Antibody Technique
• Liver/drug effects
• Liver Cirrhosis/physiopathology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• T-Lymphocytes/physiology
• Thioacetamide/pharmacology
• Transcriptome

• Novartis/Canadian Liver Foundation Hepatology Research Chair at the Université de Montréal

• developmental engineering
• in vitro morphogenesis
• micropatterning
• soft lithography
• tissue engineering

• Animals
• Biocompatible Materials/pharmacology
• Cell Culture Techniques/methods
• Extracellular Matrix/drug effects
• Extracellular Matrix/metabolism
• Humans
• Microtechnology/methods
• Signal Transduction/drug effects
• Tissue Engineering/methods

• R21 HL121757 NHLBI NIH HHS

• Liver progenitor cells (LPCs)
• hepatic stellate cells (HSCs)
• liver cirrhosis
• liver failure
• liver regeneration
• mesenchymal stem cells (MSCs)
• stem cells

• cirrhosis
• clinical trials
• end-stage liver disease
• liver fibrosis
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

Chronic liver diseases with different aetiologies rely on the chronic activation of liver injuries which result in a fibrogenesis progression to the end stage of cirrhosis and liver failure. Based on the underlying cellular and molecular mechanisms of a liver fibrosis, there has been proposed several kinds of approaches for the treatment of liver fibrosis. Recently, liver gene therapy has been developed as an alternative way to liver transplantation, which is the only effective therapy for chronic liver diseases. The activation of hepatic stellate cells, a subsequent release of inflammatory cytokines and an accumulation of extracellular matrix during the liver fibrogenesis are the major obstacles to the treatment of liver fibrosis. Several targeted strategies have been developed, such as antisense oligodeoxynucleotides, RNA interference and decoy oligodeoxynucleotides to overcome this barriers. With this report an overview will be provided of targeted strategies for the treatment of liver cirrhosis, and particularly, of the targeted gene therapy using short RNA and DNA segments.

• Liver cirrhosis
• Gene therapy
• Oligodeoxynucleotides
• Antisense
• Small interfering RNA
• Micro RNA
• Decoy

• Animals
• Gene Expression Regulation
• Genetic Therapy/methods
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/therapy
• MicroRNAs/therapeutic use
• Oligonucleotides, Antisense/therapeutic use
• RNA Interference
• RNA, Small Interfering/therapeutic use
• Treatment Outcome

• HSC senescence
• anticancer treatment
• antifibrogenic treatment
• deactivated-hepatic stellate cells
• extracellular matrix
• genomics
• hepatocellular carcinoma
• in vitro-activated hepatic stellate cells
• in vivo-activated hepatic stellate cells
• intratumour heterogeneity
• secretomics
• transcriptome
• tumour-stromal microenvironment

• Carbon tetrachloride
• bone morphogenetic protein-7
• epidermal growth factor receptor
• hepatic stellate cell
• liver fibrosis

• Animals
• Blotting, Western
• Bone Morphogenetic Protein 7/metabolism
• Carbon Tetrachloride/toxicity
• Disease Models, Animal
• ErbB Receptors/biosynthesis
• Hepatic Stellate Cells/metabolism
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Mice
• Mice, Inbred ICR
• Reverse Transcriptase Polymerase Chain Reaction
• Transforming Growth Factor beta1/biosynthesis

• LX2 cells
• hepatic stellate cells
• side population
• stem cells
• transforming growth factor-β

Acute liver failure (ALF) results from the acute and rapid loss of hepatocyte function and frequently exhibits a fulminant course, characterized by high mortality in the absence of immediate state-of-the-art intensive care and/or emergency liver transplantation (ELT). The role of hepatocyte-mediated liver regeneration during acute and chronic liver injury has been extensively investigated, and recent studies suggest that hepatocytes are not exclusively responsible for the regeneration of the injured liver during fulminant liver injury. Liver progenitor cells (LPC) (or resident liver stem cells) are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. This review aims to provide an overview of the role of the LPC population during ALF, and the role of putative cytokines, growth factors, mitogens, and hormones in the LPC response. We will highlight the potential interaction among cellular compartments during ALF, and discuss the possible prognostic value of the LPC response on ALF outcomes.

• acute liver failure
• hepatic failure
• liver progenitor cells
• liver regeneration
• oval cells
• severe acute liver injury
• stem cells

Biliary atresia is an infantile destructive inflammatory cholangiopathy that causes obliteration of both intrahepatic and extrahepatic bile ducts and eventually liver cirrhosis. So far, the exact etiology and pathogenesis of biliary atresia remain unclear, and possible etiologies include congenital and genetic factors, infection, inflammation, immune reaction, maternal factors, and vascular factors. Immunoinflammatory theory has been accepted by most researchers, which is supported by liver pathological changes. This review focuses on the recent progress in understanding pathogenesis and liver pathology in biliary atresia.

• Biliary atresia
• Pathogenesis
• Liver pathology
• Etiology
• Immune reaction

• apoptosis
• fibrosis
• mandible
• myofibroblast
• osteoradionecrosis

• hepatic regeneration
• pgdf receptor
• tyrosine kinase
• lx-2 cells
• microarray

• in vitro hepatic models
• hepatocytes
• hepatotoxicity
• organotypic culture models
• microfluidic devices
• toxicity testing

• Animals
• Cell Culture Techniques
• Chemical and Drug Induced Liver Injury/etiology
• Drug Industry
• Hemodynamics
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Liver/cytology
• Liver/drug effects
• Liver/metabolism
• Risk Assessment/methods
• Tissue Culture Techniques
• Toxicity Tests/methods

• il12
• ifnγ
• il27p28 (il30)
• ebi3
• tccr
• cona

• Kupffer cell
• Liver fibrosis
• alternative macrophage activation.
• cirrhosis

• Animals
• Chronic Disease
• Epithelial-Mesenchymal Transition
• Hepatocytes/pathology
• Humans
• Liver Cirrhosis/etiology
• Liver Cirrhosis/pathology
• Liver Cirrhosis, Experimental/etiology
• Liver Cirrhosis, Experimental/pathology
• Liver Diseases/etiology
• Liver Diseases/pathology
• Myofibroblasts/pathology
• Neoplasms/etiology
• Neoplasms/pathology

Cholangiocytes are the epithelial cells that line the biliary tree. In the adult liver, they are a mitotically dormant cell population, unless ductular reaction is triggered by injury. The ability of cholangiocytes to proliferate is important in many different human pathological liver conditions that target this cell type, which are termed cholangiopathies (i.e. primary biliary cirrhosis, primary sclerosing cholangitis and biliary atresia). In our article, we provide background information on the morphological and functional heterogeneity of cholangiocytes, summarize what is currently known about their proliferative processes, and briefly describe the diseases that target these cells. In addition, we address recent findings that suggest cholangiocyte involvement in epithelial-to-mesenchymal transformation and liver fibrosis, and propose directions for future studies.

• Biliary epithelium
• Cholangiopathies
• Cholestasis
• Integrins
• Liver fibrosis
• Proliferation