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Inflammation responses have identified as a key mediator of in various liver diseases with high morbidity and mortality. cGAS-STING signalling is essential in innate immunity since it triggers release of type I interferons and various of proinflammatory cytokines. The potential connection between cGAS-STING pathway and liver inflammatory diseases has recently been reported widely. In our review, the impact of cGAS-STING on liver inflammation and regulatory mechanism are summarized. Furthermore, many inhibitors of cGAS-STING signalling as promising agents to cure liver inflammation are also explored in detail. A comprehensive knowledge of molecular mechanisms of cGAS-STING signalling in liver inflammation is vital for exploring novel treatments and providing recommendations and perspectives for future utilization.

Liver diseases have a global prevalence of 25%, accounting for 4% of all deaths worldwide, and are associated with a 36% increased risk of fatal and nonfatal cardiovascular events. Metabolic dysfunction-associated steatotic liver disease constitutes the liver expression of metabolic syndrome and represents the primary type of liver disease. Microscopical analysis of biopsies, which allows the evaluation of a small portion of tissue with inferences made to the entire organ, is considered the gold standard for determining the presence of liver diseases. However, potential sampling errors in liver biopsies are conceivable because the obtained tissue represents only a tiny fraction of the entire liver mass and may not accurately reflect the true pathological state. Studies have demonstrated the existence of sampling errors in liver biopsies, particularly concerning the severity of inflammation, degree of fibrosis, and the presence of cirrhosis. Also, clinical studies have shown that histopathological abnormalities are better detected in humans when liver samples are collected from both the right and the left lobes. However, a gap exists in clinical investigation to clarify the role of differences between these lobes in improving the diagnostic and prognostic for liver diseases. Building upon the heterogeneous nature of pathological alterations observed in liver lobes, this perspective review provided recommendations to enhance the precision of diagnosis and prognostic accuracy of liver diseases.

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The placenta contains multiple biologically active substances, which exert antioxidation, anti-inflammatory, immunomodulatory, and delayed aging effects. Its extract can improve hepatic morphology and function: on the one hand, it can reduce liver interstitial collagen deposition, lipogenesis, and inflammatory cell infiltration and improve fibrosis; on the other hand, it can prevent hepatocellular degeneration by scavenging reactive oxygen species (ROS) and inhibiting inflammatory cytokine production, further improve hepatocyte apoptosis and necrosis, and promote hepatocyte regeneration, making it a promising liver-protective agent. Current research on placenta extract (PE) mainly focuses on treating a specific type of liver injury, and there are no systematic reports. Therefore, this review comprehensively summarizes the treatment reports of PE on liver injury and analyzes its mechanism of action.

Background & Aims: Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied., Methods: We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros-SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1-knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression)., Results: In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis - induced by canonical inflammasome signaling in BMM cultures - was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers., Conclusion: These findings identify the Ikaros-SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers., Lay Summary: This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros-SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The liver is an important immunological site that can promote immune tolerance or activation. Natural killer (NK) cells are a major immune subset within the liver, and therefore understanding their role in liver homeostasis and inflammation is crucial. Due to their cytotoxic function, NK cells are important in the immune response against hepatotropic viral infections but are also involved in the inflammatory processes of autoimmune liver diseases and fatty liver disease. Whether NK cells primarily promote pro-inflammatory or tolerogenic responses is not known for many liver diseases. Understanding the involvement of NK cells in liver inflammation will be crucial in effective treatment and future immunotherapeutic targeting of NK cells in these disease settings. Here, we explore the role that NK cells play in inflammation of the liver in the context of viral infection, autoimmunity and fatty liver disease., (© 2021. The Author(s).)

NLRP3 inflammasome-driven inflammation represents a key trigger for hepatic fibrogenesis during cholestatic liver injury. However, whether sphingosine 1-phosphate (S1P) plays a role in NLRP3 inflammasome priming and activation remains unknown. Here, we found that the expression of NLRP3 in macrophages and NLRP3 inflammasome activation were significantly elevated in the liver injured by bile duct ligation (BDL). In vitro, S1P promoted the NLRP3 inflammasome priming and activation via S1P receptor 2 (S1PR2) in bone marrow-derived monocyte/macrophages (BMMs). Focusing on BMMs, the gene silencing of Gα 12 or Gα 13 by specific siRNA suppressed NLRP3 inflammasome priming and pro-inflammatory cytokine (IL-1β and IL-18) secretion, whereas Gα (i/o) and Gα q were not involved in this process. The MAPK signaling pathways (P38, ERK, and JNK) mediated NLRP3 inflammasome priming and IL-1β and IL-18 secretion, whereas blockage of PI3K, ROCK, and Rho family had no such effect. Moreover, JTE-013 (S1PR2 inhibitor) treatment markedly reduced NLRP3 inflammasome priming and activation in BDL-injured liver. Collectively, S1P promotes NLRP3 inflammasome priming and pro-inflammatory cytokines (IL-1β and IL-18) secretion via the S1PR2/Gα (12/13) /MAPK pathway, which may represent an effective therapeutic strategy for liver disease. KEY MESSAGE: • Hepatic NLRP3 expression was significantly elevated in BMMs of BDL-injured mouse liver. • S1P promoted NLRP3 inflammasome priming and activation in BMMs, depending on the S1PR2/Gα (12/13) /MAPK pathway. • Blockade of S1PR2 by JTE-013 reduced NLRP3 inflammasome priming and activation inflammasome in vivo.

Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

Gut inflammation caused by various factors including microbial infection leads to disorder of absorption of dietary nutrients and decrease in egg production in laying hens. We hypothesized that intestinal inflammation may affect egg production in laying hens through its impact on liver function. Dextran sodium sulphate (DSS) is known to induce intestinal inflammation in mammals, but whether it also induces inflammation in laying hens is not known. The goal of this study was to assess whether oral administration of DSS is a useful model of intestinal inflammation in laying hens and to characterize the effects of intestinal inflammation on egg production using this model. White Leghorn hens (350-day old) were administrated with or without 0.9 g of DSS/kg BW in drinking water for 5 D (n = 8, each). All laid eggs were collected, and their whole and eggshell weights were recorded. Blood was collected every day and used for biochemical analysis. Liver and intestinal tissues (duodenum, jejunum, ileum, cecum, cecal-tonsil, and colon) were collected 1 D after the final treatment. These tissue samples were used for histological analysis and PCR analysis. Oral administration of DSS in laying hens caused 1) histological disintegration of the cecal mucosal epithelium and increased monocyte/macrophage infiltration and IL-1β, IL-6, CXCLi2, IL-10, and TGFβ-4 gene expression; 2) decreased egg production; 3) increased leukocyte infiltration and IL-1β, CXCLi2, and IL-10 expression in association with a high frequency of lipopolysaccharide-positive cells in the liver; and 4) decreased expression of genes related to lipid synthesis, lipoprotein uptake, and yolk precursor production. These results suggested that oral administration of DSS is a useful method for inducing intestinal inflammation in laying hens, and intestinal inflammation may reduce egg production by disrupting egg yolk precursor production in association with liver inflammation., (Copyright © 2019. Published by Elsevier Inc.)

Gut microbiota play an essential role in shaping immune cell responses. The liver was continuously exposed to metabolic products of intestinal commensal bacterial through portal vein and alteration of gut commensal bateria was always associated with increased risk of liver inflammation and autoimmune disease. Considered as a unique immunological organ, the liver is enriched with a large number of innate immune cells. Herein, we summarize the available literature of gut microbiota in shaping the response of hepatic innate immune cells including NKT cells, NK cells, γδ T cells and Kupffer cells during health and disease. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of innate immune cell-related liver disease.

The nonstructural protein NS1 of human parvovirus B19 (B19) is known to exacerbate disease activity in systemic lupus erythematosus (SLE). However, no specific medicine for B19 infection is available. The roots of Gentiana macrophylla Pall. (GM), the traditional Chinese medicine "Qinjiao," have been used for centuries to treat rheumatic disease, including SLE. Herein, we aimed to investigate the effects of GM root extract (100 and 300 mg/kg body weight) on B19-NS1-exacerbated liver injury in NZB/W F1 mice; liver tissues were assessed by hematoxylin-eosin staining and immunoblotting. The GM root extract significantly decreased B19-NS1-exacerbated liver inflammation by suppressing the expressions of hepatic inducible nitric oxide synthase, cyclooxygenase type 2 (COX-2), interleukin (IL)-1β proteins, values of serum asparate transaminase (AST) and alanine transaminase (ALT), and lymphocyte infiltration (P < .05). It also significantly reduced the B19-NS1-exacerbated hepatic matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA) expressions by downregulating tumor necrosis factor (TNF)-α/NF-κB (p65) signaling. These findings suggest a therapeutic potential of GM root extract against B19-NS1-exacerbated liver inflammation in SLE.

Hepatoprotective effects of natural compounds have been frequently attributed to their antioxidant properties and the ability to mobilize endogenous antioxidant defense system. Because of involvement of oxidative stress in virtually all mechanisms of liver injury, it is a reasonable presumption that antioxidant properties of these compounds may play a key role in the mechanism of their hepatoprotective activity. Nevertheless, growing evidence suggests that other pharmacological activities of natural compounds distinct from antioxidant are responsible for their therapeutic effects. In this review, we discussed currently known molecular mechanisms of the hepatoprotective activity of 27 most intensively studied phytochemicals. These compounds have been shown to possess anti-inflammatory, antisteatotic, antiapoptotic, cell survival and antiviral activity through interference with multiple molecular targets and signaling pathways. Additionally, antifibrotic properties of phytochemicals have been closely associated with apoptosis of hepatic stellate cells and stimulation of extracellular matrix degradation. However, although these compounds exhibit a pronounced hepatoprotective effects in animal and cell culture models, the lack of clinical studies remains a bottleneck for their official acceptance by medical experts and physicians. Therefore, controlled clinical trials have an imperative in confirmation of the therapeutic activity of potentially hepatoprotective compounds. Understanding the principles of the hepatoprotective activity of phytochemicals could guide future drug development and help prevention of clinical trial failure. Also, the use of new delivery systems that enhances bioavailability of poorly water soluble compounds may improve the results already obtained. Most importantly, available data suggest that phytochemicals possess a various degree of modulation of specific signaling pathways, pointing out a need for usage of combinations of several hepatoprotective compounds in both experimental studies and clinical trials.

Till to date, the advancement of medical science and technology is still unable to provide inclusive treatment to liver inflammation caused by neither microbial invasion nor antibiotics nor environmental toxins. Therefore, this article provides the basic knowledge of liver inflammation up to the cellular level and its current medical treatment for inflammatory symptom suppression. Because of the adverse effects of drug treatment, people start looking for comprehensive alternative nowadays. Herbal medicine is believed to be the best of choice because it is being practiced until now for centuries. Although numerous herbal plants have been reported for their efficacies in liver protection, Andrographis paniculata is the most widely used herb for hepatoprotection, particularly in Ayurveda and traditional Chinese medicine. This review covers the significant observation on the biochemical responses due to the experimental induction of liver damage in vitro and in vivo using the marker compound of the herb, namely andrographolide and its derivatives. The standardized extract of A. paniculata with the right phytochemical composition of diterpenic labdanes is likely to have tremendous potential for the development of hepatoprotective medicine. This standardized herbal medicine may not provide immediate remedy, but it can be considered as a comprehensive therapy for liver inflammation., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Changes in plasma protein glycosylation are known to functionally affect proteins and to associate with liver diseases, including cirrhosis and hepatocellular carcinoma. Autoimmune hepatitis (AIH) is a liver disease characterized by liver inflammation and raised serum levels of IgG, and is difficult to distinguish from other liver diseases. The aim of this study was to examine plasma and IgG-specific N-glycosylation in AIH and compare it with healthy controls and other liver diseases. Methods: In this cross-sectional cohort study, total plasma N-glycosylation and IgG Fc glycosylation analysis was performed by mass spectrometry for 66 AIH patients, 60 age- and sex-matched healthy controls, 31 primary biliary cholangitis patients, 10 primary sclerosing cholangitis patients, 30 non-alcoholic fatty liver disease patients and 74 patients with viral or alcoholic hepatitis. A total of 121 glycans were quantified per individual. Associations between glycosylation traits and AIH were investigated as compared to healthy controls and other liver diseases. Results: Glycan traits bisection (OR: 3.78 [1.88–9.35], p-value: 5.88 × 10− 3), tetraantennary sialylation per galactose (A4GS) (OR: 2.88 [1.75–5.16], p-value: 1.63 × 10− 3), IgG1 galactosylation (OR: 0.35 [0.2–0.58], p-value: 3.47 × 10− 5) and hybrid type glycans (OR: 2.73 [1.67–4.89], p-value: 2.31 × 10− 3) were found as discriminators between AIH and healthy controls. High A4GS differentiated AIH from other liver diseases, while bisection associated with cirrhosis severity. Conclusions: Compared to other liver diseases, AIH shows distinctively high A4GS levels in plasma, with potential implications on glycoprotein function and clearance. Plasma-derived glycosylation has potential to be used as a diagnostic marker for AIH in the future. This may alleviate the need for a liver biopsy at diagnosis. Glycosidic changes should be investigated further in longitudinal studies and may be used for diagnostic and monitoring purposes in the future. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcoholactivated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IαB&, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications. [ABSTRACT FROM AUTHOR]

The aim of this study is to review and analyze the pleiotropic effects of TGF-β in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-β is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-β plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-β levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-β has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases. [ABSTRACT FROM AUTHOR]

Liver disease-related mortality is a major cause of death worldwide. Hepatic innate and adaptive immune cells play diverse roles in liver homeostasis and disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells. MDSCs can be broadly divided into monocytic MDSCs and polymorphonuclear or granulocytic MDSCs, and they functionally interact with both liver parenchymal and nonparenchymal cells, such as hepatocytes and regulatory T cells, to impact liver disease progression. The infiltration and activation of MDSCs in liver disease can be regulated by inflammatory chemokines and cytokines, tumor-associated fibroblasts, epigenetic regulation factors, and gut microbiota during liver injury and cancer. Given the pivotal roles of MDSCs in advanced liver diseases, they can be targeted to treat primary and metastatic liver cancer, liver generation, alcoholic and nonalcoholic liver disease, and autoimmune hepatitis. Currently, several treatments such as the antioxidant and anti-inflammatory agent berberine are under preclinical and clinical investigation to evaluate their therapeutic efficacy on liver disease and their effect on MDSC infiltration and function. Phenotypic alteration of MDSCs in different liver diseases that are in a model-dependent manner and lack special markers for distinct MDSCs are challenges for targeting MDSCs to treat liver disease. Multi-omics study is an option to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment. In summary, MDSCs play important roles in the pathogenesis and progression of liver disease by regulating both intrahepatic innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Chronic liver diseases can lead to fibrotic changes that may progress to the development of cirrhosis, which poses a significant risk for morbidity and increased mortality rates. Metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and viral hepatitis are prevalent liver diseases that may lead to cirrhosis. The advanced stages of cirrhosis can be further complicated by cancer development or end-stage liver disease and liver failure. Hence, early detection and diagnosis of liver fibrosis is crucial for preventing the progression to cirrhosis and improving patient outcomes. Traditionally, invasive liver biopsy has been considered the gold standard for diagnosing and staging liver fibrosis. In the last decade, research has focused on non-invasive methods, known as liquid biopsies, which involve the identification of disease-specific biomarkers in human fluids, such as blood. Among these alternative approaches, extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools for various diseases, including chronic liver diseases. EVs are released from stressed or damaged cells and can be isolated and quantified. Moreover, EVs facilitate cell-to-cell communication by transporting various cargo, and they have shown the potential to reduce the expression of profibrogenic markers, making them appealing tools for novel anti-fibrotic treatments. This review focuses on the impact of EVs in chronic liver diseases and exploring their potential applications in innovative therapeutic and diagnostic approaches. [ABSTRACT FROM AUTHOR]

The aim of this study is to review and analyze the pleiotropic effects of TGF-β in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-β is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-β plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-β levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-β has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases.

Over 240 million people worldwide are chronically infected with Hepatitis B Virus (HBV), a hepatotropic DNA virus with an evolutionary root of over 400 million years. Persistent HBV infection exhibits distinct and diverse phases of disease, from minimal liver pathology to fulminant Hepatitis, that vary in duration and severity among individuals. Although huge progress has been made in HBV research which has yielded an effective prophylactic vaccine and potent antiviral therapy, our understanding of its virology and immunobiology is still far from complete. For example, the recent re-discovery of serum HBV RNA in chronic Hepatitis B (CHB) patients has led to the proposal of noncanonical viral particles such as RNA virion and capsid-derived immune complex (Capsid-Antibody-Complexes, CACs) that contradict long-established basic theory. Furthermore, the existence of capsid-derived immune complex may hint at novel mechanism of HBV-induced liver disease. Here, we summarize the past and recent literature on HBV-induced immune complex. We propose that the release of capsid-derived particles by HBV has its deep evolutionary origin, and the associated complement activation serves as an indispensable trigger for intrahepatic damage and a catalyst for further cell-mediated immunopathology. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer. [ABSTRACT FROM AUTHOR]

Yinyanghuo, a famous herb, includes the folium of Epimedium brevicornu Maxim. and Epimedium sagittatum Maxim. It is believed that their processed products, the prepared slices of the folium of Epimedium brevicornu Maxim. (PFEB) and Epimedium sagittatum Maxim. (PFES) have greater efficacy in tonifying kidney Yang to treat kidney-Yang deficiency syndrome (KDS). However, there are few studies comparing the pharmacological effects of PFEB and PFES, and the underlying mechanisms. This study compared their effects on improving hypothalamic-pituitary-adrenal (HPA) axis, immune system and sexual characteristic, as well as repairing liver injury complications in the KDS model mice. Additionally, the mechanisms of the effects relevance to their main components were explored. It was found that PFEB was more effective than PFES in increasing cAMP/cGMP ratio, SOD activity, CRH and ACTH levels, eNOS and testosterone levels, splenic lymphocytes proliferation, while in decreasing MDA content, atrophy of spleen and thymus, splenic lymphocytes apoptosis, and PDE5 level. PFES showed stronger protection than PFEB in decreasing triglyceride and hepatic lipid. The contents of baohuoside I and epimedin A, B were much higher in PFEB, while Epimedin C, Icariin, 2-O″-rhamnosylicaridide II were higher in PFES. Consequently, PFEB exhibits superior efficacy over PFES in tonifying the kidney-Yang by improving the neuroendocrine-immune network, including HPA axis, immune systems, and corpus cavernosum. However, PFES has better recovery effect on mild hepatic lipid caused by KDS. The efficacy difference between PFEB and PFES in kidney-Yang and liver may be attributed to the content variations of baohuoside I. [Display omitted] [ABSTRACT FROM AUTHOR]

Traditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a highly dynamic and active event that is essential to counteract the dysregulated inflammatory response that drives diverse disease states. Abrogation of the hepatic inflammatory response through the stimulation of proresolving mechanisms represents a new paradigm in the setting of chronic inflammatory-driven liver diseases. Elucidation of the role of different cells of the innate and adaptive immune system has highlighted the interplay between them as an important orchestrator of liver repair. A finely tuned interaction between neutrophils and macrophages has risen as revolutionary mechanism that drives the restoration of hepatic function and architecture. Specialized proresolving mediators have also been shown to act as stop signals of the inflammatory response and promote resolution as well as tissue regeneration. In this review, we discuss the discovery and understanding of the mechanisms by which inflammation is resolved and highlight novel proresolving pathways that represent promising therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: Nonalcoholic steatohepatitis (NASH) has become a prominent liver disease in contemporary society because of the changing dieting styles. Complicated syndromes often accompanied by obesity and diabetes makes no standard treatment for NASH. Therefore, we investigated the potential role of Antrodia cinnamomea mycelium (ACM) as nutraceutical supplementation in the treatment of NASH in this 6-month randomized, double-blind, placebo-controlled study.Method: 28 Participants were treated with three capsules per day containing either 420 mg of ACM or 420 mg of starch as a placebo. The participants were required to follow a predetermined regular visit to hospital every three months during the intervention period (6 months). During each study visit, subjects underwent anthropometric measurements and blood testing for biochemical analysis, immune function assay, inflammatory cytokines assay, and FibroMax test.Results: The ACM supplemented group had a significant improvement in steatosis and decreased in the inflammatory marker of TNF-α after three and six months. NASH patients who received ACM showed a significant decrease in the SteatoTest mean value from 0.66 at baseline to 0.49 at 6 months (p < 0.029) and the ActiTest mean value decreased from 0.46 at baseline to 0.30 at 6 months (p < 0.029).Conclusion: This is the first clinical investigation that explores the hepatoprotective effect of A. cinnamomea mycelium in patients with NASH. No participants experienced any adverse events during the study, which suggested that ACM is a safe alternative treatment for NASH. [ABSTRACT FROM AUTHOR]

Chlorpyrifos (CPF) is an organophosphate insecticide commonly used to treat fruit and vegetable crops. CPF can cause severe adverse effects on body organs including the liver and central nervous system. This study investigated the CPF-induced inflammation in mice and explored the role of intestinal flora changes in liver inflammation. Adult C57BL/6 male mice were exposed to a CPF of 0.01-, 0.1-, 1- and 10-mg/kg bodyweight for 12 weeks. The mice in experimental group given CPF solution dissolved in corn oil vehicle by gavage, was administered by intraoral gavage for 5 days per week for 12 weeks. Histopathological examination and inflammatory factor detection were performed on mice liver tissue. Faeces were used for 16S ribosomal RNA high-throughput sequencing to explore the impact of CPF on intestinal flora structure and diversity. The results showed that 1- and 10-mg/kg CPF caused different degrees of liver focal inflammation. The structure of intestinal flora changed significantly in mice including the decreased beneficial bacteria (Akkermansia, Prevotella and Butyricimonas) and increased pathogenic bacteria (Helicobacter and Desulfovibrio). Meanwhile, the results of Q-RT-PCR showed that there was more total bacterial DNA in the liver tissue of the mice treated with 10-mg/kg groups. In conclusion, the imbalance of intestinal flora, the decreased abundance of beneficial bacteria and the increased abundance of pathogenic bacteria, as well as the increase of total bacterial DNA in the liver tissues, maybe associated with the liver focal inflammation induced by CPF. [ABSTRACT FROM AUTHOR]

Summary: Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma‐glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742‐0.839), 0.783 (95% CI: 0.717‐0.849) and 0.791 (95% CI: 0.716‐0.867) in the entire patients with CHB, HBeAg‐positive CHB patients and HBeAg‐negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg‐negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with GGT in HBeAg‐negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg‐positive CHB. [ABSTRACT FROM AUTHOR]

Background & Aim Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well-characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. Methods Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in Jα18 wild-type ( Lck-CD1dTgJα18 + ; type I NKT cell sufficient) and Jα18 -deficient ( Lck-CD1dTgJα18 o , type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. Results Lck-CD1dTgJα18 o and Lck-CD1dTgJα18 + mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in T h 1-skewing and impaired T h 2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. Conclusions Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a T h 1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the development of chronic autoimmune liver disease. [ABSTRACT FROM AUTHOR]

Background & Aims Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation. Methods Intrahepatic CD14 + myeloid cells from healthy donors (n = 19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n = 15) were subjected to detailed phenotypic, molecular and functional characterisation. Results Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14 + HLA-DR hi CD206 + cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14 + HLA-DR hi CD206 + cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury. Conclusions Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14 + HLA-DR hi CD206 + myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206 + myeloid cells in viral-related liver disease patients. Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients. [ABSTRACT FROM AUTHOR]

With the development of the social economy, unhealthy living habits and eating styles are gradually affecting people's health in recent years. As a chronic liver disease, NAFLD is deeply affected by unhealthy living habits and eating styles and has gradually become an increasingly serious public health problem. As a protein complex in clinical research, the inflammasomes play a crucial role in the development of NAFLD, atherosclerosis, and other diseases. This paper reviews the types, composition, characteristics of inflammasomes, and molecular mechanism of the inflammasome in NAFLD. Meanwhile, the paper reviews the drugs and non-drugs that target NLRP3 inflammasome in the treatment of NAFLD in the past decades. we also analyzed and summarized the related experimental models, mechanisms, and results of NAFLD. Although current therapeutic strategies for NAFLD are not effective, we expect that we will be able to find an appropriate treatment to address this problem in the future with further research on inflammasome. [ABSTRACT FROM AUTHOR]

Resveratrol is a naturally occurring polyphenol, possesses several pharmacological activities including anticancer, antioxidant, antidiabetic, antinociceptive, and antiasthmatic activity. Little is known about its hepatoprotective action mechanisms. This study was conceived to explore the possible protective mechanisms of resveratrol compared with the hepatoprotective silymarin in thioacetamide (TAA)-induced hepatic injury in rats. Thirty-two rats were equally divided into four groups; normal control (i), TAA (100 mg/kg) (ii), TAA + silymarin (50 mg/kg) (iii), and TAA + resveratrol (10 mg/kg) (iv). Liver function and histopathology, pro-inflammatory cytokines, oxidative stress, and apoptotic markers were examined. Data were analyzed using ANOVA test followed by Tukey post hoc test. Compared to TAA-intoxicated group, resveratrol mitigated liver damage, and inflammation as noted by less inflammatory infiltration, hydropic degeneration with decreased levels of tumor necrosis factor-alpha, interleukin-6, and interferon-gamma by 78.83, 18.12, and 64.49%, respectively. Furthermore, it reduced (P < 0.05) alanine and aspartate aminotransferases by 36.64 and 48.09%, respectively, restored hepatic glutathione content and normalized superoxide dismutase and malondialdehyde levels. While it inhibited nuclear factor-kappa B, cytochrome 2E1, and enhanced apoptosis of necrotic hepatocytes via increasing caspase-3 activity. Our findings indicated that the potential hepatoprotective mechanisms of resveratrol are associated with inhibition of inflammation, enhancing the apoptosis of necrotic hepatocytes, and suppression of oxidative stress. [ABSTRACT FROM AUTHOR]

We had previously shown that microcystin-LR (MCLR) could induce lung and liver inflammation after acute exposure. The biological outcomes following prolonged exposure to MCLR, although more frequent, are still poorly understood. Thus, we aimed to verify whether repeated doses of MCLR could damage lung and liver and evaluate the dose-dependence of the results. Male Swiss mice received 10 intraperitoneal injections ( i . p .) of distilled water (60 μL, CTRL) or different doses of MCLR (5 μg/kg, TOX5), 10 μg/kg (TOX10), 15 μg/kg (TOX15) and 20 μg/kg (TOX20) every other day. On the tenth injection respiratory mechanics (lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance) was measured. Lungs and liver were prepared for histology (morphometry and cellularity) and inflammatory mediators (KC and MIP-2) determination. All mechanical parameters and alveolar collapse were significantly higher in TOX5, 10, 15 and 20 than CTRL, but did not differ among them. Lung inflammatory cell content increased dose-dependently in all TOX groups in relation to CTRL, being TOX20 the largest. The production of KC was increased in lung and liver homogenates. MIP-2 increased in the liver of all TOX groups, but in lung homogenates it was significantly higher only in TOX20 group. All TOX mice livers showed steatosis, necrosis, inflammatory foci and a high degree of binucleated hepatocytes. In conclusion, sub-chronic exposure to MCLR damaged lung and liver in all doses, with a more important lung inflammation in TOX20 group. [ABSTRACT FROM AUTHOR]

Background & Aims Liver fibrosis is the most worrisome feature of non-alcoholic steatohepatitis (NASH). Growing evidence supports a link between hepatocyte apoptosis and liver fibrogenesis. Our aim was to determine the therapeutic efficacy and safety of liver Bid , a key pro-apoptotic molecule, suppression using RNA interference (RNAi) for the treatment of fibrosis. Methods First, we optimized the delivery system for Bid siRNA in mice using ten different stealth RNAi siRNAs and two lipid formulations -Invivofectamine2.0 and a newly developed Invivofectamine3.0 – that have been designed for high efficacy accumulation in the liver, assessed via real-time PCR of Bid mRNA. Next, C57BL/6 mice were placed on a choline-deficient L-amino acid defined (CDAA) diet. After 19 weeks of the CDAA diet, a time point that results in severe fibrotic NASH, mice were injected with the selected Bid siRNA-Invivofectamine3.0 biweekly for three weeks. Additionally hepatocyte-specific Bid deficient ( Bid Δhep ) mice were placed on CDAA diet for 20 weeks. Results A maximum Bid knockdown was achieved at 1.5 mg/kg siRNA with Invivofectamine3.0, whereas it was at 7 mg/kg with Invivofectamine2.0. In NASH mice, after 3 weeks of treatment, BID protein was reduced to 10% and this was associated with an improvement in liver fibrosis and inflammation associated with a marked reduction in TUNEL positive cells, caspase 3 activation, and a reduction in mitochondrial BAX and BAK. Bid Δhep mice showed similar protection from fibrotic changes. Conclusion Our data demonstrate that liver Bid suppression by RNAi technology, as well as hepatocyte-specific Bid deficiency, improves liver fibrosis coupled with a reduction of inflammation in experimental NASH. These findings are consistent with existing evidence that hepatocyte apoptosis triggers hepatic stellate cell activation and liver fibrosis and suggest that Bid inhibition may be useful as an antifibrotic NASH therapy. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the effects of dietary silicon-enriched spirulina (SES) on atherosclerosis. Methods: Hamsters (six per group) on a high-fat (HF) diet received SES or non-enriched spirulina (both at 57 mg/kg body weight) daily. This corresponded to 0.57 mg silicon/kg body weight daily. Results: The HF diet induced dyslipidemia, insulin resistance, oxidative stress, and vascular dysfunction. Compared with the HF group, SES attenuated increases of lipemia and prevented insulin resistance (IR) (P = 0.001). SES protected against oxidative stress through a reduction of heart (P = 0.006) and liver (P < 0.0001) nicotinamide adenine dinucleotide phosphate-oxidase activity and by sparing the activity of superoxide dismutase (P = 0.0017) and glutathione peroxidase (P = 0.01861). SES decreased inflammation, lowering tumor necrosis factor-a (P = 0.0006) and interleukin-6 levels (P = 0.0112), decreasing polymorphonuclear cells and preventing nuclear factor-xB activity (P = 0.0259). SES corrected plasma level of monocyte chemoattractant protein-1 (P = 0.0380), which was increased by the HF diet. Finally, SES supplementation prevented vascular and endothelial functions assessed respectively by the contractile response to the agonist phenylephrine and the relaxation induced by acetylcholine. Conclusion: SES protects against metabolic imbalance, inflammation, oxidative stress, and vascular dysfunction induced by an HF diet, and could prevent the atherogenic processes. Synergistic effects between spirulina and silicon were observed. [ABSTRACT FROM AUTHOR]

Objectives: Chronic hepatitis C (CHC) or liver inflammation resulting from infection with hepatitis C virus (HCV) is the cause of chronic liver disease and leads to cirrhosis and hepatocellular carcinoma. The burden of chronic HCV-related liver disease in Egypt continues to rise and the interaction of liver inflammation with biomarkers and response to therapy is scarcely discussed. Moreover, serum alanine transaminase (ALT) is considered as a moderately accurate test for indicating liver inflammation. This study aims to evaluate the correlation of liver inflammation with response to therapy and with alpha-fetoprotein (AFP), and to assess the potential efficiency of AFP as a marker for liver inflammation. Methods: The study included 134 consecutive Egyptian chronic HCV patients. Sustained virological response (SVR) was assessed by the detection of HCV by reverse polymerase reaction (PCR). Furthermore, fibrosis and necroinflammation were assessed before treatment. Results: Severe liver inflammation was significantly associated with higher pretreatment levels of ALT, aspartate aminotransferase (AST) and AFP. AFP overcomes ALT as marker of inflammation by ROC curve analysis. Early virologic response (EVR), end-of-treatment response (ETR) and SVR was significantly higher in patients with mild inflammation than those with moderate and severe inflammation. Conclusion: Pretreatment AFP levels should be considered as a surrogate marker in predicting liver inflammation. Mild liver inflammation was more prevalent than moderate and severe inflammation in responders by means of EVR, ETR and SVR. [ABSTRACT FROM AUTHOR]

Background: The possibility of extracting RNA and measuring RNA expression from paraffin sections can allow extensive investigations on stored paraffin samples obtained from diseased livers and could help with studies of the natural history of liver fibrosis and inflammation, and in particular, correlate basic mechanisms to clinical outcomes. Results: To address this issue, a pilot study of multiplex gene expression using branched-chain DNA technology was conducted to directly measure mRNA expression in formalin-fixed paraffin-embedded needle biopsy samples of human liver. Twenty-five genes were selected for evaluation based on evidence obtained from human fibrotic liver, a rat BDL model and in vitro cultures of immortalized human hepatic stellate cells. The expression levels of these 25 genes were then correlated with liver fibrosis and inflammation activity scores. Statistical analysis revealed that three genes (COL3A1, KRT18, and TUBB) could separate fibrotic from non-fibrotic samples and that the expression of ten genes (ANXA2, TIMP1, CTGF, COL4A1, KRT18, COL1A1, COL3A1, ACTA2, TGFB1, LOXL2) were positively correlated with the level of liver inflammation activity. Conclusion: This is the first report describing this multiplex technique for liver fibrosis and has provided the proof of concept of the suitability of RNA extracted from paraffin sections for investigating the modulation of a panel of proinflammatory and profibrogenic genes. This pilot study suggests that this technique will allow extensive investigations on paraffin samples from diseased livers and possibly from any other tissue. Using identical or other genes, this multiplex expression technique could be applied to samples obtained from extensive patient cohorts with stored paraffin samples in order to correlate gene expression with valuable clinically relevant information. This method could be used to provide a better understanding of the mechanisms of liver fibrosis and inflammation, its progression, and help development of new therapeutic approaches for this indication. [ABSTRACT FROM AUTHOR]

Background: Activated hepatic stellate cells (HSC) and other fibrogenic cell types are frequently found around hepatocellular carcinoma. It is unknown whether hepatocarcinoma cells regulate the biological functions of HSC. Aims: This study aimed to investigate the paracrine effects of hepatocarcinoma cells on human HSC using a co-culture system. Methods: Huh7 or HepG2 cells, human hepatocarcinoma cell lines, were co-cultured with primary human HSC. Intracellular calcium mobilization, proliferation, migration, expression of pro-angiogenic and fibrogenic genes, smooth muscle α-actin (α-SMA) protein expression, inflammatory properties (nuclear factor kappa B activation and interleukin 8 secretion) and intracellular signalling pathways (AKT and ERK) were analysed in HSC. Results: Culture of HSC with Huh7 cells for 24 h stimulated HSC proliferation, migration and expression of pro-angiogenic genes. The migration effect was corroborated with HepG2 cells. The effects of Huh7 cells on cell proliferation and migration were mediated mainly by PI3K/AKT activation. Moreover, Huh7 cells reduced the expression of genes involved in fibrogenesis, while they did not modify the inflammatory properties of HSC. The expression of α-SMA was induced by Huh7 cells. Because hepatitis C virus (HCV) infection is a major cause of hepatocarcinoma, we next investigated whether these effects are regulated by the expression of HCV in hepatocarcinoma cells. Expression of a subgenomic replicon expressing HCV nonstructural proteins (NS3–NS5) in Huh7 cells did not affect paracrine actions in HSC (cell proliferation and migration). Conclusions: These results suggested that there is a cross-talk between hepatocarcinoma cells and HSC. Activated HSC may be stimulated by cancer cells to accumulate and express angiogenic genes. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Dependence on total parenteral nutrition in intestinal failure or short bowel syndrome patients can lead to many complications. The most significant complication is progressive liver injury leading to liver failure. This study assesses the potential of hepatocyte growth factor (HGF) in modulating the hepatic response in a rat cholestatic liver injury model. Methods: Female Sprague-Dawley rats were divided into 3 groups: control (n = 5), chronic liver injury (α-naphtylisocyocyanate [ANIT] every 3.5 days at 75 mg/kg; n = 5), and chronic liver injury plus HGF (ANIT + HGF at 250 μg kg−1 d−1; n = 5). The rats initially underwent massive (80%) small bowel resections. Seven days later, they were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic minipump for continuous intravenous saline or HGF. Intraperitoneal saline or ANIT injections were subsequently administered every 3.5 days to create a chronic cholestatic model. After 14 days, the animals were euthanized, and liver biopsies were obtained. The liver biopsies were evaluated by histology, immunofluorescence staining for interleukin-6 and tumor necrosis factor α, and assessment of apoptosis by terminal dUTP-transferase-mediated nick end labeling (TUNEL) technique. Results: In this chronic liver injury model, HGF did not effect the grade of inflammation. However, HGF did induce retention of the ductal structures and avoided ductal proliferation, damage, and evidence of primary sclerosing cholangitis (P < .05). Hepatocyte growth factor induced less interleukin-6 (P < .011) and tumor necrosis factor α (P < .01) expression. Apoptotic activity was also significantly less in the HGF group (P < .01). Conclusion: Hepatocyte growth factor preserved the hepatic ductal system, modulated the hepatic inflammatory response, and reduced the apoptotic index in this chronic cholestatic liver injury model. It may diminish or prevent liver damage in patients with total parenteral nutrition–induced liver injury. [Copyright &y& Elsevier]

We have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor-β receptor (dnTGF-βRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8+ T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8+ T cells, we have determined herein whether administration of β-glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8+ T cell responses and to down-regulate tissue inflammation. Accordingly, dnTGF-βRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liver-infiltrating CD8+ T cells, accompanied by a significant decrease in activated CD44high CD8+ T cell populations. Further, there was a significant reduction in portal inflammation in GC-treated mice. Interestingly, there were no changes in anti-mitochondrial antibodies, CD4+ T cells, CD19+ B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liver-infiltrating CD8+ T cells. These data suggest that further work on GC in models of CD8+ T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease. [ABSTRACT FROM AUTHOR]

Abstract: Polyinosinic–polyctidylic acid (Poly I:C) is a viral RNA mimic that can induce immune responses similar to that seen during viral infection. Although poly I:C administration into mice is associated increased NK cell infiltrates in the liver, the mechanisms underlying increased hepatic NK cell accumulation in response to poly I:C administration are incompletely defined. In the current study, we have identified a novel and important role for γδT cells in driving the accumulation and activation of NK cells in the liver during poly I:C-mediated viral liver infection. Specifically, NK cell accumulation but not activation in γδT cell deficient mice following poly I:C administration was significantly attenuated in comparison to that seen in poly I:C-treated wildtype mice. The ability of γδT cells to promote NK cell accumulation and activation in the liver may be virus-specific since NK cell accumulation in the liver was not altered by TCRγδ deficiency following adenovirus administration. [Copyright &y& Elsevier]

Abstract: Chronic hepatitis C (HCV) represents one of the most common chronic infections worldwide and is a major indication for liver transplantation. Liver inflammation is the main predictor of advanced fibrosis in HCV. Inflammatory cells are recruited to the liver by chemokines. Recently, a novel class of chemokine receptors has been characterized that lack signaling functions and are termed scavenger receptors. We determine here whether genetic variations of the scavenger receptor D6 contribute to the grade of liver inflammation in HCV. Four haplotype tagging single nucleotide polymorphisms (SNPs) were identified from HapMap that cover the genetic information of D6 (CCBP2). Among these SNPs, rs4683336 was associated with liver inflammation in qualitative (p = 0.003) and quantitative (p = 0.0086) genotype analysis. This association was confirmed in an independent cohort of HCV-infected patients (p = 0.006 for qualitative and p = 0.0046 for quantitative analysis, respectively). Furthermore, the haplotype that is tagged by marker rs4683336 was significantly correlated with liver inflammation when compared with the most common D6 haplotype (p = 0.014). The importance of genetic variations in D6 was supported through the demonstration of an association of D6 mRNA expression with histologic inflammation in liver biopsies and a considerable range of D6 mRNA expression in isolated human hepatocytes. In conclusion, we demonstrate that variations in a chemokine scavenging receptor are significantly correlated with clinical inflammatory phenotypes such as HCV infection. [Copyright &y& Elsevier]

The present study examined the role of hepatocyte NF-κB activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-κB activation and liver injury. C57BL/6 mice underwent 90 mm of partial hepatic ischemia and up to 8 h of reperfusion. Body temperature was regulated during the ischemic period between 35 and 37°C, 33 and 35°C, 29 and 33°C or unregulated, where temperature fell to <29°C. Liver injury, as measured by serum alanine aminotransferase as well as liver histopathology, was inversely proportional to regulated body temperature, with the unregulated group (<29°C) being highly protected and the normothermic group (35-37°C) displaying the greatest injury. Inflammation, as measured by production of TNF-α and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-κB activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IκB proteins, IκB-α and IκB-β, was greatest in the normothermic group, suggesting an alternate NF-κB regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-κB p65 protein was increasingly degraded in normothermic versus hypothermic groups, and this degradation was specific for hepatocytes and was associated with decreased expression of the peptidyl-prolyl isomerase Pin1. The data suggest that NF-κB activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-κB p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-κB, and enhanced hepatocellular injury. [ABSTRACT FROM AUTHOR]

The effect of pegylated interferon or its combination with lamivudine on liver histology of patients with chronic hepatitis B (CHB) is unknown. In a double-blinded, randomized, multi-center study we assessed histological changes in 110 hepatitis B e-antigen (HBeAg)-positive CHB patients treated for 52 weeks with Pegylated interferon α-2b (PEG-IFN) in combination with either lamivudine or placebo. Liver biopsies were taken before and at the end of treatment. All biopsies were blinded and scored according to the Ishak system. Results: Necroinflammatory score improved (defined as a decrease of at least two points) in 25 patients (48%) of the PEG-IFN/lamivudine combination therapy group and in 31 patients (53%) of the PEG-IFN monotherapy group. The fibrosis score improved (decrease of at least 1 point) in 17 patients (33%) of the combination therapy group vs. 13 patients (22%) of the PEG-IFN monotherapy group ( P=0.23). Responders ( n=42), defined as serum HBeAg negative at the end of therapy, showed a larger decline in necroinflammatory score than non-responders (mean decline 2.3 and 1.2 points, respectively, P=0.02). Among patients receiving PEG-IFN monotherapy necroinflammation improved more frequently in responders (78% of responders vs. 43% of non-responders, P=0.01) and in patients who showed normalization of ALT (76% of patients with normal ALT vs. 40% of patients with abnormal ALT, P=0.01). Fibrosis score in the PEG-IFN monotherapy group improved more often in responders (39%) than in non-responders (15%, P=0.04). In the PEG-IFN/lamivudine combination therapy group, we found no significant association between virological and biochemical endpoints and histological improvement. Conclusions: Treatment with PEG-IFN therapy improves liver necroinflammation in HBeAg-positive CHB patients, particularly in responders to therapy. PEG-IFN also improves fibrosis in responders. Addition of lamivudine to PEG-IFN did not further improve the histological outcome. [ABSTRACT FROM AUTHOR]

Objective To analyze the relationships of serum ferritin (SF) level, degree of Liver inflammation and types in patients with liver disease. Methods Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (ALB) (by automatic biochemical analyzer) and SF (by immune turbidimetry), serum iron (SI) (by complex legal) were detected and analyzed in 203 hospital patients of acute or chronic liver injury, whose SF were higher than normal. The correlations between SF, SI and indicators of liver inflammation were analyzed as well as the changes of SF and SI in patients with different liver cancer types and pathological degrees. Results Positively correlation was detected between the SF, SI and the ALT, AST (all P<0.01). SF was negatively correlated with ALB (P<0.01). The degree of elevated SF was the order of HEV infection , drug-induced hepatitis, HBV infection and HCV infection (χ2 =13.551, P<0.01) in different etiology, and meanwhile, ALT and AST followed the same order. The SI levels showed no statistical significance in different etiology (P>0.05). The levels of serum ferritin in acute hepatitis and liver failure patients were significantly higher than those in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. SI level was the lowest in hepatocellular carcinoma, and the difference in the remaining four groups performed no statistical significance (P>0.05). Conclusions SF is positively correlated with indicators of liver inflammation (ALT, AST). In patients with hepatitis C and liver failure, SF can evaluate liver function more objectively and accurately than ALT and AST in clinical. [ABSTRACT FROM AUTHOR]

The expression of the selectin receptor LAM-1/Leu 8 was analysed in normal and in inflamed liver tissue and its expression on mononuclear inflammatory cells was correlated with their topographical distribution in various compartments of the inflamed liver, in order to obtain new insights on possible molecular mechanisms involved in the traffic of mononuclear inflammatory cells throughout the diseased hepatic parenchyma. In normal liver tissue, few scattered mononuclear cells in portal and lobular parenchyma corresponded lo both CD4+ and CD8+, as well as to CD45RA+ (2H4+) naive and CD45RO+ (UCHLI+) memory T cells, and were LAM-1/Leu 8+. In acute and chronic inflamed liver biopsies. CD45RO+ (UCHLI+)CD4+ and CD8+ memory T cells largely predominated in both portal and lobular parenchyma. The expression of LAM- 1/Leu 8 antigen on these memory T cells varied according to their localization in the liver parenchyma, and it was not correlated with specific aetiological causes. In acute hepatitis, the vast majority of T lymphocytes were LAM-1/Leu 8 . In chronic active hepatitis, memory T cells in portal tracts expressed LAM-1/Leu8, whereas virtually all intralobular T cells accumulating in areas of periporial and intralobular inflammation were LAM-1/Leu8+. In chronic persistent hepatitis, the LAM-1/Leu8+ T cells largely predominated among the numerous mononuclear inflammatory cells within enlarged portal tracts, whereas LAM-1/Leu 8 T cells were restricted to areas of intralobular "spotty" inflammation. Therefore, two phenotypical populations can be recognized among the memory T cells in inflamed liver tissue, according to their topographical localization: LAM-1/Leu8+ T cells predominating in portal tracts, and LAM-1/Leu 8- T cells predominating in the lobular parenchyma. These data show that during their migration through the inflamed liver parenchyma, memory T lymphocytes undergo phenotyical changes (LAM-1/Leu8 shedding) according to their localization indifferent liver compartments (portal tracts vs. lobular parenchyma), suggesting multiple cellular and molecular mechanisms involved in the regulation of the leucocyte traffic through inflamed liver tissue. [ABSTRACT FROM AUTHOR]