Role of Macrophages in Liver Fibrosis.

Liver fibrosis, which ultimately leads to liver cirrhosis and hepatocellular carcinoma, is a major health burden worldwide. The progression of liver fibrosis is the result of the wound-healing response of liver to repeated injury. Hepatic macrophages are cells with high heterogeneity and plasticity and include tissue-resident macrophages termed Kupffer cells, and recruited macrophages derived from circulating monocytes, spleen and peritoneal cavity. Studies have shown that hepatic macrophages play roles in the initiation and progression of liver fibrosis by releasing inflammatory cytokines/chemokines and pro-fibrogenic factors. Furthermore, the development of liver fibrosis has been shown to be reversible. Hepatic macrophages have been shown to alternately regulate both the regression and turnover of liver fibrosis by changing their phenotypes during the dynamic progression of liver fibrosis. In this review, we summarize the role of hepatic macrophages in the progression and regression of liver fibrosis.

The Screening of Hepatitis B and Hepatitis C Virus Infection among HIV-Infected Inpatients and Evaluation of Correlated Characteristics in a General Hospital in Shenyang, Liaoning, China.

Background: In this study, we surveyed the prevalence of hepatitis B virus (HBV) surface antigen (HBsAg) and hepatitis C virus (HCV) antibody (anti-HCV) among inpatients with human immunodeficiency virus (HIV) infection and analyzed the correlated factors. Methods: We conducted a retrospective data collection of the HIV-infected inpatients in our hospital from January 2010 to December 2020. We utilized multivariate logistic regression to identify the correlated factors. Results: The proportion of patients screened for HBsAg was 81.8%, which increased from 66.7% in 2010 to 85.7% in 2020. The proportion of patients with anti-HCV screening was 73.9%, which increased from 58.3% in 2010 to 86.7% in 2020. The prevalence of HBsAg positivity was 10.9%, which decreased from 15.0% in the period of 2010−2015 to 9.0% during 2016−2020. Positive anti-HCV was identified in 4.1% of cases. Compared to 4.8% in the period of 2010−2015, there was a similar prevalence of anti-HCV at 3.1% during 2016−2020. Among the HBsAg-positive cases, HBV deoxyribonucleic acid was screened in 70.8% of cases. Among the anti-HCV positive cases, HCV ribonucleic acid (RNA) was screened in 90% of cases. Albumin < 30 g/L, thrombocytopenia and aspartate aminotransferase (AST) > 40 U/L were associated with HBsAg positivity. AST > 40 U/L and higher CD4-positive T lymphocyte counts were associated with HIV/HCV coinfection. Conclusions: The routine screening for both HBV and HCV among HIV-positive inpatients has been greatly improved in the past decade. However, screening for the complete HBV serological markers in HIV-positive inpatients and HCV genotyping among HCV RNA-positive cases leaves much to be desired. A concerted effort should be made to improve HBV vaccine compliance in the HIV-positive population and provide direct-acting antiviral therapies to HCV RNA-positive patients.

Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4+ and CD8+ T cells.

Introduction: Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives: We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods: We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results: Spred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro. Conclusion: We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin.

The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2-/- mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2-/- lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2-/- and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2-/- fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2-/- mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

Tumor necrosis factor-alpha-induced reduction of glomerular filtration rate in rats with fulminant hepatic failure.

The mechanism of renal failure during fulminant hepatic failure (FHF) or end-stage of liver disease is not fully understood. The present study aims to delineate the mechanisms of decreased glomerular filtration rate (GFR) in acute hepatic failure. A rat model of renal insufficiency in severe liver injury was established by lipopolysaccharide (LPS) plus D-galactosamine (GalN) exposure. GFR was evaluated by continuous infusion of fluorescein isothiocyanate-inulin with implanted micro-osmotic pumps. GalN/LPS intoxication resulted in severe hepatocyte toxicity as evidenced by liver histology and biochemical tests, whereas renal morphology remained normal. GFR was reduced by 33% of the controls 12 h after GalN/LPS exposure, accompanied with a decreased serum sodium levels, a marked increase in serum TNF-α and ET-1 levels as well as significantly upregulated renal type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) expression. The upregulated IP3R1 expression was abrogated by the treatment of anti-TNF-α antibodies, but not by 2-aminoethoxydiphenylborate (2-APB), which blocks the inositol 1,4,5-trisphosphate signaling pathway. Treatments with either TNF-α antibodies or 2-APB also significantly improved the compromised GFR, elevated serum urea nitrogen and creatinine levels, and reversed the decrease in glomerular inulin space and the increase in glomerular calcium content in GalN/LPS-exposed rats. The extent of acute liver injury as reflected by serum ALT levels was much more attenuated by anti-TNF-α antibodies than by 2-APB. Liver histology further confirmed that anti-TNF-α antibodies conferred better protection than 2-APB in GalN/LPS-exposed rats. LPS-elicited TNF-α over-production is responsible for decreased GFR through IP3R1 overexpression, and the compromised GFR resulted in the development of acute renal failure in rats with FHF.

Clinical features and factors associated with severity and fatality among patients with severe fever with thrombocytopenia syndrome Bunyavirus infection in Northeast China.

BACKGROUND: In 2009, severe fever with thrombocytopenia syndrome virus (SFTSV) was identified as a novel member of the genus phlebovirus in the Bunyaviridae family in China. The detailed clinical features of cases with SFTSV infection have not been well described, and the risk factors for severity among patients and fatality among severe patients remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Clinical and laboratory features of 115 hospitalized patients with SFTSV infection during the period from June 2010 to December 2011 in Northeast China were retrospectively reviewed. We assessed the risk factors associated with severity in confirmed cases and fatality in severe cases by multivariate analysis. One hundred and three (89.6%) of 115 patients presented with multiple organ dysfunction, and 22 (19.1%) of 115 proceeded to the stage of life threatening multiple organ failure. Of the 115 patients, 14 fatalities (12.2%) were reported. Multivariate analysis demonstrated that the independent predictors of risk for severity were: albumin ≤ 30 g/l (OR, 8.09; 95% CI, 2.58-25.32), APTT ≥ 66 seconds (OR, 14.28; 95% CI, 3.28-62.24), sodium ≤ 130 mmol/l (OR, 5.44; 95% CI, 1.38-21.40), and presence of neurological manifestations (OR, 7.70; 95% CI, 1.91-31.12). Among patients with severe disease, presence of acute lung injury/acute respiratory distress syndrome (HR, 4.59; 95% CI, 1.48-14.19) and disseminated intravascular coagulation (HR, 4.24; 95% CI, 1.38-13.03) were independently associated with fatality. CONCLUSIONS/SIGNIFICANCE: SFTSV infection may present with more severe symptoms and laboratory abnormalities than hitherto reported. Due to infection with a novel bunyavirus, the patients may sufferer multiple organ dysfunction and die of multiple organ failure. In the clinical assessment of any case of SFTS, independent factors relating to prognosis need to be taken into account by clinicians.

Alterations of blood-brain barrier and associated factors in acute liver failure.

Brain edema in acute liver failure (ALF) remains lethal. Cytotoxic mechanisms associated with brain edema have been well recognized, but the role of vasogenic mechanisms of brain edema has not been explored. Intact tight junctions (TJs) between brain capillary endothelial cells are critical for normal BBB function. Recent reports found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood-brain barrier (BBB) integrity. However, the role of TJ in ALF has not been completely understood. This paper reviews the role of the paracellular tight junction in the increased selective BBB permeability that leads to brain edema in ALF and furthermore explores the effect of systemic inflammatory cytokines on the tight junction dysfunction.

Association of polymorphisms in the interleukin-4 gene with response to hepatitis B vaccine and susceptibility to hepatitis B virus infection: a meta-analysis.

OBJECTIVE: The aim of this meta-analysis is to evaluate the associations between functional polymorphisms in the interleukin-4 (IL4) gene and individuals' responses to hepatitis B vaccine and their susceptibility to hepatitis B virus (HBV) infection. METHODS: A literature search on articles published before December 1st, 2012 was conducted in PubMed, Embase, Web of Science and China BioMedicine (CBM) databases. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using the STATA 12.0 software. RESULTS: Eight studies were eligible for inclusion in this meta-analysis, including five cross-sectional studies on individual's response to hepatitis B vaccine and three case-control studies on HBV infection risk. The meta-analysis results showed that the T allele of rs2243250, the T allele of rs2070874, and the C allele of rs2227284 in IL4 gene were associated with high responses to hepatitis B vaccine. Further subgroup analysis by ethnicity showed that there was a significant association between IL4 genetic polymorphisms and an individual's responses to hepatitis B vaccine among Asian populations, but similar association was not found among Caucasian populations. However, there was no evidence indicating a correlation between IL4 genetic polymorphism and susceptibility to HBV infection. CONCLUSION: Our current meta-analysis suggests that rs2243250, rs2070874 and rs2227284 polymorphisms in IL4 gene may play an important role in determining the response to hepatitis B vaccine, especially among Asian populations. However, further studies are still needed to evaluate the associations between IL4 genetic polymorphisms and HBV infection risk.

Expression of IFNAR2 mRNA in peripheral blood mononuclear cells of patients with HCV infection.

BACKGROUND: To investigate the differences of interferon-alpha/beta receptor 2 (IFNAR2) mRNA expression level in peripheral blood mononuclear cells (PBMCs) between different stages of hepatitis C virus (HCV) infection and to determine the correlation with the effectiveness of interferon therapy. METHODOLOGY: 58 patients, positive for anti-HCV antibodies, were divided into three groups depending on their clinical symptoms: acute hepatitis (4 cases), chronic hepatitis (46 cases) and liver cirrhosis (8 cases). 15 volunteers served as healthy controls. PBMCs were purified by density gradient centrifugation and IFNAR2 mRNA was amplified from these cells by a reverse transcription-polymerase chain reaction (RT-PCR) assay. RESULTS: The detection rate of IFNAR2 mRNA was 87.9% (51/58 cases) in the PBMCs of patients with HCV infection, significantly higher than that in the control group (333%, 5/15 cases; P < 0.05). While the positive rate was 93.5% (43/46 cases) in the chronic hepatitis group, which was significantly higher than that in the liver cirrhosis group (50%, 4/8 cases; P < 0.05). Furthermore, there is no significant difference in the positive rates for HCV-RNA of PBMCs among groups (P > 0.05). The positive rate of IFNAR2 mRNA in PBMCs was not correlated with the viral load of HCV-RNA in serum (P > 0.05). However, higher expression of IFNAR2 mRNA in the PBMCs did correlate with the effectiveness of interferon therapy (P < 0.05). CONCLUSIONS: HCV infection up-regulates the expression of IFNAR2 mRNA in PBMCs. IFNAR2 mRNA expression in the chronic hepatitis group was higher than that in the liver cirrhosis group, and significantly correlated with the effectiveness of interferon therapy, which was independent of the viral load.