Different effects of rat interferon alpha, beta and gamma on rat hepatic stellate cell proliferation and activation

BACKGROUND: Liver fibrosis is the common sequel of chronic liver diseases. Recent studies have identified hepatic stellate cells as the primary cell type mediating hepatic fibrogenesis. It has been demonstrated that hepatic stellate cells undergo a process of activation during the development of liver fibrosis. During the activation process, hepatic stellate cells acquire myofibroblast-like phenotype featuring the expression of smooth muscle alpha actin. Interferons have been employed for the treatment of viral hepatitis. However, it is unclear what is the effect of interferons on the prevention and treatment of liver fibrosis. Moreover, it is not clear whether there are any differences among interferon alpha, interferon beta, and interferon gamma in the treatment of liver fibrosis. Therefore, our objective in current study is to investigate the effects of rat interferon-α, interferon-β, and interferon-γ on the proliferation and activation of rat hepatic stellate cells. RESULTS: Rat interferon-β and interferon-γ significantly inhibited rat hepatic stellate cell proliferation while rat interferon-α did not affect the cell proliferation under the same culture condition. Inhibition of cell proliferation was confirmed by both WST-1 cell proliferation assay and 5-bromo-2'-deoxy-uridine incorporation assay. Similar results were observed regarding interferons regulation of hepatic stellate cell activation. Both rat interferon-β and interferon-γ reduced smooth muscle α-actin abundance after 6 days treatment, but rat interferon-α did not alter smooth muscle α-actin level. CONCLUSIONS: Our results indicate that rat interferon-α and interferon-β have different biological effects on rat hepatic stellate cells and suggest that there are different signaling events between interferon-α and interferon-β in hepatic stellate cells

Principles in the Management of Chronic Hepatitis B Viral Infection

Recently licensed and promising new experimental agents should have a profound impact on the treatment of patients with chronic hepatitis B virus (HBV) infection. However, certain management principles should remain unaltered. Recognizing the need for more urgent treatment in some individuals, being able to identify which patients require treatment and those who are most likely to respond to treatment, and selecting the optimal timing for treatment are clinical decisions that must continue to be addressed regardless of the antiviral agent ‘of the month’. This review outlines general principles and provides a generic, timeless approach to the management of patients with chronic HBV infection

Hepatitis B Viral Mutants and Their Relevance to the Canadian Health Care System

Over the past 10 years, an increasing number of mutations in the hepatitis B virus genome have been described. While the majority of these mutations appear to be ‘silent’ or not clinically relevant, some have been described in association with increased severity of disease (core and basic core promoter mutations), evasion of immunological surveillance (S escape mutants), hepatocellular carcinogenesis (X mutants) and resistance to antiviral agents (DNA polymerase mutations). The molecular events and the clinical consequences thereof are reviewed

Long-Term, Low-Dose Exposure to Microcystin-LR Does not Cause or Increase the Severity of Liver Disease in Rodents

Background: Acute exposure to high concentrations of microcystin-LR (MC-LR) can cause significant hepatocyte injury. Aim. To document the effects of long-term, low-dose MC-LR exposure on hepatic inflammation and fibrosis in mice with healthy and diseased livers. Material and methods: Male CD1 mice (N = 20/group) were exposed to 1.0 μg/L of MC-LR in drinking water; 1.0 μg/L MC-LR plus 300 mg/L of the hepatotoxin thioacetamide (MC-LR/TAA); or 300 mg/L TAA alone for 28 weeks. Liver biochemistry and histology were documented at the end of the study period. In addition, hepatic stellate cells (HSCs), were exposed in vitro to MC-LR (0.1-10,000 μg/L) and monitored for changes in cell metabolism, proliferation and activation. Results: Liver biochemistry and histology were essentially normal in MC-LR alone exposed mice. MC-LR/TAA and TAA alone exposed mice had significant hepatic inflammation and fibrosis but the extent of the changes were similar in the two groups. In vitro, MC-LR had no effect on HSC metabolism, proliferation or activation. Conclusion: Long-term, low-dose exposure to MC-LR is unlikely to lead to chronic liver disease in the setting of a normal liver or exacerbate existing liver disease in the setting of ongoing hepatitis

Evidence of Hepatitis B Virus Infection in Cancer and Noncancer Stem Cells Associated with Human Hepatocellular Carcinoma

Both the hepatitis B virus (HBV) and cancer stem cells (CSCs) have been independently implicated in the pathogenesis of hepatocellular carcinoma (HCC). To date, there have been no reports describing HBV infection within CSCs. In this report we describe HBV core (HBcAg) and HBx protein expression within CSCs associated with human HCC. HBV markers were also identified in nonmalignant stem cells present in adjacent nontumor tissue. These findings provide new insights into the pathogenesis of HBV-induced HCC and are potentially relevant to the treatment of both HCC and chronic HBV

Prevalence of Liver Disease and Utilization of a Hepatology Consultation Service at an Urban Tertiary Care Hospital

Purpose: The prevalence of liver disease and frequency of consultations to a Hepatology Consultation service for patients with liver enzyme/function abnormalities admitted to a clinical teaching unit at an urban tertiary care hospital have not been previously described. To document these data, a retrospective chart review of adult patients admitted for non-hepatobiliary problems to a general Internal Medicine clinical teaching unit at an urban, tertiary care hospital during a three month period was performed. Methods: Laboratory test results were reviewed to determine if liver enzymes and function tests had been ordered during the first five days of admission and, in those with abnormal results, whether referrals had been sent to the hospital’s Hepatology Consultation service for further investigations and/or management. Results: A total of 506 admissions occurred during the study period. Of these, 452 (89%) were for patients with no known liver disease. Liver biochemistry testing was obtained in 218 (48.2%) of these individuals. In 192 (88.1%), liver enzyme or function tests were abnormal and in 91 (41.7%), both enzymes and function tests were abnormal (suggesting more advanced disease). Referrals to the Hepatology Consultation service were requested for 5/91 (5.5%) patients with more advanced disease and none with only liver enzyme or function tests abnormalities. Conclusions: Although liver enzymes and/or function test abnormalities are common in this patient population, screening for liver disease is relatively uncommon and consultation to a Hepatology Consultation service occurs in less than 10% of cases

Cancer Stem Cells are Depolarized Relative to Normal Stem Cells Derived from Human Livers

Introduction and aim. The inability to distinguish cancer (CSCs) from normal stem cells (NSCs) has hindered attempts to identify safer, more effective therapies for hepatocellular carcinoma (HCC). The aim of this study was to document and compare cell membrane potential differences (PDs) of CSCs and NSCs derived from human HCC and healthy livers respectively and determine whether altered GABAergic innervation could explain the differences.Material and methods. Epithelial cell adhesion molecule (EpCAM) positive stem cells were isolated from human liver tissues by magnetic bead separations. Cellular PDs were recorded by microelectrode impalement of freshly isolated cells. GABAA receptor subunit expression was documented by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence.Results. CSCs were significantly depolarized (-7.0 ± 1.3 mV) relative to NSCs (-23.0 ± 1.4 mV, p < 0.01). The depolarized state was associated with different GABAA receptor subunit expression profiles wherein phasic transmission, represented by GAGAA a3 subunit expression, was prevalent in CSCs while tonic transmission, represented by GABAA a6 subunit expression, prevailed in NSCs. In addition, GABAA subunits a3, |33, y3 and S were strongly expressed in CSCs while GABAA n expression was dominant in NSCs. CSCs and NSCs responded similarly to GABAA receptor agonists (APD: 12.5 ± 1.2 mV and 11.0 ± 3.5 mV respectively).Conclusion. The results of this study indicate that CSCs are significantly depolarized relative to NSCs and these differences are associated with differences in GABAA receptor subunit expression. Together they provide new insights into the pathogenesis and possible treatment of human HCC