Abstract
HCV infection typically induces liver injury and inflammation, which appears to be responsible for the associated fibrogenesis. To date, the mechanism underlying the different rates of disease progression remains unclear. The aim of the study is to understand the possible role of the HCV non-structural (NS) 3/4A protein in the fibrosis progression. We used NS3/4A-expressing transgenic mice (NS3/4A-Tg) to accomplish the goals of the study. Different stages of liver fibrosis were induced in wild-type and NS3/4A-Tg mice by single carbon tetrachloride (acute) or multiple injections for 4 (intermediate) or 8 (chronic) weeks. Fibrotic parameters, inflammatory responses and hepatocyte turnover were extensively examined. Hepatic expression of HCV NS3/4A did not induce spontaneous liver damage. However, NS3/4A expression exerted contrasting effects during acute and chronic liver damage. During early fibrogenesis and intermediate fibrosis (4 weeks), NS3/4A-Tg mice exhibited enhanced liver damage whereas reduced fibrosis was observed in NS3/4A-Tg during chronic liver fibrosis (8 weeks). Furthermore, attenuated inflammation was observed in NS3/4A-Tg during chronic fibrosis with increase in M2 macrophages, hepatocyte proliferation, decreased hepatocyte apoptosis and decreased ductular reaction. In conclusion, during early fibrogenesis, HCV NS3/4A contributes to liver damage. While, during chronic liver fibrosis, NS3/4A dampens inflammation and induces hepatocyte regeneration thereby contributing to slow fibrosis progression to promote its survival or persistence.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic hepatitis with increasing morbidity and mortality
Acute liver injury was induced in HCV NS3/4A-Tg and wild-type control mice (S1 Fig, panel A), and expression of extracellular matrix (ECM) proteins and hepatic stellate cells (HSCs) markers was determined
Since it has been shown that HCV infected patients have varied degree of fibrosis, we investigated if HCV NS3/4A influences fibrosis progression at different stages of fibrosis
Summary
Hepatitis C virus (HCV) is a major cause of chronic hepatitis with increasing morbidity and mortality. An estimated 3% of the world population-more than 170 million people worldwide are infected with hepatitis C virus [1,2]. Progression to chronic Hepatitis C occurs in most people acutely infected (55% to 86%) with HCV, and persistent infection is an important cause of cirrhosis, end-stage liver disease and hepatocellular carcinoma [4]. The disease is mild and stable or slowly progressive in about 70% of chronically infected patients, the remaining 30% develop progressive liver disease culminating in cirrhosis and hepatocellular carcinoma [5,6]. Progression to liver cirrhosis usually takes 20–40 years but in some patients severe fibrosis can develop rapidly leading to death within 5–10 years from the onset of infection [7]. The role of viral proteins and key cell types hepatic stellate cells (HSCs) and macrophages in fibrosis progression has not been investigated yet
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