Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

Abstract

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.

Keywords: exosomes; fibrosis; hepatic stellate cells; hepatitis C virus; non-coding RNAs.

Figure 1

Exosomes carrying microRNAs and long non-coding RNAs (lncRNAs) released from hepatitis C virus (HCV)-infected hepatocytes enter into quiescent hepatic stellate cells (qHSCs) and activate hepatic stellate cells (aHSCs). This phenomenon triggers aHSCs towards liver fibrosis.

Figure 2

Communication among HCV-infected hepatocytes, quiescent HSCs (qHSCs) and Kupffer cells. HCV-infected hepatocytes secrete soluble mediators (cytokines/chemokines) and exosomes, and interact with qHSCs. On the other hand, circulating HCV released from infected hepatocytes interact with Kupffer cells and promote secretion of proinflammatory cytokines/chemokines, including IL-1β, IL-18 and CCL5. These mediators help quiescent hepatic stellate cells (qHSCs) activate HSCs (aHSCs), enhancing the deposition of the extracellular matrix (ECM) into the liver for fibrosis.