Introduction
Liver fibrosis is a wound healing response to various types of injury, and it can progress into liver cirrhosis and even to hepatocellular carcinoma (HCC). Alcohol abuse, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and nonalcoholic steatohepatitis (NASH) are the main causes of liver fibrosis. In the European Union, 0.1% of the population is affected by cirrhosis, which leads to approximately 170,000 deaths each year.(1) In China, the morbidity rate of HBV was 9.75% in 1992, and approximately 300,000 patients died of HBV-related diseases (2). Unfortunately, there are currently no effective drugs for liver fibrosis, especially liver cirrhosis.
The etiopathogenesis of liver fibrosis is very complex. Many cells, including hepatic stellate cells (HSCs), fibroblasts, bone marrow-derived myofibroblasts, hepatocytes, Kupffer cells, and natural killer (NK) cells, are involved in this pathological processs(3-7) . These cells interact with each other through cytokines, resulting in the accumulation of extracellular matrix, as it is formed faster than it is degraded, and the gradual formation of fibrotic tissue that can further develop into cirrhosis. In particular, tumor necrosis factor α (TNFα), interleukins (ILs), and transforming growth factor β (TGF-β) are involved in the formation and development of liver fibrosis(8-11). However, whether these cytokines exhibit obvious changes with the development of liver fibrosis or whether those changes differ depending on the fibrosis stimulus is not fully understood.
Biliary cirrhosis is caused by biliary obstruction and cholestasis (12). Cholestasis leads to the sedimentation of bilirubin, bile salts, bile acids, cholesterol and other substances in the liver. Long-term cholestasis causes liver fibrosis and even cirrhosis(13). Bile duct ligation (BDL) is a common way to establish an animal model of cholestatic liver fibrosis (12). The animal model can simulate human liver fibrosis caused by long-term cholestasis, with good repeatability and a high success rate.
Thioacetamide (TAA) has hepatotoxicity and leads to the destruction of liver cells (14). Long-term and low-dose exposure to TAA may promote gradual hepatocyte necrosis, which is similar to the pathological process of human liver fibrosis, meaning that it is a good model for chronic liver injury and liver fibrosis(15).
This paper focuses on comparing the early stage of liver fibrosis or cirrhosis (caused by choledochal ligation for 1 month) with the late stage of cirrhosis (treated with TAA for 3 months) and exploring the similarities and differences in the main cytokines and signaling pathways in female and male rats to identify the common factors promoting liver fibrosis and find new targets or target groups for the treatment of liver fibrosis and cirrhosis.