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.