I think I would start with liver fibrosis. Liver fibrosis is cause by chronic liver disease and would lead to liver cirrhosis, end stage of liver failure, or even hepatocellular carcinoma. According to statistics of United States and Europe, the main reasons to cause liver fibrosis are HCV infection and steotohepatitis. The most important thing is that how does liver become fibrosis. The fact is that there are many myofibroblasts in the liver, and the main reason of liver fibrosis is that myofibroblasts secrete type I collagen which accumulates in the liver tissues and leads to liver fibrosis. However, there are many kinds of precursor of myofibroblast. They could be the cells derived from bone marrow, such as fibrocytes, or fibroblasts which are in the tissues originally, or sometimes hepatocytes could be changed into myofibroblast by stimulation of specific chemokines, but the main precursor is activated stellate cells. Hepatic stellate cells (HSCs) are in quiescent state in usual time, and they contain abundant lipid droplets which can store vitamin A. Quiescent HSCs could be activated by some conditions which could be liver injury, stimulation of lipopolysaccharide which is in the cell walls of gram-negative bacterium, or stimulation of specific chemokines. After HSCs being activated, they might have extra abilities such as proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, or releasing inflammatory signals. In addition, infiltration of immune cells could also lead to liver fibrosis.Fortunately, these mechanism of liver fibrosis could be regulated by some proteins like Timp-1, Tgf-beta, Mmp9, and IL-10.
Recently, the relation between coagulation cascade and liver fibrogenesis has been found. When coagulation cascade is activated, thrombins will be formed and platelets aggregation will be caused in the same time. If platelets aggregation occurs in liver, it will lead to HSCs proliferation. However, the key molecules of this mechanism are still unknown. One thing we know for sure is that platelets aggregation is caused by platelets activation. When tissues were injured, the collagen in the tissue may contact with blood stream, and the Von willebrand factor (vWF) in the blood stream would bind to collagen. The GPIIb-IIIa receptor on platelets membrane could bind to vWF and be activated after that. The activated platelets would release some coagulation factors, stored in platelets granules, to blood stream and caused clot formation, and one of the coagulation factors called fibrinogen could also bind to GPIIb-IIIa receptor. This would also make platelets to be activated and have the ability to link with each others and cause platelets aggregation. Interestingly, there are not only coagulation factors but also chemokines that are stored in platelet granules, and these chemokines would also be released to blood stream when platelets are activated. CXCL4 is an abundant chemokine in platelets. Actually, CXCL4 is both a chemokine and a coagulation factor. It is also called platelet factor 4 and it cause the formation of thrombus as a coagulation factor and it could activate monocytes as a chemokine. Recent studies show that CXCL4 mRNA was detected at elevated levels in the livers of patients with alcoholic liver disease ,and CXCL4 serum levels were elevated in patients with viral hepatitis. These evidences indirectly imply the potential of CXCL4 in liver disease. Therefore, the aim of this paper is to investigate the role of the platelet-derived CXCL4 in human experimental liver fibrosis.
In this experiment, both serum concentrations and intrahepatic CXCL4 mRNA were measured in patients with chronic liver disease and in mouse models. Electron microscopy and immunohistochemistry were utilized to determine platelet aggregation. Wild-type and CXCL4-/- mice were treated with CCl4 and thioacetamide (TAA) which are used to induce chronic liver damage. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and hepatic stellate cells were treated with recombinant murine CXCL4 in vitro. The results showed that CXCL4 serum levels and intrahepatic CXCL4 mRNA concentrations were increased in patients with advanced hepatitis C virus-induced liver fibrosis or nonalcoholic steatohepatisis. Platelets aggregation was obviously near collagen fibrils in the liver tissue. The treatment of CCl4 and TAA caused an increase of hepatic CXCL4 levels, platelet activation and aggregation in mice. Deletion of CXCL4 could reduce liver fibrosis significantly which is proved by histological and biochemical examinations. The results showed that the expression of fibrosis-related genes (tissue inhibitor of matrix metalloproteinase 1 [Timp-1], matrix metalloproteinase 9 [Mmp9], transforming growth factor beta [Tgf-β], interleukin 10 [IL-10]) were changed significantly in CXCL4-/- mice. In addition, infiltration of immune cells (neutrophils and CD8-positive T cells) into the liver was decreased in CXCL4-/- mice. In vitro results showed that hepatic stellate cells were activated after treating recombinant murine CXCL4 and showed the abilities of proliferation, chemotaxis, and chemokine expression.
In conclusion, when liver injury occur, platelets could be recruited to the injured site and be activated. Then activated platelets secrete CXCL4 which activates quiescent HSCs, and activated HSCs start to proliferate. This might cause the increasing of myofibroblasts since activated HSCs are the main precursor cells of myofibroblasts. Thus, increasing of myofibroblasts accelerate the accumulation of type I collagen. The collagen was accumulated in liver tissue not only cause liver fibrosis but also recruit much more platelets aggregate in liver and be activated at the same time. Then activated platelets secrete CXCL4 again. This mechanism speeds up the progress of liver fibrosis. However, when we knock out CXCL4 gene, activated platelets could not secrete CXCL4, so HSCs could not be activated. Which means that there are no more myofibroblasts increasing and no more accumulation of type I collagen in tissue. Therefore, the progress of liver fibrosis will be slow down.
That is pretty much it about my seminar subject. Honestly, it takes me about a week to finish this article. Maybe this article doesn't make any sense because of my unsuitable description in English. Let me know when it does happen.
