Portal tract fibrogenesis in the liver

The portal area is the 'main entrance' and one of the two main exits of the liver lobule. Through the main entrance portal and arterial blood reach the liver sinusoids. Through the exit the bile flows towards the duodenum. The three main structures, portal vein and artery with their own wall (and vascular smooth muscle cells) and bile duct with its basal membrane, are surrounded by loose myofibroblasts and by the first layer of hepatocytes and non-parenchymal cells. Chronic diseases of the liver can lead to development of liver cirrhosis, characterized by formation of fibrotic septa which can be portal-portal in the case of the chronic biliary damage or portal-central in the case of the chronic viral hepatitis. Central-central septa can also be observed under other pathological conditions. When damaging noxae are introduced to the liver, inflammatory cells are first recruited to the portal field, the first layer of hepatocytes may be destroyed (enlargement of the portal field) and portal (myo)fibroblasts become activated. A similar reaction may take place when the target of inflammation is the bile duct with consecutive reduction of the bile flow, activation of the portal (myo)fibroblasts, proliferation of bile ducts and destruction of the hepatocytes around the portal field. Increased matrix deposition may be the consequence. During the past years several publications dealt with the pathomechanisms of portal fibrogenesis as well as with its resolution. One of the most intriguing observations was that it is not hepatic stellate cells of the hepatic sinusoid, but portal (myo)fibroblasts which rapidly acquire the phenotype of 'activated' (myo)fibroblasts in the early stages of cholestatic fibrosis. These may also become the main mesenchymal cells of the porto-portal or porto-central fibrotic septa. This article reviews the similarities as well as differences between the mesenchymal cells of the portal tract and of the fibrotic septa vs 'activated' stellate cells of the hepatic sinusoids, and discusses the debate over their relative contributions to liver fibrogenesis.