Cooperation of Liver Cells in the Process of Liver Fibrosis
Fibrosis is the common response to chronic liver injury from various origins including metabolic diseases, viral infections, alcohol abuse, and various chemicals. Liver fibrosis is characterized by both quantitative and qualitative changes in the composit
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Fibrosis is the common response to chronic liver injury from various origins including metabolic diseases, viral infections, alcohol abuse, and various chemicals. Liver fibrosis is characterized by both quantitative and qualitative changes in the composition and distribution of extracellular matrix (ECM) that are reflected by a three- to fivefold net increase of ECM and replacement of low-density basement membranelike material by interstitial type matrix abundant in fibril-forming collagens {Friedman 1993; Gressner 1998). This gross remodeling of ECM in the fibrotic liver represents an imbalance between the deposition and degradation of ECM molecules. Hepatic stellate cells, which are involved in the regulation of ECM production and degradation (Table 10), have been found to play a pivotal role in the initiation and progression of hepatic fibrosis (Friedman 1993, 2000; Gressner 1998). Following acute or chronic liver injury, hepatic stellate cells transdifferentiate: they proliferate, lose lipid droplets, change morphology from the star-shaped cells to that of myofibroblasts with the expression of smooth muscle a-actin (reviewed by Gressner 1998), and migrate to sites of tissue damage (Ikeda et al. 1999; Marra et al. 1998b). Activation of stellate cells that initiates the development of the inflammatory process results from multiple interactions between many cell types (injured hepatocytes, Kupffer cells, endothelial cells, platelets, infiltrating inflammatory cells) mediated by cytokines and reactive oxygen species, and from the changes in the composition of the perisinusoidal matrix (Arthur 2000; Gressner 1998). In the case of chronic liver damage, HSC activation persists during the "perpetuation phase" (Friedman 1993; Gressner 1998), and progressive accumulation of ECM leads to liver fibrosis, and finally to cirrhosis. The key role of hepatic stellate cells in the development of liver fibrosis may be deduced from the correlation between the number of HSC and the extent of liver fibrosis observed both in experimental liver injury (Friedman 1993) or in patients with chronic hepatitis C treated with interferon (Sakaida et al.1999). 14.1 Factors Involved in the Activation of Hepatic Stellate Cells
Fibrogenesis is regarded as a dynamic process related to the extent and duration of parenchymal cell injury. The cascade of events that leads in vivo to the development of liver fibrosis is initiated by noxious agents that may be different in various kinds of liver damage.lt is, however, widely believed that injury to hepatocytes and/or Kupffer and endothelial cells results in the release of many substances that cause transformation of quiescent stellate cells into myofibroblast-like cells. The activation ofHSC may Z. Kmieć, Cooperation of Liver Cells in Health and Disease © Springer-Verlag Berlin Heidelberg 2001
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result from both direct action of toxic molecules such as reactive oxygen species or paracrine and autocrine effects of many mediators (Friedman 2000). It has been assumed that the in vivo activation of hep
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