Cellular communications and cell-matrix interactions in the pathogenesis of fibroproliferative diseases: liver fibrosis as a paradigm.

In vitro and in vivo studies suggest a strong cooperation between hepatocytes and mesenchymal cells and between the different non-parenchymal cell types in liver injury and fibrogenesis. The fibrogenic reaction might be described as a dynamic cascade of mechanisms beginning with hepatocyte necrosis and followed by inflammation, activation of macrophages, release of fibrogenic mediators, activation of fat-storing cells, stimulated extracellular matrix synthesis, and diminished matrix degradation resulting in a net matrix accumulation. In detail the initial events of hepatocyte injury and necrosis are followed by local proliferation of Kupffer cells, by influx of blood macrophages and by an aggregation of platelets in necroinflammatory areas. Through phagocytosis and endotoxin challenge, macrophages are activated and convert molecular oxygen into radicals and hydrogen peroxide which might be deleterious to hepatocytes. Furthermore, activated Kupffer cells and degranulating platelets release a number of polypeptide growth regulators stimulating thus fat-storing cell proliferation (transforming growth factor (TGF) alpha/epidermal growth factor, platelet-derived growth factor), transformation into myofibroblasts (transforming growth factor beta, tumor necrosis factor (TNF) alpha) and extracellular matrix synthesis of fat-storing cells and myofibroblasts (TGF-beta, TGF-alpha TNF-alpha). An impressive amount of literature exists demonstrating the central role of fat-storing cells and of its transformed counterpart, ie the highly active and synthetic myofibroblasts in fibrogenesis. These cells produce the majority of the extracellular matrix components, eg collagens, proteoglycans, glycoproteins, and hyaluronan. They have the ability to stimulate themselves via production of growth regulators in an autocrine way. The multiple interactions of the different cells involved in fibrogenesis, the findings that combinations of growth regulators may act additively, synergistically or antagonistically, the fact that certain growth regulators induce the synthesis or receptor expression of others and even of themselves and, findings suggesting an interaction between growth regulators, cell surface receptors, binding proteins (scavengers) and extracellular matrix components indicate a very complex network in fibrogenesis. To get further inside these complicated mechanisms, experimental designs that provide better images of the in vivo situation than conventional techniques used presently are required.