Activation of hepatic stellate cells--a key issue in liver fibrosis

Hepatic fibrosis describes the presence of excess collagen due to new fiber formation, laid down as part of the tissue repair response to chronic liver injury. The causes of injury include toxins, disorders of the immune system, viral and parasitic infections, as well as rarer liver diseases such as haemochromatosis, Wilson's disease and galactosaemia. Whatever the cause of injury, the cells and soluble factors contributing to this wound healing response are similar. The principal effector of hepatic fibrogenesis is now widely recognized as the hepatic stellate cell. Stellate cells are usually quiescent cells, but in response to liver injury they undergo an activation process in which they become highly proliferative and synthesize a fibrotic matrix rich in type I collagen. Initiation of stellate cell activation is largely due to paracrine stimulation, whereas perpetuation of activation involves autocrine as well as paracrine loops, and is dependent on a number of functional changes. The principal paracrine and autocrine factors currently thought to be involved in these processes are discussed in this review, as are the roles of the extracellular matrix, the nuclear receptor superfamily, non-peptide ligands, and oxidative stress.