Efectos de mediadores de la inflamación sobre monocitos y células estelares hepáticas

Résumé

EFFECTS OF INFLAMMATION MEDIATORS ON MONOCYTES AND HEPATIC STELLATE CELLS. The activation of monocyte/macrophages that leads to the secretion of pro-inflammatory cytokines and proteases of the extracellular matrix, as well as to the elevation of the levels of NO, is essential in the development of inflammatory diseases. In the present work we investigated the effect of the peroxynitrite donor SIN-1 on apoptosis and production of metalloproteases of monocytes. After a hepatic injury, the liver responds in a generalized manner with the process denominated fibrogenesis, a dynamic mechanism of repair by which components of the extracellular matrix are synthesized, and that is normally associated to an inflammatory component. Since hepatic stellate cells are the main source of extracellular matrix proteins and profibrogenic cytokines, apoptosis induced by nitric oxide produced by macrophages and by peptides derived from the proteolysis of matrix proteins by the action of metalloproteases, could contribute to the control of the repair process, avoiding adverse effects. In the present work we analyzed the apoptotic effect of SIN-1 and of fibronectin and collagen peptides, on two cellular lines of hepatic stellate cells (HSC), CFSC-2G and LX-2, of human and rat origin, respectively. Since the peroxynitrite generator (SIN-1), promoted apoptosis in monocytes, CFCS-2G and LX-2 based on oligonucleosomal DNA fragmentation, caspase-3 and -9 activation, Bcl-2 depletion and accumulation of Bax proteins, we tested the hypothesis that nitration of specific proteins could result in apoptotic cell death. Among the tyrosine-nitrated protein, Lyn was identified. Using specific inhibitors for different signalling and effector molecules involved in the apoptotic process we demonstrate that NO, via protein-nitration, could play an important role in resolution of liver fibrosis by controlling the inflammatory response and regulation of activity of hepatic stellate.