INTERFERON-GAMMA DECREASES HEPATIC STELLATE CELL ACTIVATION AND EXTRACELLULAR-MATRIX DEPOSITION IN RAT-LIVER FIBROSIS

Interferon gamma (IFN-gamma) inhibits in vitro the activation of hepat ic stellate cells (HSC), the primary extracellular matrix-producing ce lls in liver fibrosis. This study was undertaken to determine in vivo the effect of IFN-gamma in the rat model of liver fibrosis induced by dimethylnitrosamine (DMN), where HSC activation represents an early re sponse to cell injury. Rats were killed after 1 or 3 weeks of treatmen t with DMN, IFN-gamma, DMN + IFN-gamma, or saline. Immunohistochemistr y was used to identify proliferating (desmin-positive/bromodeoxyuridin e (BrdU)-positive cells) and activated (alpha-smooth-muscle actin [alp ha-SMA]-positive cells) HSCs. Collagen deposition was determined color imetrically and by morphometry. The parenchymal extension of desmin- a nd actin-positive cells and of fibrotic tissue was measured by pointco unting technique and expressed as a percentage of area. Western blot w as used to determine laminin and fibronectin accumulation. The levels of messenger RNA (mRNA) for procollagen type I, fibronectin, and lamin in were evaluated by Northern blot, No differences were observed in ra ts treated with either saline or IFN-gamma alone. IFN-gamma reduced HS C activation induced by liver injury, as shown by the decreased number of proliferating HSC and the reduction of parenchymal area occupied b y alpha-SMA-positive cells observed in DMN + IFN-gamma-treated animals compared with the DMN group. This was associated with reduced collage n, laminin, and fibronectin accumulation and lower levels of mRNA for procollagen type I, fibronectin, and laminin in the DMN + IFN-gamma gr oup. Thus, this study indicates that IFN-gamma reduces extracellular m atrix deposition in vivo by inhibition of HSC activation.