procollagen type I, fibronectin, and laminin in the DMN Interferon gamma (IFN-g) inhibits in vitro the activa-/ IFN-g group. Thus, this study indicates that IFN-g retion of hepatic stellate cells (HSC), the primary extracelduces extracellular matrix deposition in vivo by inhibilular matrix-producing cells in liver fibrosis. This study tion of HSC activation. (HEPATOLOGY 1996;23:1189-1199.) was undertaken to determine in vivo the effect of IFN-g in the rat model of liver fibrosis induced by dimethylnitrosamine (DMN), where HSC activation represents an Hepatic fibrosis is a common response to chronic liver early response to cell injury. Rats were killed after 1 or injury of variable origin (viral, metabolic, or toxic). Re-3 weeks of treatment with DMN, IFN-g, DMN / IFN-g, gardless of the etiologic factor, liver fibrosis is characor saline. Immunohistochemistry was used to identerized by increased production of extracellular matrix tify proliferating (desmin-positive/bromodeoxyuridine components that form the hepatic scars and consists of (BrdU)-positive cells) and activated (a-smooth-muscle fibril-forming collagens, particularly collagen type actin [a-SMA]-positive cells) HSCs. Collagen deposition I, 1-4 and matrix glycoconjugates such as proteoglycans, was determined colorimetrically and by morphometry. The parenchymal extension of desmin-and actin-posi-fibronectins, and hyaluronic acid. 5 tive cells and of fibrotic tissue was measured by point-Hepatic stellate cells (HSC) (also known as fat-storcounting technique and expressed as a percentage of ing or Ito cells) have been identified as the primary area. Western blot was used to determine laminin and source of excess extracellular matrix accumulation in fibronectin accumulation. The levels of messenger RNA liver fibrosis. 6 In normal rat liver, HSCs are situated (mRNA) for procollagen type I, fibronectin, and laminin in the space of Disse and are characterized by the preswere evaluated by Northern blot. No differences were ence of vitamin A 7 and their positivity for desmin. 8 Durobserved in rats treated with either saline or IFN-g ing the development of fibrosis, HSCs proliferate 9 and alone. IFN-g reduced HSC activation induced by liver undergo a process of activation, developing a myofiinjury, as shown by the decreased number of proliferatbroblastlike appearance. Activated HSCs are characing HSC and the reduction of parenchymal area occu-
pied by a-SMA-positive cells observed in DMN / IFN-terized by cell enlargement with increased rough endog-treated animals compared with the DMN group. This plasmic reticulum and loss of retinoids, 10 and was associated with reduced collagen, laminin, and fiexpression of a-smooth-muscle actin (a-SMA). 6,[11][12][13][14][15] bronectin accumulation and lower levels of mRNA for Activated HSC may be seen within scars in close contact with collagen fibrils positive for collagen types I and III. 16,17 Collagen-specific transcripts have been de-Abbreviations: HSC, hepatic stellate cells; a-SMA, a-smooth-muscle actin;
tected in these cells by in situ hybridization. 18,19 IFN-g, interferon gamma; mRNA, messenger RNA, DMN, dimethylnitros-A variety of cytokines are able to modulate the proamine; BrdU, bromodeoxyuridine; ALT, alanine transaminase; IgG, immunoduction of matrix proteins. 20 Platelet-derived growth globulin G; ALP, alkaline phosphatase.