LOBULAR - BUT NOT PERIOVULAR - INHIBITION OF COLLAGEN DEPOSITION IN THE LIVER OF SCHISTOSOMA-MANSONI-INFECTED MICE USING INTERFERON-GAMMA

Background/Aims: Interferon-gamma (IFN gamma) elicits anti-proliferati ve and antifibrogenic activity in a variety of mesenchymal cells, incl uding hepatic stellate cells (Ito cells), and therefore represents a p ossible drug for liver fibrosis. However, IFN gamma binds to heparan s ulfate, and is localized by these molecules in a restricted area withi n the tissue. For example, in rat liver, it has been shown that follow ing injection, IFN gamma was concentrated in a restricted area by hepa ran sulfate. The aim of this study was to analyze, at the tissular lev el in the liver, the antifibrogenic activity of IFN gamma. Methods: Ch ronic inflammation due to Schistosoma infection induces hepatic fibrog enesis around the parasite eggs (portal fibrosis) and in the parenchym a (lobular fibrosis). Infected mice were treated with recombinant IFN gamma, and the collagen content of the liver was evaluated by means of biochemical dosages, histologic and morphometric examination of liver tissue, and electron microscopic analysis. Results: IFN gamma reduced the whole liver collagen content by 28% compared to control mice. In control mice, collagen was found around eggs and infiltrating the pare nchyma, associated with a diffuse array of inflammatory cells, while i n treated mice the collagen was present only around eggs and surrounde d by a dense layer of inflammatory cells. Therefore, collagen was meas ured in isolated granulomas and in the remaining parenchyma. We found that IFN gamma strongly reduced the parenchymal collagen (74%), but ha d no effect on the granuloma collagen content. Conclusions: Together t hese data demonstrate that IFN gamma did not act in a homogeneous mann er in the liver. Since granulomas are almost completely devoid of hepa ran sulfate, these data could suggest, among others hypotheses, that h eparan sulfate which binds IFN gamma either localizes or mediates the cytokine activity outside the granulomas.