A. Di Sario

Proliferation of Hepatic Stellate Cells and Lipid Peroxidation: Changes Due to Polyphenols.

Hepatic fibrosis represents the final steps of chronic liver injury and consists of excessive deposition of extracellular matrix components. Hepatic stellate cells (HSC) are responsible for this event when, through a process of activation, they proliferate and acquire a myofibroblatic phenotype. In this article, we review the role of oxidative stress in liver fibrosis. Moreover we also demonstrate that lipid peroxidation products, directly or released by damaged hepatocytes, stimulate HSC proliferation and collagen synthesis. This effect can be inhibited by resveratrol, a novel polyphenolic antioxidant.

P.01.7 ANTIBODIES TO GP2: A NOVEL SEROLOGICAL MARKER FOR CROHN'S DISEASE AND ITS POTENTIAL ASSOCIATION WITH DISEASE ACTIVITY AND LOCATION

ANTIBODIES TO GP2: A NOVEL SEROLOGICALMARKER FOR CROHN’S DISEASE AND ITS POTENTIAL ASSOCIATIONWITH DISEASE ACTIVITY AND LOCATION P. Rossetti∗ ,2, P. Sassaroli 2 , S. Gemini 2, A. Di Sario2, A. Benedetti 2 , G. Ciarrocchi 1 , M. Tocchini 1, E. Bendia2 1Ospedali Riuniti-Universita Politecnica delle Marche, Laboratorio Analisi, Ancona, Italy; 2Universita Politecnica delle Marche-Ospedali Riuniti-Clinica di Gastroenterologia, Ancona, Italy

Leptin mediates a proliferative response in human cholangiocarcinoma

lower levels of lAb than those isolated from normal animals (LDC Tx: 25±8%; SDC Tx: 83±5%; LDC Wt: 74±8%; SDC Wt: 80±3%). When LDC and SDC isolated from Tx mice were used as stimulatory cells in a 72 hr MLC they show an impaired T-cell stimulatory activity as respect to DC isolated from Wt animals (see figure). Conclusions: our data show that in the early phase of hepatocarcinogenesis there is a systemic immundepression since both resident LDC and SDC isolated from tx mice have a weak T-cell stimulator activity, as compared to Wt animals. However the poor T-cell stimulator activity of LDC and SDC was regardless of lAb expression. This study was supported by MIUR grant no. 2003069954.

Differential expression of ras isoforms in hepatic stellate cells

DIFFERENTIAL EXPRESSION OF RAS ISOFORMS IN HEPATIC STELLATE CELLS E Ridolfi, A. Benedetti, A. Di Sario, S. Saccomanno, L. Marucci, E. Bendia, A.M. Jezequel, G. Sve~liati Baroni Dept. of Gastroenterology and Inst. of Exp. Pathology, University of Ancona, Ancona, Italy. Ras proteins represent the products of three different Ras genes (H-, K-, and N-ms) and are plasma membrane-associated GTPases that function as relay switches transducing biological information from extracellular signals to the nucleus. One or the other isoform may predominate in a different cell type where they play a key role in transforming activity and regulating cell proliferation. Hepatic stellate cell (HSC) proliferation close to area of necrosis represent a key event in liver fibrosis and PDGF represents the main mitogen. Aims of the present study ware thus:l)to evaluate the expression of Ras isoforms in activated HSC;2)to determine the effect of blocking Ras signaling on HSC proliferation;3)to determine the intracellular pathways which transduce extracellular signal to the nucleus via Ras proteins. By immunoprecipitation, the H-Ras isoform only was detected in total HSC lysate. This was confirmed by immunohistochemisffy by which the H-Ras isofonn was detected preferentially in the cytoplasmic area. PDGF-stimulated HSC showed a 4-fold increase in cell proliferation as determined by BrdU incorporation in S-phase nuclei. This was blocked by chaetomellic acid (a H-Ras processing inhibitor) which reduced cell proliferation down to control value starting at 2 pM. In addition, chaetomellic acid reduced PDGF-induced ERKll2 phosphorylation while had no effect on 70 kD

The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen α1(I), TIMP-1 and MMP-2

6 kinase (a downstream component of the PI3Kinase pathway) activation as determined by Western blot. This study thus indicates that PDGF-induced HSC proliferation is driven by H-Res. Since a non toxic inhibition of Ras processing has been obtained in vivo, H-Ras represents a plausible target for the experimental therapy of hepatic fibrosis. [ P/C03/38 ]