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Bacterial cell-wall derived products induce a pro-inflammatory and pro-fibrogenetic phenotype in murine hepatic stellate cells

Abstract number: 902_p1051

Brun P.

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Although activation of hepatic stellate cells (HSC) is recognised as the initiating event leading to fibrosis, the factor(s) responsible for HSC activation in non-alcoholic steatohepatitis (NASH) are not completely known. Since patients with NASH have a high prevalence of small intestinal bacterial overgrowth we tested the hypothesis that gut-derived bacterial products may activate HSC. We found by LAL test that endotoxin level (LPS) in portal blood of obese C57lep-/- mice was significantly increased as compared with lean controls (8.74 + 1.08 vs. 6.11 + 0.8 EU/mL). Since we also observed that murine HSC express specific mRNA transcripts encoding mCD14, TLR4, MD2, TLR2 (endotoxin receptors) and peptidoglycan recognition proteins (PGRP), we next studied the effects of LPS, lipoteichoic acid (LTA) or muramic acid (NAM) (10–0.01 mg/mL) on TGF-beta1, IL-6, PDGF-bb, MCP-1 and fibronectin (mRNA transcripts and peptides). Incubation of HSC for 24 h with LPS (1 mg/mL) increased TGF-beta1 (by 1.8-fold) and IL-6 (by 12.5-fold) mRNA transcripts levels over controls, but had no effect on fibronectin mRNA levels. LTA (10 mg/mL) increased only IL-6 (by 4.9-fold) mRNA transcripts, whereas NAM had no significant effects. Similar results were obtained also by cytokine measurements in the conditioned media. Six days exposure of HSC to 10 ng/mL of LPS alone increased TGF-beta1 and IL-6 mRNA transcripts by 2- and 3.9-fold over controls, respectively, but still had no effect on fibronectin mRNA levels. Similarly, LTA and NAM by themselves significantly increased only IL-6 mRNA transcripts by 2.1- and 1.9-fold, respectively. However, simultaneous exposure of HSC to LPS and LTA (10 ng/mL/6 days) induced a fibrogenic phenotype significantly increasing fibronectin mRNA levels by 1.95-fold over controls. In summary, we report that LPS levels are increased in the portal blood of obese mice and that short-term exposure of HSC to bacterial derived cell wall products can induce a pro-inflammatory phenotype whereas a long-term exposure induces a pro-fibrogenic phenotype. We speculate that in obese patients the intestinal barrier function is compromised causing a rise in LPS levels in the portal blood that in turn may contribute to the activation of HSC thus leading to the development of fibrosis in NASH patients.

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Session Details

Date: 01/08/2007
Time: 00:00-00:00
Session name: XXIst ISTH Congress
Subject:
Location: Oxford, UK
Presentation type:
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