Endotoxin attenuates fibrogenic activity of hepatic stellate cells: a novel mechanism of limiting liver fibrosis (144.5)

Abstract

Chronic liver injury follows tightly regulated sequence involving inflammation, and activation of hepatic stellate cells (HSCs) that gain proliferating and fibrogenic phenotype. Activated HSCs are the primary cells to cause liver fibrosis. Bacterial endotoxin (lipopolysaccharide; LPS) has been shown to promote hepatic fibrosis by modulating TGFβ signaling in quiescent HSCs. However, whether LPS, levels of which are elevated in liver diseases, exerts similar effects on activated HSCs is not known. Here, we found that a single administration of LPS (5 mg/kg; ip) to rats that had developed CCl4‐induced liver fibrosis resulted in significant down‐regulation of α‐smooth muscle actin (α‐SMA; HSC‐activation marker) and type I collagen expression, increased the expression of matrix metalloproteinase 3, and reduced fibrosis as determined by Sirius red staining. LPS also reduced liver injury as indicated by lower serum ALT levels. In culture‐activated HSCs, LPS down‐regulated the expression of α‐SMA, and of TGFβ1 (a potent fibrogenic cytokine) and its receptor, and up‐regulated the expression of TFGβ1 pseudo‐receptor BAMBI. These effects of LPS on HSCs were accompanied by phenotypical alterations (reduced size and α‐SMA) and increased expression of inducible nitric oxide (NO) synthase Furthermore, both in fibrotic liver tissue and cultured HSCs, LPS up‐regulated expression of decorin, which regulates collagen fibrillogenesis, blocks bioactivity of TGFβ1 and exerts protective effect against fibrosis. Our findings suggest that these effects of LPS on activated HSCs may be an intrinsic mechanism of limiting fibrosis in chronic liver disease.