LIVER

A role for thrombin in liver fibrosis

J Gillibert Duplantier^1,2, L Dubuisson^1,2, N Senant², G Freyburger³, I Laurendeau⁴, J-M Herbert⁵, A Desmoulière^1,2, J Rosenbaum^1,2

¹ GREF, INSERM E362, Université Bordeaux 2, Bordeaux, France
² IFR 66, Université Bordeaux 2, Bordeaux, France
³ Laboratoire d’Hématologie, Hôpital Pellegrin, Bordeaux, France
⁴ Laboratoire de Génétique Moléculaire UPRES 3618, Faculté des Sciences Pharmaceutiques et Biologiques de Paris, France
⁵ Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, Toulouse, France

Correspondence to:
Correspondence to:
Dr J Rosenbaum
GREF, INSERM E362, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France; jean.rosenbaum{at}gref.u-bordeaux2.fr

Background/Aim: Several lines of evidence incriminate the serine proteinase thrombin in liver fibrogenesis either through its procoagulant function or its signaling via cell-surface receptors. The aim of this study was therefore to evaluate the effect of thrombin inhibition on experimental liver fibrosis.

Methods: Fibrosis was induced in rats by administration of CCl₄ for either three or seven weeks. Oral administration of the thrombin antagonist SSR182289 started one week after the start of CCl₄ intoxication. Fibrosis and the area occupied by alpha smooth muscle actin (ASMA) positive cells were quantified with histomorphometry. Expression of fibrosis related genes was measured by real time RT-PCR.

Results: After three weeks of CCl₄, treatment with SSR182289 did not significantly decrease the area of fibrosis but significantly decreased the area of ASMA positive cells by 22% (p = 0.03) and the expression of TIMP-1 mRNA by 52% (p = 0.02). There was no effect on gene expression of collagen I, MMP-2, or TIMP-2. After seven weeks of CCl₄, treatment with SSR182289 resulted in a significant decrease in fibrosis (–30%, p = 0.04) and ASMA positive areas (–35%, p = 0.05). SSR182289 alone had no effect on the measured parameters. Additionally, it did not alleviate the acute toxicity of CCl₄ as shown by measuring levels of serum aminotransferases and the area of necrosis.

Conclusions: These data provide evidence that thrombin antagonism can reduce liver fibrogenesis. The early effect of SSR182289 on ASMA and TIMP-1 expression suggests that it is beneficial in reducing fibrogenic cell activation.

Abbreviations: aPTT, activated partial thrombin time; ASMA, alpha smooth muscle actin; CCl₄, carbon tetrachloride; GAPDH, glyceraldehyde-3-phosphate-dehydrogenase; MMP, matrix metalloproteinase; PAR, protease activated receptor; TIMP, tissue inhibitor of matrix metalloproteinase

Keywords: myofibroblasts; protease activated receptor; tissue inhibitor of matrix metalloproteinase-1; SSR182289; thrombin

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