A role for thrombin in liver fibrosis.
OBJECTIVE
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.
Duplantier
J Gillibert
JG
GREF, INSERM E362, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
Dubuisson
L
L
Senant
N
N
Freyburger
G
G
Laurendeau
I
I
Herbert
J-M
JM
Desmoulière
A
A
Rosenbaum
J
J
D000199:Actins / Q000378:metabolism; D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002251:Carbon Tetrachloride; D005786:Gene Expression Regulation / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics
D000199:Actins; D000631:Aminopyridines; C469682:N-(3-((((4-(5-amino-2-pyridinyl)-1-((4-difluoromethylene)-1-piperidinyl)carbonyl)butyl)amino)sulfonyl)(1,1'-biphenyl)-2-yl) acetamide; D012333:RNA, Messenger; D013449:Sulfonamides; D019715:Tissue Inhibitor of Metalloproteinase-1; D002251:Carbon Tetrachloride; D013917:Thrombin