Inhibition of rat liver fibrogenesis through noradrenergic antagonism.
The effect of adrenergic innervation and/or circulating catecholamines on the function of liver fibrogenic cells is poorly understood. Our aim was to investigate the effects of noradrenergic antagonism on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Two weeks of CCl4 induced an approximately 5-fold increase in the area of fibrosis as compared with controls. The addition of 6-hydroxydopamine (OHDA), a toxin that destroys noradrenergic fibers, decreased fibrosis by 60%. After 6 weeks of CCl4, the area of fibrosis increased about 30-fold in CCl4-treated animals and was decreased by 36% with OHDA. At 2 weeks, OHDA abrogated the CCl4-induced increase in mRNA level of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), an inhibitor of extracellular matrix degradation, and it greatly reduced it at 6 weeks. Finally, when rats treated with CCl4 for 2 weeks also received prazosin, an antagonist of alpha1-adrenergic receptors, fibrosis was decreased by 83%. In conclusion, destruction of noradrenergic fibers or antagonism of noradrenergic signaling through alpha1 receptors inhibited the development of liver fibrosis. Because adrenoreceptor antagonists have a very sound safety profile, they appear as attractive drugs to reduce liver fibrogenesis.
Dubuisson
Liliane
L
Groupe de Recherches pour l'Etude du Foie, INSERM E9917, Université Victor Segalen Bordeaux 2, Bordeaux, France.
Desmoulière
Alexis
A
Decourt
Boris
B
Evadé
Laetitia
L
Bedin
Christiane
C
Boussarie
Liliane
L
Barrier
Laurence
L
Vidaud
Michel
M
Rosenbaum
Jean
J
D018663:Adrenergic Agents / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D016627:Oxidopamine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics
D018663:Adrenergic Agents; D000317:Adrenergic alpha-Antagonists; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016627:Oxidopamine; D002251:Carbon Tetrachloride; D009638:Norepinephrine; D011224:Prazosin