Abstract
Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are known to be pivotal cytokines in liver fibrosis development. The aim of our current study was to elucidate the effects of dual inhibition of PDGF and TGF-beta by combination of the clinically used imatinib mesylate (STI-571) and perindopril (an ACE-inhibitor; ACE-I), respectively, on ongoing liver fibrosis development in rats. The effects of STI-571 and ACE-I at clinically comparable low doses were examined in a rat model of CCl4-induced liver fibrogenesis. Treatment with both STI-571 and ACE-I inhibited liver fibrogenesis and suppressed activation of hepatic stellate cells (HSCs). Administration of both agents exerted a more potent inhibitory effect than administration of either single agent. Our in vitro study demonstrated that STI-571 and ACE-I suppressed PDGF receptor (PDGFR) phosphorylation and TGF-beta expression in activated HSCs, respectively. Dual suppression of PDGF and TGF-beta with a combination of clinically comparable low doses of STI-571 and ACE-I exerted a significant inhibitory effect on ongoing liver fibrosis development. Since both agents are widely used in clinical practice, this combination therapy may provide a new strategy against liver fibrosis in the future.
MeSH terms
-
Actins / analysis
-
Angiotensin-Converting Enzyme Inhibitors / administration & dosage
-
Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
-
Animals
-
Benzamides
-
Carbon Tetrachloride
-
Drug Synergism
-
Drug Therapy, Combination
-
Imatinib Mesylate
-
Immunohistochemistry
-
Liver / chemistry
-
Liver / drug effects
-
Liver / pathology
-
Liver Cirrhosis, Experimental / chemically induced
-
Liver Cirrhosis, Experimental / metabolism
-
Liver Cirrhosis, Experimental / prevention & control*
-
Male
-
Muscle, Smooth / chemistry
-
Phosphorylation / drug effects
-
Piperazines / administration & dosage
-
Piperazines / therapeutic use*
-
Platelet-Derived Growth Factor / antagonists & inhibitors
-
Platelet-Derived Growth Factor / metabolism*
-
Protein Kinase Inhibitors / administration & dosage
-
Protein Kinase Inhibitors / therapeutic use
-
Pyrimidines / administration & dosage
-
Pyrimidines / therapeutic use*
-
Rats
-
Rats, Inbred F344
-
Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
-
Receptors, Platelet-Derived Growth Factor / metabolism
-
Severity of Illness Index
-
Transforming Growth Factor beta / antagonists & inhibitors
-
Transforming Growth Factor beta / metabolism*
Substances
-
Actins
-
Angiotensin-Converting Enzyme Inhibitors
-
Benzamides
-
Piperazines
-
Platelet-Derived Growth Factor
-
Protein Kinase Inhibitors
-
Pyrimidines
-
Transforming Growth Factor beta
-
Imatinib Mesylate
-
Carbon Tetrachloride
-
Receptors, Platelet-Derived Growth Factor