Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-beta with a combination of imatinib mesylate and ACE inhibitor in rats.
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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Noguchi
Ryuichi
R
Ikenaka
Yasuhide
Y
Yoshii
Junichi
J
Yanase
Koji
K
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yamazaki
Masaharu
M
Asada
Kiyoshi
K
Akahane
Takemi
T
Tsujimoto
Tatsuhiro
T
Uemura
Masahito
M
Fukui
Hiroshi
H
D000199:Actins / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides; D002251:Carbon Tetrachloride; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009130:Muscle, Smooth / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D002251:Carbon Tetrachloride; D017479:Receptors, Platelet-Derived Growth Factor