JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1.
OBJECTIVE
The aim of this study was to assess the effects of cyclooxygenase (COX)-2 inhibition on rat experimental liver fibrogenesis.


METHODS
We investigated the inhibitory effects of a selective COX-2 inhibitor, JTE-522, on liver fibrosis induced by a choline-deficient, l-amino acid-defined diet (CDAA). Inhibitory effect was also tested in a second model of thioacetamide (TAA)-induced liver fibrosis.


RESULTS
CDAA induced liver fibrosis and preneoplastic foci at 12 weeks and cirrhosis at 36 weeks. Hepatocellular carcinoma was noted in 13 of 15 rats (87%). JTE-522 significantly inhibited fibrosis and development of preneoplastic lesions in a dose-dependent manner and completely inhibited generation of cirrhosis and hepatocellular carcinoma at both low and high doses (10 and 30 mg/kg body wt/day, respectively). JTE-522 administrated only from 12 weeks to 36 weeks also prevented cirrhosis and formation of hepatocellular carcinoma. JTE-522 itself did not cause local or systemic gross or histopathologic changes at 36 weeks. Mechanistic studies indicated that the CDAA model displayed up-regulation of several biomarkers, including COX-2, arachidonate metabolite (prostaglandin E(2)), serum aspartate aminotransferase, and c-myc expression. The model also showed an increased proportion of activated hepatic stellate cells, proliferating cell nuclear antigen index, and CD45-positive inflammatory cells in the liver. JTE-522 effectively diminished these changes. JTE-522 exhibited similar antifibrosis effects in the TAA model.


CONCLUSIONS
Our results suggest that COX-2 is involved in CDAA- and TAA-induced liver fibrosis. Our data also indicate that JTE-522 is a potent chemopreventive agent of rat liver fibrosis with low toxicity.
Yamamoto
Hirofumi
H
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita-City, Osaka 565-0871, Japan. kobunyam@surg2.med.osaka-u.ac.jp
Kondo
Motoi
M
Nakamori
Shoji
S
Nagano
Hiroaki
H
Wakasa
Ken-Ichi
K
Sugita
Yurika
Y
Chang-De
Jin
J
Kobayashi
Shogo
S
Damdinsuren
Bazarragchaa
B
Dono
Keizo
K
Umeshita
Koji
K
Sekimoto
Mitsugu
M
Sakon
Masato
M
Matsuura
Nariaki
N
Monden
Morito
M
D000199:Actins / Q000032:analysis; D000818:Animals; D001557:Benzenesulfonates / Q000627:therapeutic use*; D001835:Body Weight; D002796:Choline Deficiency / Q000150:complications; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D004249:DNA Damage; D016259:Genes, myc; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000502:physiology; D008099:Liver / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D008297:Male; D010080:Oxazoles / Q000627:therapeutic use*; D011230:Precancerous Conditions / Q000209:etiology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D000096926:Benzenesulfonamides
D000199:Actins; D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D010080:Oxazoles; D018809:Proliferating Cell Nuclear Antigen; D011451:Prostaglandin-Endoperoxide Synthases; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides