title: JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1.
abstract: 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.
authors.affiliation: 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
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Motoi
authors.initials: M
authors.lastname: Kondo
authors.forename: Shoji
authors.initials: S
authors.lastname: Nakamori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Wakasa
authors.forename: Yurika
authors.initials: Y
authors.lastname: Sugita
authors.forename: Jin
authors.initials: J
authors.lastname: Chang-De
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Bazarragchaa
authors.initials: B
authors.lastname: Damdinsuren
authors.forename: Keizo
authors.initials: K
authors.lastname: Dono
authors.forename: Koji
authors.initials: K
authors.lastname: Umeshita
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Sekimoto
authors.forename: Masato
authors.initials: M
authors.lastname: Sakon
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.forename: Morito
authors.initials: M
authors.lastname: Monden
mesh_terms: 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
chemical_list: 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