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Gut 58:1517-1527 doi:10.1136/gut.2008.157420
  • Hepatology

Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats

  1. Y-H Paik1,
  2. J K Kim1,
  3. J I Lee2,
  4. S H Kang1,
  5. D Y Kim1,
  6. S H An1,
  7. S J Lee1,
  8. D K Lee1,
  9. K-H Han1,
  10. C Y Chon1,
  11. S I Lee1,
  12. K S Lee1,
  13. D A Brenner3
  1. 1
    Department of Internal Medicine, Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, Korea
  2. 2
    Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
  3. 3
    Department of Medicine, University of California, San Diego, California, USA
  1. Correspondence to Professor K S Lee, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 146-92 Dogok-Dong, Gangnam-Gu, Seoul, Korea (135-720); leeks519{at}yuhs.ac
  • Revised 20 November 2008
  • Accepted 17 December 2008
  • Published Online First 6 February 2009

Abstract

Background and aims: Activated hepatic stellate cells (HSCs) but not quiescent HSCs express cyclo-oxygenase-2 (COX-2), suggesting that the COX-2/prostanoid pathway has an active role in hepatic fibrogenesis. However, the role of COX-2 inhibitors in hepatic fibrogenesis remains controversial. The aim of this study was to investigate the antifibrotic effects of celecoxib, a selective COX-2 inhibitor.

Methods: The effects of various COX inhibitors—that is, ibuprofen, celecoxib, NS-398 and DFU, were investigated in activated human HSCs. Then, the antifibrotic effect of celecoxib was evaluated in hepatic fibrosis developed by bile duct ligation (BDL) or peritoneal thioacetamide (TAA) injection in rats.

Results: Celecoxib, NS-398 and DFU inhibited platelet-derived growth facor (PDGF)-induced HSC proliferation; however, only celecoxib (⩾50 μM) induced HSC apoptosis. All COX inhibitors completely inhibited prostaglandin E2 (PGE2) and PGI2 production in HSCs. Separately, PGE2 and PGI2 induced cell proliferation and extracellular signal-regulated kinase (ERK) activation in HSCs. All COX inhibitors attenuated ERK activation, but only celecoxib significantly inhibited Akt activation in HSCs. Celecoxib-induced apoptosis was significantly attenuated in HSCs infected with adenovirus containing a constitutive active form of Akt (Ad5myrAkt). Celecoxib had no significant effect on PPARγ (peroxisome proliferator-activated receptor γ) expression in HSCs. Celecoxib inhibited type I collagen mRNA and protein production in HSCs. Oral administration of celecoxib (20 mg/kg/day) significantly decreased hepatic collagen deposition and α-SMA (α-smooth muscle actin) expression in BDL- and TAA-treated rats. Celecoxib treatment significantly decreased mRNA expression of COX-2, α-SMA, transforming growth factor β1 (TGFβ1) and collagen α1(I) in both models.

Conclusions: Celecoxib shows a proapoptotic effect on HSCs through Akt inactivation and shows antifibrogenic effects in BDL- and TAA-treated rats, suggesting celecoxib as a novel antifibrotic agent of hepatic fibrosis.

Footnotes

  • Funding This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (No. A050021) (to K-HH) and by a grant from Yonsei University College of Medicine (6-2005-0035) (to Y-HP).

  • Competing interests None.

  • Provenance and Peer review Not commissioned; externally peer reviewed.

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