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

 Y-H Paik  ;  J K Kim  ;  J I Lee  ;  S H Kang  ;  D Y Kim  ;  S H An  ;  S J Lee  ;  D K Lee  ;  K-H Han  ;  C Y Chon  ;  S I Lee  ;  K S Lee  ;  D A Brenner 
 GUT, Vol.58(11) : 1517-1527, 2009 
Journal Title
Issue Date
Animals ; Apoptosis/drug effects* ; Celecoxib ; Cells, Cultured ; Cyclooxygenase Inhibitors/administration & dosage* ; Hepatic Stellate Cells/drug effects* ; Hepatic Stellate Cells/physiology ; Humans ; Liver Cirrhosis, Experimental/prevention & control* ; Male ; Pyrazoles/administration & dosage* ; Rats ; Sulfonamides/administration & dosage*
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 (> or =50 microM) induced HSC apoptosis. All COX inhibitors completely inhibited prostaglandin E(2) (PGE(2)) and PGI(2) production in HSCs. Separately, PGE(2) and PGI(2) 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 PPARgamma (peroxisome proliferator-activated receptor gamma) 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 alpha-SMA (alpha-smooth muscle actin) expression in BDL- and TAA-treated rats. Celecoxib treatment significantly decreased mRNA expression of COX-2, alpha-SMA, transforming growth factor beta1 (TGFbeta1) and collagen alpha1(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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Kim, Ja Kyung(김자경) ORCID logo https://orcid.org/0000-0001-5025-6846
Paik, Yong Han(백용한)
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Lee, Kwan Sik(이관식) ORCID logo https://orcid.org/0000-0002-3672-1198
Lee, Dong Ki(이동기) ORCID logo https://orcid.org/0000-0002-0048-9112
Lee, Se Joon(이세준) ORCID logo https://orcid.org/0000-0002-2695-2670
Chon, Chae Yoon(전재윤)
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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