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, doyoung kim, SangHoon Ahn, S. J. Lee, DongKi Lee, KwangHyub Han, C. Y. Chon, S. I. Lee, K. S. Lee, D. A. Brenner

Research output: Contribution to journalArticle

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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 plateletderived 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.

Original languageEnglish
Pages (from-to)1517-1527
Number of pages11
JournalGut
Volume58
Issue number11
DOIs
Publication statusPublished - 2009 Nov 1

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Celecoxib
Hepatic Stellate Cells
Fibrosis
Apoptosis
Liver
Thioacetamide
Prostaglandin-Endoperoxide Synthases
Bile Ducts
Ligation
Cyclooxygenase Inhibitors
Extracellular Signal-Regulated MAP Kinases
Epoprostenol
Dinoprostone
Collagen
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Paik, Y. H. ; Kim, J. K. ; Lee, J. I. ; Kang, S. H. ; kim, doyoung ; Ahn, SangHoon ; Lee, S. J. ; Lee, DongKi ; Han, KwangHyub ; Chon, C. Y. ; Lee, S. I. ; Lee, K. S. ; Brenner, D. A. / Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats. In: Gut. 2009 ; Vol. 58, No. 11. pp. 1517-1527.
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title = "Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats",
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 plateletderived 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.",
author = "Paik, {Y. H.} and Kim, {J. K.} and Lee, {J. I.} and Kang, {S. H.} and doyoung kim and SangHoon Ahn and Lee, {S. J.} and DongKi Lee and KwangHyub Han and Chon, {C. Y.} and Lee, {S. I.} and Lee, {K. S.} and Brenner, {D. A.}",
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Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats. / Paik, Y. H.; Kim, J. K.; Lee, J. I.; Kang, S. H.; kim, doyoung; Ahn, SangHoon; Lee, S. J.; Lee, DongKi; Han, KwangHyub; Chon, C. Y.; Lee, S. I.; Lee, K. S.; Brenner, D. A.

In: Gut, Vol. 58, No. 11, 01.11.2009, p. 1517-1527.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats

AU - Paik, Y. H.

AU - Kim, J. K.

AU - Lee, J. I.

AU - Kang, S. H.

AU - kim, doyoung

AU - Ahn, SangHoon

AU - Lee, S. J.

AU - Lee, DongKi

AU - Han, KwangHyub

AU - Chon, C. Y.

AU - Lee, S. I.

AU - Lee, K. S.

AU - Brenner, D. A.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - 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 plateletderived 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.

AB - 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 plateletderived 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.

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