Paik Y-H, Kim J K, Lee J I, Kang S H, Kim D Y, An S H, Lee S J, Lee D K, Han K-H, Chon C Y, Lee S I, Lee K S, Brenner D A
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 135-720, Korea.
Gut. 2009 Nov;58(11):1517-27. doi: 10.1136/gut.2008.157420. Epub 2009 Feb 6.
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.
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.
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.
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.
活化的肝星状细胞（HSCs）而非静止的HSCs表达环氧化酶-2（COX-2），这表明COX-2/前列腺素途径在肝纤维化形成过程中发挥着积极作用。然而，COX-2抑制剂在肝纤维化形成中的作用仍存在争议。本研究的目的是探讨选择性COX-2抑制剂塞来昔布的抗纤维化作用。
研究了多种COX抑制剂，即布洛芬、塞来昔布、NS-398和DFU对活化的人HSCs的作用。然后，在胆管结扎（BDL）或腹腔注射硫代乙酰胺（TAA）诱导的大鼠肝纤维化模型中评估塞来昔布的抗纤维化作用。
塞来昔布、NS-398和DFU抑制血小板衍生生长因子（PDGF）诱导的HSC增殖；然而，只有塞来昔布（≥50μM）诱导HSC凋亡。所有COX抑制剂均完全抑制HSCs中前列腺素E2（PGE2）和前列环素（PGI2）的产生。另外，PGE2和PGI2诱导HSCs细胞增殖和细胞外信号调节激酶（ERK）激活。所有COX抑制剂均减弱ERK激活，但只有塞来昔布显著抑制HSCs中Akt激活。在感染含有组成型活性形式Akt的腺病毒（Ad5myrAkt）的HSCs中，塞来昔布诱导的凋亡显著减弱。塞来昔布对HSCs中过氧化物酶体增殖物激活受体γ（PPARγ）的表达无显著影响。塞来昔布抑制HSCs中I型胶原mRNA和蛋白的产生。口服塞来昔布（20mg/kg/天）显著降低BDL和TAA处理大鼠的肝胶原沉积和α-平滑肌肌动蛋白（α-SMA）表达。在两种模型中，塞来昔布治疗均显著降低COX-2、α-SMA、转化生长因子β1（TGFβ1）和胶原α1（I）的mRNA表达。
塞来昔布通过Akt失活对HSCs显示促凋亡作用，并在BDL和TAA处理的大鼠中显示抗纤维化作用，提示塞来昔布是一种新型的肝纤维化抗纤维化药物。
