Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial-to-mesenchymal transition of hepatocytes

• Published in: Journal of gastroenterology and hepatology Vol. 29; no. 11; pp. 1932 - 1942
• Main Authors: Wen, Shi-Lei, Gao, Jin-Hang, Yang, Wen-Juan, Lu, Yao-Yao, Tong, Huan, Huang, Zhi-Yin, Liu, Zhang-Xu, Tang, Cheng-Wei
• Format: Journal Article
• Language: English
• Published: Australia Blackwell Publishing Ltd 01.11.2014
• Subjects: Animals; Celecoxib; cirrhosis; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase 2 Inhibitors - therapeutic use; Disease Models, Animal; Down-Regulation - drug effects; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; epithelial-to-mesenchymal transition; hepatic fibrosis; hepatocyte; Hepatocytes - physiology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver Cirrhosis, Experimental; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Thioacetamide; Transforming Growth Factor beta1; hepatocyte; hepatic fibrosis; celecoxib; cirrhosis; epithelial-to-mesenchymal transition
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.12641

Background and Aim The epithelial–mesenchymal transition (EMT) of hepatocytes is a key step for hepatic fibrosis and cirrhosis. Long‐term administration of celecoxib, a selective cyclooxygenase‐2 (COX‐2) inhibitor, can ameliorate hepatic fibrosis. This research aimed to examine the effect of celecoxib on the EMT of hepatocytes during the development of liver cirrhosis. Methods Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). Thirty‐six rats were randomly assigned to control, TAA, and TAA + celecoxib groups. Hepatic expressions of tumor necrosis factor‐α (TNF‐α), interleukin 6 (IL‐6), COX‐2, prostaglandin E2 (PGE2), matrix metalloproteinase (MMP)‐2 and ‐9, transforming growth factor‐β1 (TGF‐β1), Phospho‐Smad2/3, Snail1, α‐smooth muscle actin (α‐SMA), vimentin, collagen I, fibroblast‐specific protein (FSP‐1), E‐cadherin and N‐cadherin were quantitated. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and Ishak's scoring system. Results Exposed to TAA treatment, hepatocytes underwent the process of EMT during hepatic fibrosis. Compared with those in TAA group, celecoxib significantly downregulated the hepatic expressions of TNF‐α, IL‐6, COX‐2, PGE2, MMP‐2, MMP‐9, TGF‐β1, Phospho‐Smad2/3, Snail1, α‐SMA, FSP‐1, and vimentin while greatly restoring the levels of E‐cadherin. The fibrotic areas and collagen I levels of TAA + celecoxib group were much lower than those in TAA group. Conclusions Celecoxib could ameliorate hepatic fibrosis and cirrhosis in TAA‐rat model through suppression of the mesenchymal biomarkers in the hepatocytes while restoring the levels of their epithelial biomarkers. The inhibitory effect of celecoxib on the EMT of hepatocytes is associated with reduction of intrahepatic inflammation, preservation of normal basement matrix, and inhibition of TGF‐β1/Smad pathway.