Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2020; 26(28): 4094-4107
Published online Jul 28, 2020. doi: 10.3748/wjg.v26.i28.4094
Celecoxib attenuates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced cirrhotic rats
Wei Su, Yang Tai, Shi-Hang Tang, Yan-Ting Ye, Chong Zhao, Jin-Hang Gao, Bi-Guang Tuo, Cheng-Wei Tang
Wei Su, Cheng-Wei Tang, Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Wei Su, Bi-Guang Tuo, Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563003, Guizhou Province, China
Yang Tai, Shi-Hang Tang, Yan-Ting Ye, Chong Zhao, Jin-Hang Gao, Cheng-Wei Tang, Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Tang CW and Gao JH designed and coordinated the study; Su W, Tai Y, Tang SH, Ye YT, and Zhao C performed the experiments and acquired and analyzed the data; Su W and Tang CW interpreted the data; Tuo BG provide technical assistance; Su W wrote the manuscript; Tang CW reviewed the manuscript, all authors approved the final version of the article.
Supported by the National Natural Science Fund of China, No. U1702281, No. 81670551, and No. 81873584.
Institutional animal care and use committee statement: The animal procedures were approved by the Animal Use and Care Committee of Sichuan University and were conducted according to regulations formulated by Sichuan University (Licence No. 2017005A).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this manuscript.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Cheng-Wei Tang, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu 610041, Sichuan Province, China. shcqcdmed@163.com
Received: January 30, 2020
Peer-review started: January 30, 2020
First decision: April 22, 2020
Revised: May 21, 2020
Accepted: June 25, 2020
Article in press: June 25, 2020
Published online: July 28, 2020
Processing time: 180 Days and 1 Hours
Abstract
BACKGROUND

Endoplasmic reticulum (ER) stress is an important mechanism in the progression of chronic and acute liver diseases, especially in the progression and recovery of liver fibrosis. Excessive and long-term ER stress induces apoptosis. ER stress-induced apoptosis is considered to be an important pathway in the development of liver fibrosis. Cyclooxygenase-2 (COX-2) induction is also closely related to ER stress. In our previous studies, we showed that celecoxib, a COX-2 inhibitor, improves liver fibrosis and portal hypertension. However, the role and mechanism of celecoxib in alleviating liver fibrosis remain unclear.

AIM

To investigate whether celecoxib alleviates liver fibrosis by inhibiting hepatocyte apoptosis via the ER stress response.

METHODS

Cirrhosis was induced by intraperitoneal injections of thioacetamide (TAA) for 16 wk (injection dose is 200 mg/kg per 3 d for the first 8 wk and 100 mg /kg per 3 d after 8 wk). Thirty-six male Sprague-Dawley rats were randomly divided into three groups, namely, control group, TAA group, and TAA + celecoxib group. In the last 8 wk, TAA-induced cirrhotic rats received celecoxib (20 mg/kg/day) or the vehicle by gastric gavage. After 16 wk, the rats were sacrificed, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) were detected. The hepatic fibrosis areas were evaluated by Sirius red staining and the degree of fibrosis was assessed by measuring the level of hydroxyproline. ER stress levels were evaluated by detecting the marker proteins glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP), PKR-like ER protein kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1α). Apoptosis levels were evaluated by detecting caspase-12 and caspase-3.

RESULTS

The serum ALT and AST levels in the liver were significantly reduced by celecoxib; however, the serum ALB had no significant changes. Celecoxib significantly reduced the degree of liver fibrosis and the levels of hydroxyproline (-38% and -25.7%, respectively, P < 0.01). Celecoxib ameliorated ER stress by reducing the level of GRP78 compared to the TAA group (P < 0.05). Consistently, after celecoxib administration, the upregulation of TAA-induced hepatic apoptosis markers (caspase-12 and caspase-3) and CHOP were significantly inhibited. In addition, after celecoxib treatment, the expression of key molecules associated with ER stress (PERK, ATF6, and IRE1) was decreased (P < 0.05).

CONCLUSION

Therapeutic administration of celecoxib effectively reduces hepatic apoptosis in TAA-induced cirrhotic rats. The mechanism of action may be attributed to the suppression of CHOP expression, which subsequently inhibits ER stress.

Keywords: Liver fibrosis; Endoplasmic reticulum stress; Celecoxib; Cyclooxygenase-2; CCAAT/enhancer binding protein homologous protein; Apoptosis

Core tip: This study aimed to explore the important role of celecoxib in modulating hepatocyte apoptosis during the development of liver fibrosis, and to clarify that the mechanism of its regulation is mediated by endoplasmic reticulum stress, which in turn affects the progression of liver fibrosis. We concluded that therapeutic administration of celecoxib can effectively reduce hepatic apoptosis in thioacetamide-induced cirrhotic rats. The mechanism of action may be attributed to the suppression of CCAAT/enhancer binding protein homologous protein expression, which subsequently inhibits endoplasmic reticulum stress.