Published online Jul 28, 2020. doi: 10.3748/wjg.v26.i28.4094
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
Liver fibrosis is a significant sign of chronic liver diseases, which could be treated and even reversed in the early stage. Inhibition of hepatocyte apoptosis is an important cause of reversal of liver fibrosis. Endoplasmic reticulum (ER) stress-mediated apoptosis is one of the important mechanisms of liver fibrosis. The cyclooxygenase-2 inhibitor celecoxib can improve the thioacetamide (TAA)-induced liver fibrosis in rats, and thus reverse the development of liver fibrosis. Whether celecoxib can inhibit apoptosis by inhibiting ER stress and further reverse liver fibrosis remains to be further studied.
Celecoxib has been widely used in the clinical treatment of rheumatoid arthritis and osteoarthritis. However, whether celecoxib can suppress apoptosis by inhibiting ER stress and further reverse liver fibrosis remains to be further studied.
This study aimed to explore the important role of celecoxib in modulating hepatocyte apoptosis during the development of liver fibrosis, and to clarify whether its regulatory mechanism is mediated by ER stress.
Cirrhosis was induced by intraperitoneal injections of thioacetamide (TAA) for 16 wk (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: control, TAA, and TAA + celecoxib groups. 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.
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 was 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).
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.
Our results indicate that celecoxib may play a role in inhibiting ER stress in rat liver fibrosis by inhibiting the expression of CHOP in the ER stress signaling pathway. Our data provide a new target for the treatment of liver fibrosis.