Celecoxib attenuates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced cirrhotic rats

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.

Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis

“…However, NLRP3 inflammasome-derived IL-1β secretion and pyroptosis in macrophages and collagens deposition were blocked by pharmaceutical inhibition or genetic knockdown of COX-2 ( 84 ). Consistently, COX-2 promotes the development of liver cirrhosis ( 85 ) by inducing ROS ( 86 , 87 ) and ER stress ( 88 ), indicating that COX-2 might contribute to liver cirrhosis via macrophage-derived inflammasomes. However, further studies are needed to determine how COX-2 regulates the activation of macrophage-derived inflammasomes and pyroptosis of macrophages in the context of liver fibrosis.…”

Mechanistic Insights into Ameliorating Effect of Geraniol on d-Galactose Induced Memory Impairment in Rats

“…The latter activates the RNase to induce the splicing of X-box binding protein 1 (XBP1), a critical ER stress sensor, which triggers pro-apoptotic signaling pathway [ 38 ]. Moreover, PERK phosphorylates the eukaryotic initiation factor eIF2α, conducting apoptosis by activating CHOP which is the main determinant of cell fate and ER stress-induced apoptosis [ 39 ].…”

Novel Anti-inflammatory Treatments in Cirrhosis. A Literature-Based Study

“…Celecoxib (25)(26)(27)(28)(29)67), aspirin (30,31), etanercept (32), curcumin (33)(34)(35)(36)(37)(38)(39), kahweol (40,41), pentoxifylline (42,68), diosmin (42)(43)(44), glycyrrhizin arginine salt (45), statins (18,19,(46)(47)(48)(49)(50), emricasan (20-22, 51, 69) and lanifibranor (52) and formayl receptor 2 agonist-WKYMVm (53).…”

“…COX-2, an enzyme expressed due to inflammation, is increased in inflammatory, vascular endothelial lining, and expressed by Kupffer cells in the cirrhotic liver (72,73). Celecoxib has anti-inflammatory effects to relieve cirrhosis complications and reduce portal hypertension in several rat studies (25)(26)(27)(28)(29)67) (Supplementary Table 3a). Celecoxib was administered to prevent cirrhosis in experimental animal models where cirrhosis was induced by peritoneal injections of thioacetamide (TAA).…”