Celecoxib Does Not Protect against Fibrosis and Inflammation in a Carbon Tetrachloride-Induced Model of Liver Injury

Abstract

The cyclooxygenase-2 (COX-2) selective inhibitor celecoxib is widely used in the treatment of pain and inflammation. Celecoxib has been explored as a possible treatment of liver fibrosis with contradictory results, depending on the model. The present study reports the effect of celecoxib in a 5-week carbon tetrachloride (CCl₄)-induced liver fibrosis mouse model. Celecoxib alone and in combination with inhibitors of the enzyme-soluble epoxide hydrolase (sEH), as well as a dual inhibitor that targets both COX-2 and sEH, were administered via osmotic minipump to mice receiving intraperitoneal injections of CCl₄ Collagen deposition was elevated in the mice treated with both celecoxib and CCl₄ compared with the control or CCl₄-only groups, as assessed by trichrome staining. Histopathology revealed more extensive fibrosis and cell death in the animals treated with both celecoxib and CCl₄ compared with all other experimental groups. Although some markers of fibrosis, such as matrix metalloprotease, were unchanged or lowered in the animals treated with both celecoxib and CCl₄, overall, hepatic fibrosis was more severe in this group. Cotreatment with celecoxib and an inhibitor of sEH or treatment with a dual inhibitor of COX-2 and sEH decreased the elevated levels of fibrotic markers observed in the group that received both celecoxib and CCl₄ Oxylipid analysis revealed that celecoxib reduced the level of prostaglandin E₂ relative to the CCl₄ only group. Overall, celecoxib treatment did not decrease liver fibrosis in CCl₄-treated mice.