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Published on: February 10, 2015
Effect of celecoxib on experimental liver fibrosis in rat
Alex Yui Hui1, Wai Keung Leung, Henry Lik Yuen Chan
1Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
Background/Aim:
Cyclooxygenase-2 (COX-2), an inducible enzyme that catalyzes prostaglandin synthesis, has been implicated in a number of hepatic stellate cell (HSC) functions. In the current study, we assessed the in vivo effect of celecoxib, a COX-2-selective inhibitor, in experimental liver fibrosis in rats.
Methods:
Male Sprague-Dawley rats received experimental treatments for 5 weeks. Serum alanine transminase at the time of sacrifice was measured. Quantitative assessment of liver fibrosis was performed by computerized morphometry. Expression of COX-2, alpha smooth muscle actin and connective tissue growth factor (CTGF) was evaluated by immunohistochemistry. Real-time quantitative PCR was used to determine the expression of genes associated with fibrogenesis and extracellular matrix degradation.
Results:
Liver fibrosis was significantly worse in rats that received both carbon tetrachloride (CCl4) and celecoxib, compared with rats that received CCl4 and gavage of water (P = 0.037). There was also more HSC activation, and upregulation of collagen alpha1(I), heat-shock protein 47, alphaB crystallin, matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitor of MMP (TIMP)-2. The expression of TIMP-1 and CTGF was not significantly different between the two groups. The pro-fibrogenic effect of celecoxib in toxin-induced liver fibrosis in rats was further confirmed in thioacetamide model of liver injury.
Conclusions:
Celecoxib potentiates experimental liver fibrosis; further studies are warranted to investigate the potential pro-fibrogenic effect of celecoxib in other animal models of liver fibrosis and in patients with chronic hepatitis.
Insights
Celecoxib, a COX-2 inhibitor, worsened liver fibrosis in rats by increasing HSC activation and collagen. This suggests celecoxib may promote liver fibrosis, warranting further investigation in chronic hepatitis patients.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Cyclooxygenase-2 (COX-2) plays a role in hepatic stellate cell (HSC) functions.
- COX-2 selective inhibitors, like celecoxib, are used clinically.
- The effect of COX-2 inhibition on liver fibrosis is not fully understood.
Purpose of the Study:
- To investigate the in vivo effect of celecoxib on experimental liver fibrosis in rats.
- To assess the impact of celecoxib on HSC activation and fibrogenesis markers.
Main Methods:
- Rats were treated with carbon tetrachloride (CCl4) or thioacetamide to induce liver fibrosis.
- Celecoxib or vehicle was administered concurrently.
- Liver fibrosis was quantified using computerized morphometry.
- Expression of fibrogenic genes and proteins was analyzed via immunohistochemistry and qPCR.
Main Results:
- Celecoxib significantly exacerbated liver fibrosis in the CCl4 model.
- Increased HSC activation and upregulation of collagen alpha1(I), HSP47, alphaB crystallin, MMP-2, MMP-9, and TIMP-2 were observed with celecoxib treatment.
- The pro-fibrogenic effect was confirmed in the thioacetamide-induced liver injury model.
Conclusions:
- Celecoxib potentiates experimental liver fibrosis in rats.
- Further research is needed to explore the pro-fibrogenic potential of celecoxib in other models and in patients with chronic hepatitis.
