Effect of celecoxib on experimental liver fibrosis in rat.
OBJECTIVE
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.
Hui
Alex Yui
AY
Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
Leung
Wai Keung
WK
Chan
Henry Lik Yuen
HL
Chan
Francis Ka Leung
FK
Go
Minnie Yin Yin
MY
Chan
Ka Kui
KK
Tang
Bao Dong
BD
Chu
Eagle Siu Hong
ES
Sung
Joseph Jao Yiu
JJ
D000818:Animals; D001707:Biopsy, Needle; D000068579:Celecoxib; D055513:Connective Tissue Growth Factor; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D017874:Immediate-Early Proteins / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000473:pathology*; D008111:Liver Function Tests; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism; D011336:Probability; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000494:pharmacology*
C526316:CCN2 protein, rat; D052246:Cyclooxygenase 2 Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D055513:Connective Tissue Growth Factor; D051546:Cyclooxygenase 2; D020782:Matrix Metalloproteinases; D000068579:Celecoxib