The anti‐inflammatory effect of celecoxib does not prevent liver fibrosis in bile duct‐ligated rats

Yu, Jun; Hui, Alex; Chu, Ellie S.M.; Go, Minnie Y.Y.; Cheung, Kin F.; Wu, Chung Wah; Chan, Henry Lik‐Yuen; Sung, Joseph J.Y.

doi:10.1111/j.1478-3231.2008.01760.x

Cited by 27 publications

(27 citation statements)

References 37 publications

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“…In contrast to the results in this study, some studies arguing against the effects of celecoxib on anti-fibrosis have been reported [29], [30]. The experiment term of cirrhotic model used in Yu’s group was quite shorter than that in our study, 2 weeks vs. 16 weeks of TAA treatment.…”

Section: Discussioncontrasting

confidence: 94%

Celecoxib Ameliorates Portal Hypertension of the Cirrhotic Rats through the Dual Inhibitory Effects on the Intrahepatic Fibrosis and Angiogenesis

et al. 2013

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BackgroundIncreased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension.ObjectiveTo verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it.MethodsCirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated.ResultsCompared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1α (HIF-1α), and c-fos were also down-regulated after celecoxib treatment.ConclusionsLong term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1α- VEGF and p-ERK- c-fos- VEGFR-2.

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Section: Discussioncontrasting

confidence: 94%

Celecoxib Ameliorates Portal Hypertension of the Cirrhotic Rats through the Dual Inhibitory Effects on the Intrahepatic Fibrosis and Angiogenesis

et al. 2013

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“…The comparison may suggest that a chronic moderate inflammatory injury might be indicated for application of celecoxib for prevention or amelioration of hepatic fibrosis. Besides, other studies used rat models induced by bile duct ligation and porcine serum, which may interpret the discrepancies of the data among Yu's, Liu's 47,48 and our studies. In conclusion, our data demonstrate that celecoxib could ameliorate hepatic fibrosis and cirrhosis in TAA-rat model through intervention of multi-links during EMT process of hepatocytes, including reduction of intrahepatic inflammation via inhibition of COX-2 dependent way, downregulation of MMP-2 and MMP-9 in hepatocytes, and suppression of TGF-β1/Smads pathway.…”

Section: Discussioncontrasting

confidence: 64%

Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial‐to‐mesenchymal transition of hepatocytes

Wen

Gao

Yang

et al. 2014

J of Gastro and Hepatol

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Celecoxib could ameliorate hepatic fibrosis and cirrhosis in TAA-rat model through suppression of the mesenchymal biomarkers in the hepatocytes while restoring the levels of their epithelial biomarkers. The inhibitory effect of celecoxib on the EMT of hepatocytes is associated with reduction of intrahepatic inflammation, preservation of normal basement matrix, and inhibition of TGF-β1/Smad pathway.

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“…A leukotriene receptor antagonist, montelukast, attenuates liver damage and fibrosis in a bile duct ligation (BDL) and resection rat model (El-Swefy and Hassanen, 2009). A COX inhibitor, meloxicam, reduces fibrosis in this same model (Kim et al , 2008), although contradictory results have been reported using celecoxib (Yu et al , 2009). …”

Section: Introductionmentioning

confidence: 86%

Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

Harris

Bettaieb

Kodani

et al. 2015

Toxicology and Applied Pharmacology

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Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl4)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl4-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl4-treated group relative to the control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl4-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress.

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The anti‐inflammatory effect of celecoxib does not prevent liver fibrosis in bile duct‐ligated rats

Abstract: The present study provides morphological and molecular biological evidences for the role of celecoxib in cholestatic liver fibrosis. Celecoxib protects against hepatic inflammation in the early stage of BDL rats, but does not have an effect on liver fibrosis.

Cited by 27 publications

References 37 publications

Celecoxib Ameliorates Portal Hypertension of the Cirrhotic Rats through the Dual Inhibitory Effects on the Intrahepatic Fibrosis and Angiogenesis

Celecoxib Ameliorates Portal Hypertension of the Cirrhotic Rats through the Dual Inhibitory Effects on the Intrahepatic Fibrosis and Angiogenesis

Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial‐to‐mesenchymal transition of hepatocytes

Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

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