Basic Research
Copyright ©2005 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jan 14, 2005; 11(2): 232-236
Published online Jan 14, 2005. doi: 10.3748/wjg.v11.i2.232
Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure
Chi-Jen Chu, Ching-Chin Hsiao, Teh-Fang Wang, Cho-Yu Chan, Fa-Yauh Lee, Full-Young Chang, Yi-Chou Chen, Hui-Chun Huang, Sun-Sang Wang, Shou-Dong Lee
Chi-Jen Chu, Ching-Chin Hsiao, Fa-Yauh Lee, Full-Young Chang, Yi-Chou Chen, Hui-Chun Huang, Shou-Dong Lee, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, China
Teh-Fang Wang, Armed Forces Sungshan Hospital, Taipei, Taiwan, China
Cho-Yu Chan, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, China
Fa-Yauh Lee, Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, China
Sun-Sang Wang, Taipei Municipal Gan-Dau Hospital, Taipei, Taiwan, China
Chi-Jen Chu, Ching-Chin Hsiao, Cho-Yu Chan, Fa-Yauh Lee, Full-Young Chang, Hui-Chun Huang, Sun-Sang Wang, Shou-Dong Lee, National Yang-Ming University School of Medicine, Taipei, Taiwan, China
Author contributions: All authors contributed equally to the work.
Supported by the National Science Council of Taiwan (grant no. NSC 92-2314-B-075-036) and Taipei Veterans General Hospital (VGH-93-212)
Correspondence to: Dr. Fa-Yauh Lee, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, China. fylee@vghtpe.gov.tw
Telephone: +886-2-28757308 Fax: +886-2-28739318
Received: March 9, 2004
Revised: March 12, 2004
Accepted: April 9, 2004
Published online: January 14, 2005
Abstract

AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure.

METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg.d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg.d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α (TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay.

RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs 5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438±102 vs 841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-α (indomethacin vs N/S: 22±5 vs 10±1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S.

CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant hepatic failure.

Keywords: Hepatic Encephalopathy; Fulminant hepatic failure; Prostacyclin; Indomethacin