title: Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure.
abstract: OBJECTIVE
  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-alpha (TNF-alpha, an index of liver injury) and 6-keto-PGF(1alpha) (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-alpha (indomethacin vs N/S: 22+/-5 vs 10+/-1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1alpha (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, China.
authors.forename: Chi-Jen
authors.initials: CJ
authors.lastname: Chu
authors.forename: Ching-Chin
authors.initials: CC
authors.lastname: Hsiao
authors.forename: Teh-Fang
authors.initials: TF
authors.lastname: Wang
authors.forename: Cho-Yu
authors.initials: CY
authors.lastname: Chan
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.forename: Full-Young
authors.initials: FY
authors.lastname: Chang
authors.forename: Yi-Chou
authors.initials: YC
authors.lastname: Chen
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.forename: Sun-Sang
authors.initials: SS
authors.lastname: Wang
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D007213:Indomethacin / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D044062:Prostaglandins I / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D044062:Prostaglandins I; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D015121:6-Ketoprostaglandin F1 alpha; D003404:Creatinine; D001663:Bilirubin; D007213:Indomethacin