title: [Hyperammonemia-induced hepatic injury in rats: characterization of a new animal model].
abstract: OBJECTIVE
  To establish an accurate new rat model of hyperammonemia-induced liver injury for use in studies of the molecular mechanisms underlying acute liver failure (ALF).
  
  
  METHODS
  Twenty-six Sprague-Dawley rats were administered D-galactosamine (400 mg/kg) and endotoxin (50 mug/kg) via intraperitoneal injection to induce ALF and sacrificed at 12 h post-injection (ALF-12 group, n = 10) or 24 h post-injection (ALF-24 group, n = 16). Ten rats administered physiological saline served as the control group. In addition, 20 rats were given serial oral administrations of 10% NH4Cl solution (10 ml/kg, every 8 hrs) to establish the hyperammonemia-induced liver injury model; an additional 20 rats were prepared in parallel to serve as the ALF control group (n = 10; D-galactosamine at 800 mg/kg every 6 d for 30 days) and the physiological saline control group (n = 10). Serum samples were collected from each mouse and used to detect markers of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alpha-fetal protein (AFP), and gamma-glutamyltransferase (GGT), as well as blood ammonia (BA) level and prothrombin time activity (PT-A). Affects on liver histology was assessed by hematoxylin and eosin staining of resected liver tissues, and on apoptosis by TUNEL assay and calculating the apoptotic index (AI).
  
  
  RESULTS
  ALF rats showed elevated levels of ALT (1202.51+/-282.00 U/L), AST (1560.14+/-298.98 U/L), and BA (165.9+/-23.6 mumol/L) as early as 6 hrs after model establishment; these levels peaked at 12 hrs after model establishment (ALT: 774.40+/-207.65 U/L; AST: 967.60+/-121.94 U/L; BA: 143.4+/-18.1 mumol/L; P less than 0.05). No significant variations were detected in the levels of AFP (except for the ALF-24 group) or GGT. Liver tissues of the ALF-12 and ALF-24 groups showed large or diffuse hemorrhagic necroses with sinusoidal congestion or spotty bleeding, as well as increased AI. Hyperammonemia-induced liver injury rats showed elevated levels of ALT and BA as early as 6 hrs after model establishment. Similar to the ALF rats, AFP and GGT were unaffected and AI increased. However, in contrast to the ALF rats, the liver tissues of the hyperammonemia-induced liver injury rats showed no signs of hepatocyte swelling, necrosis, or inflammatory cell invasion.
  
  
  CONCLUSIONS
  ALF rats and hyperammonemia-induced liver injury rats have elevated BA and marked hepatocyte necrosis. Given that reducing the level of ammonemia can improve the animal's biochemistry indexes, it is likely that hyperammonemia plays a role in acute liver injury or ALF consequent to repeated injury. The pathogenic mechanisms of repeated injury may involve promotion of hepatocyte apoptosis in conjunction with inhibition of cellular regeneration.
authors.affiliation: Department of Infectious Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Zu-jiang
authors.initials: ZJ
authors.lastname: Yu
authors.forename: Ran
authors.initials: R
authors.lastname: Sun
authors.forename: Xiao-rui
authors.initials: XR
authors.lastname: Liu
authors.forename: Jing-ya
authors.initials: JY
authors.lastname: Yan
authors.forename: Xiao-juan
authors.initials: XJ
authors.lastname: Gao
authors.forename: Bin
authors.initials: B
authors.lastname: Jia
authors.forename: Quan-Cheng
authors.initials: QC
authors.lastname: Kan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D022124:Hyperammonemia / Q000150:complications*; D017114:Liver Failure, Acute / Q000209:etiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley