Walden, Lindsay B.

Background. Graft pretreatment to limit postoperative damage has the advantage of overcoming a current issue in liver transplantation (LT). The strategic potential of graft pretreatmentin vivoby a specific agonist forγ-aminobutyric acid receptor (GABAR) was investigated in the rat LT model with a small-for-size graft (SFSG).Methods. Recipient rats were divided into three groups according to donor treatments and recipient surgeries: (i) saline and laparotomy, (ii) saline and split orthotopic liver transplantation (SOLT) with 40%-SFSG, and (iii) GABAR agonist and SOLT with 40%-SFSG. Survival was evaluated. Blood and liver samples were collected 6 h after surgery. Immunohistological assessment for apoptotic induction and western blotting for 4-hydroxynonenal, ataxia-telangiectasia mutated kinase (ATM), histone H2AX, phosphatidylinositol-3 kinase (PI3K), Akt, and free radical scavenging enzymes were performed.Results. Pretreatment by GABAR showed improvement in survival, histopathological assessment, and biochemical tests. Apoptotic induction and oxidative stress were observed after SOLT with an SFSG, and this damage was limited by GABAR regulation. GABAR regulation appeared to reduce DNA damage via the ATM/H2AX pathway and to promote cell survival via the PI3K/Akt pathway.Conclusions. Pretreatmentin vivoby GABAR regulation improves graft damage after SOLT with an SFSG. This strategy may be advantageous in LT.

AimIf progressive liver injury and subsequent hepatic encephalopathy can be prohibited in fulminant liver failure (FLF), it would be ideal for intensive care of FLF and provide an expanded opportunity for liver transplantation (LT). We hypothesized that matrix metalloproteinase (MMP)‐9 plays an important role in FLF progression, and investigated MMP‐9 behaviors in a murine FLF model, especially at the coma stage.MethodsThe murine FLF model with azoxymethane recapitulates FLF in humans. The detailed coma status was evaluated, on the assumption that LT is indicated at early, but not late, stage 3. To investigate whether MMP‐9 deletion or reduction has beneficial effects, an MMP‐9 inhibitor (GM6001) and transfection of tissue inhibitor of metalloproteinases (TIMP)‐1 cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP‐1 plasmid transfection 24 h before disease onset; and FLF with TIMP‐1 plasmid transfection 48 h before disease onset. Neurological findings, including survival, were followed. Samples were obtained at early and late stage 3. Biochemical examinations and histopathological assessments were performed. The expression and function of MMP‐9 and TIMP‐1 were evaluated by western blotting and zymography. A brain permeability study was also performed.ResultsMMP‐9 was strongly increased in FLF. The MMP‐9 inhibitions worked well, and prolonged the survival, interval to stage 3 and duration of early stage 3. MMP‐9 inhibition improved the liver and subsequent brain injuries at early stage 3, with no remarkable improvements at late stage 3.ConclusionMMP‐9 has therapeutic potential for FLF progression.