Dose Variation of Hepatocyte Growth Factor and its Effects on an Animal Model of TPN-Induced Liver Injury

Abstract

Total parenteral nutrition (TPN) induced liver failure is the leading indication for transplantation in children. Our previous research demonstrated the benefit of a specific intravenous dose of hepatocyte growth factor (HGF) in the amelioration of TPN-induced liver injury. This study was designed to ascertain the optimum concentration of HGF in an animal model of TPN-induced liver injury. Twenty adult female Sprague-Dawley rats underwent 70% small bowel resection and placement of venous catheters connected to subcutaneous osmotic minipumps. Four groups (n=5 each) based on the contents of the osmotic pump were utilized as follows: group 1 (control): saline; group 2: HGF 75 mcg/kg/d; group 3: HGF 150 mcg/kg/d; and group 4: HGF 250 mcg/kg/d. Each rat received 14d of TPN without enteral nutrition. After sacrifice, the liver was harvested. Hepatic inflammation was evaluated using antibodies for TNF-α and IL-6. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) technique. All concentrations induced statistically significantly less IL-6 and TNF- α expression compared to the control animals. Increased efficacy was demonstrated with increasing dose concentration up to 150 mcg/kg/d but not 250 mcg/kg/d. Apoptotic activity was decreased statistically significantly for all dose concentrations compared with the controls, as well as to increases in dose concentration. Increasing concentrations of HGF were directly correlated with increased modulation of inflammatory response and apoptotic index in this animal model for TPN-induced liver injury, up to 150mcg/kg/d. Further increases were significant with respect to apoptotic index only. Further investigations are warranted to determine if HGF may be useful to minimize TPN-induced liver injury in children.