Modulation of the inflammatory response and apoptosis using epidermal growth factor and hepatocyte growth factor in a liver injury model: a potential approach to the management and treatment of cholestatic liver disease

• Published in: Journal of pediatric surgery 2008-12, Vol.43 (12), p.2169-2173
• Main Authors: Thatch, Keith A, Schwartz, Marshall Z, Yoo, Edward Y, Mendelson, Kim G, Duke, Duane S
• Format: Article
• Language: English
• Subjects: 1-Naphthylisothiocyanate - toxicity; Animals; Apoptosis - drug effects; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - pathology; Cholestasis, Intrahepatic - etiology; Disease Models, Animal; Epidermal Growth Factor - administration & dosage; Epidermal Growth Factor - therapeutic use; Epithelial growth factor; Female; Hepatocyte growth factor; Hepatocyte Growth Factor - administration & dosage; Hepatocyte Growth Factor - therapeutic use; Infusion Pumps, Implantable; Interleukin-6 - analysis; Intestinal Absorption - drug effects; Liver - chemistry; Liver - pathology; Liver disease; Liver injury; Liver Regeneration - drug effects; Parenteral Nutrition, Total - adverse effects; Pediatrics; Random Allocation; Rats; Rats, Sprague-Dawley; Short bowel syndrome; Surgery; TPN; Tumor Necrosis Factor-alpha - analysis; α-Naphtylisocyocyanate
• ISSN: 0022-3468; 1531-5037
• DOI: 10.1016/j.jpedsurg.2008.08.045

Abstract Background/Purpose The major side effect of total parenteral nutrition is liver injury leading to liver failure. This study was designed to assess specific growth factors in modulating the hepatic response in an ANIT-induced liver-injury model. Methods Sprague-Dawley rats were divided into four groups: control (n = 5), liver-injury control ( α -naphtylisocyocyanate [ANIT], 100 mg/kg, n = 8), ANIT + epidermal growth factor (EGF, 150 μ g/kg per day, n = 10), and ANIT + hepatocyte growth factor (HGF, 250 μ g/kg per day, n = 9). Rats were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic mini-pump for 7 days of continuous intravenous saline (liver injury control), EGF, or HGF. Seven and 14 days later, liver biopsies were obtained and evaluated for interleukin (IL)–6 and tumor necrosis factor α expression by immunofluorescent staining, and for apoptosis, by the terminal transferase dUTP nick end labeling (TUNEL) technique. All animals were euthanized at 14 days. Results Epidermal growth factor ( P < .025) and HGF ( P < .001) groups induced less IL-6 expression at day 14 compared to liver-injury controls. In addition, the interval decrease in IL-6 expression between days 7 and 14 was greater in EGF ( P < .001) and HGF ( P < .001) groups compared to liver-injury controls. At day 14, HGF also demonstrated decreased tumor necrosis factor α expression ( P < .005). Apoptotic activity was significantly less for the EGF ( P < .011) and HGF ( P < .0012) groups. Conclusion Epidermal growth factor and HGF modulated the hepatic inflammatory response and apoptotic index in this established liver-injury model and may diminish or prevent liver damage in patients with total parenteral nutrition–induced liver injury.