Improved rat steatotic and nonsteatotic liver preservation by the addition of epidermal growth factor and insulin-like growth factor-I to University of Wisconsin solution

Liver Transpl. 2010 Sep;16(9):1098-111. doi: 10.1002/lt.22126.

Abstract

This study examined the effects of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) supplementation to University of Wisconsin solution (UW) in steatotic and nonsteatotic livers during cold storage. Hepatic injury and function were evaluated in livers preserved for 24 hours at 4 degrees C in UW and in UW with EGF and IGF-I (separately or in combination) and then perfused ex vivo for 2 hours at 37 degrees C. AKT was inhibited pharmacologically. In addition, hepatic injury and survival were evaluated in recipients who underwent transplantation with steatotic and nonsteatotic livers preserved for 6 hours in UW and UW with EGF and IGF-I (separately or in combination). The results, based on isolated perfused liver, indicated that the addition of EGF and IGF-I (separately or in combination) to UW reduced hepatic injury and improved function in both liver types. A combination of EGF and IGF-I resulted in hepatic injury and function parameters in both liver types similar to those obtained by EGF and IGF-I separately. EGF increased IGF-I, and both additives up-regulated AKT in both liver types. This was associated with glycogen synthase kinase-3beta (GSK3(beta)) inhibition in nonsteatotic livers and PPAR gamma overexpression in steatotic livers. When AKT was inhibited, the effects of EGF and IGF-I on GSK3(beta), PPAR gamma, hepatic injury and function disappeared. The benefits of EGF and IGF-I as additives in UW solution were also clearly seen in the liver transplantation model, because the presence of EGF and IGF-I (separately or in combination) in UW solution reduced hepatic injury and improved survival in recipients who underwent transplantation with steatotic and nonsteatotic liver grafts. In conclusion, EGF and IGF-I may constitute new additives to UW solution in steatotic and nonsteatotic liver preservation, whereas a combination of both seems unnecessary.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / pharmacology
  • Allopurinol / pharmacology
  • Animals
  • Cell Survival
  • Cold Ischemia
  • Disease Models, Animal
  • Epidermal Growth Factor / pharmacology*
  • Fatty Liver / pathology
  • Fatty Liver / surgery*
  • Glutathione / pharmacology
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / pharmacology*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver / surgery*
  • Liver Transplantation* / adverse effects
  • Organ Preservation / methods*
  • Organ Preservation Solutions / pharmacology*
  • PPAR gamma / metabolism
  • Perfusion
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Raffinose / pharmacology
  • Rats
  • Rats, Zucker
  • Recombinant Proteins / pharmacology
  • Reperfusion Injury / etiology
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Time Factors

Substances

  • Insulin
  • Organ Preservation Solutions
  • PPAR gamma
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • University of Wisconsin-lactobionate solution
  • Epidermal Growth Factor
  • Allopurinol
  • Insulin-Like Growth Factor I
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Glutathione
  • Adenosine
  • Raffinose