Effects of methylprednisolone and its liver-targeted dextran prodrug on ischemia-reperfusion injury in a rat liver transplantation model

Abstract

Purpose: To evaluate the effectiveness of a liver-targeted dextran prodrug (DMP) of methylprednisolone (MP) in cold preservation-warm reperfusion injury associated with liver transplantation.

Methods: The effects of donor pretreatment with single 5 mg/kg doses of MP or DMP on ischemia-reperfusion damage to the liver were studied after 8 or 24 h of cold preservation in both isolated perfused rat liver (IPRL) and syngeneic orthotopic rat liver transplantation (OLT) models.

Results: In IPRL studies, donor pretreatment with DMP, and to a lesser degree MP, significantly improved the uptake of hyaluronic acid (HA), a marker of endothelial cell function, following 8 h of cold preservation. However, neither pretreatment was protective after 24 h of preservation. In the OLT model using 24-h-preserved livers, the seven-day survival of untreated grafts was 50%. DMP pretreatment of donors significantly improved graft survival to 100%, whereas MP pretreatment was ineffective. Additionally, only DMP significantly increased the blood glucose concentrations and decreased the plasma concentrations of tumor necrosis factor-alpha after OLT. Other measured markers of liver injury were not affected by either pretreatment.

Conclusions: Selective delivery of methylprednisolone to the liver as a donor pretreatment strategy improves 24-h preserved graft survival in the OLT model.

Figure 1

The perfusate concentration-time courses of hyaluronic acid (HA) in isolated livers subjected to 8 (top panel) or 24 h (bottom panel) of cold ischemia followed by 70 min of warm reperfusion. Similar profiles in Unpreserved controls are provided for reference. Rats were pretreated intravenously, 2 h prior to liver harvest, with a single 5-mg/kg dose (MP equivalent) of MP or DMP or with saline (Control) (n=3−4/group). Symbols and bars represent the average and standard deviation values, respectively.

Figure 2

The bile flow rates in isolated livers subjected to 0, 8, or 24 h of cold ischemia followed by 70 min of warm reperfusion. Rats were pretreated intravenously, 2 h prior to liver harvest, with a single 5-mg/kg dose (MP equivalent) of MP or DMP or with saline (Control) (n=3−4/group). Symbols and bars represent the average and standard deviation values, respectively.

Figure 3

Percent survival curves of transplanted animals receiving livers preserved for 24 h in UW solution. Donor rats were pretreated with a single 5-mg/kg i.v. dose of MP or DMP or with saline (Control) 2−3 h prior to graft harvest (n=8/group).

Figure 4

Plasma concentrations of TNF-α (top) and hyaluronic acid (HA) (bottom) in OLT recipients at 1 and 6 h after implantation of livers preserved for 24 h. Donor rats were pretreated with a single 5-mg/kg i.v. dose of MP or DMP or with saline (Control) 2−3 h prior to graft harvest. Columns and bars represent mean and standard deviation values, respectively (n=3−4/group).

Figure 5

Plasma concentrations of AST (top) and ALT (bottom) in OLT recipients at 1 and 6 h after implantation of livers preserved for 24 h. Donor rats were pretreated with a single 5-mg/kg i.v. dose of MP or DMP or with saline (Control) 2−3 h prior to graft harvest. Columns and bars represent mean and standard deviation values, respectively (n=3−4/group).