Attenuation of Kupffer cell activation in cold-preserved livers after pretreatment of rats with methylprednisolone or its macromolecular prodrug.
OBJECTIVE
Activation of hepatic Kupffer cells (KCs) during organ preservation and subsequent reperfusion causes release of proinflammatory mediators and is responsible, at least in part, for rejection of transplanted livers. Our hypothesis was that donor pretreatment, before liver harvest, with methylprednisolone (MP) or its dextran prodrug (DMP) would reduce KC activation.


METHODS
Adult donor rats were administered a single 5-mg/kg (MP equivalent) IV dose of MP or DMP or saline 2 h before liver harvest. The livers were then stored in University of Wisconsin solution for 24, 48, or 96 h (n = 4/treatment/time). A recirculating perfusion model was used to study, for 180 min, the release of KC activation markers, tumor necrosis factor (TNF)-alpha and acid phosphatase, and other biochemical indices from the cold-preserved livers.


RESULTS
Cold ischemia-reperfusion resulted in release of substantial levels of TNF-alpha in untreated groups. Pretreatment of rats with MP or DMP caused a significant (p < 0.0001) reduction in TNF-alpha AUC in the perfusate, with no significant differences between MP and DMP. The maximum inhibitory effect of MP (77.5 +/- 10.2%) was observed after 48 h of preservation, whereas DMP showed maximal inhibition of TNF-alpha AUC at both 24 (74.5 +/- 15.8%) and 48 (74.8 +/- 12.6%) h of preservation. Similarly, both MP and DMP resulted in a significant (p < 0.0004) decrease in acid phosphatase levels of cold-preserved livers. However, neither pretreatment had any substantial effect on the levels of other biochemical markers.


CONCLUSIONS
Both MP and DMP pretreatments decreased the release of TNF-alpha and acid phosphatase from livers subjected to cold ischemia preservation. Therefore, pretreatment of liver donors with MP or its prodrug decreases KC activation by cold ischemia-reperfusion.
Chimalakonda
Anjaneya P
AP
School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
Mehvar
Reza
R
D000818:Animals; D015925:Cryopreservation / Q000379:methods*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver; D046911:Macromolecular Substances; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D009926:Organ Preservation / Q000379:methods*; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D046911:Macromolecular Substances; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; D008775:Methylprednisolone