Molecular pathways of regeneration and repair after liver transplantation

Injury to liver grafts due to cold ischemia, preservation, and reperfusion continues to be an important factor in patient outcome after liver transplantation. The development of therapeutic interventions that can limit ischemic injury, enhance recovery, and improve early graft function can have a major impact on patient morbidity. The mechanisms of hepatic preservation and reperfusion injury, the molecular pathways of graft recovery, and the cells involved remain poorly understood. With significant damage to parenchymal tissue following cold ischemic injury comes the need for replacement or repair of injured cells. In a rat liver transplant model, expression of cytokines and activation of transcription factors associated with the cell cycle resulting in cellular replication correlates with the length of cold ischemia and the degree of damage. The resident liver macrophage, the Kupffer cell, has been implicated as the primary source of inflammatory factors but may also be the source of important growth factors and cytokines that initiate cellular recovery and regeneration. Determining the source of the initiating signal is important, as manipulation of this signal can be used for therapeutic interventions in such fields as transplantation, tumor immunology, and inflammatory disease. These studies demonstrate the critical interrelation between parenchymal cells and cells of the immune system during signaling and recovery from preservation and reperfusion injury in the liver. Further defining the role of these immune cells and their products during the initiation of cellular recovery is essential for developing strategies to improve hepatocellular function after injury.