Liver injury induced by hepatic ischemia and reperfusion (I/R) is a major cause of liver failure after severe trauma, thermal injury, hemorrhagic and septic shock, liver resection, or liver transplantation. Hepatic I/R contributes significantly to multiple organ failure and mortality. Although various modalities and substances have been studied to reduce hepatic I/R-induced mortality, none have been entirely successful. Thus, the development of novel treatments to prevent or at least minimize hepatic I/R injury is of tremendous benefit to the patient. The market potential for hepatic I/R treatment is estimated at >$10 billion per year in the US alone. We have recently demonstrated that administration of human adrenomedullin (AM, a recently-discovered potent vasoactive peptide) in combination with human AM binding protein-1 (AMBP-1, a novel specific binding protein for AM) immediately at the onset of reperfusion, downregulated pro-inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. However, it remains unknown whether delayed administration of human AM/AMBP-1 (which is more clinically relevant) is also equally protective after hepatic I/R injury with or without pre-existing liver diseases such as hepatic injury induced by bile duct ligation (BDL). Another obstacle hampering the development of human AM/AMBP-1 as a novel therapeutic agent for hepatic I/R is the extremely high cost of commercial human AMBP-1. To overcome this, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore hypothesize that delayed administration of human AM/AMBP-1 attenuates hepatic injury and inflammation, and reduces hepatic I/R-induced mortality even under pre- existing liver diseases. The primary aim of this project is targeted toward demonstrating the feasibility of further development and commercialization of human AM/AMBP-1 as a novel therapeutic approach to reduce mortality after hepatic I/R. The optimal dosage(s) of human AM/AMBP-1 (delayed treatment) will be determined by assessing 1) the dose-response effect of human AM/AMBP-1 on tissue injury and inflammatory responses after hepatic I/R;2) the time-course of human AM/AMBP-1's beneficial effects;and 3) the effect of human AM/AMBP-1 on mortality induced by hepatic I/R with or without BDL. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with hepatic I/R injury associated with pre-existing liver conditions.
Recent advances in surgical techniques and pharmacological interventions have moderately improved the outcome of trauma surgery, liver resection, liver transplantation, and shock. However, liver failure due to ischemia-reperfusion (I/R) injury continues to be a major complication in the clinical arena. Hepatic I/R with or without pre-existing liver diseases contributes significantly to multiple organ failure and death of such patients. It is obvious that there is an urgent medical need for the development of novel treatments to prevent or at least minimize hepatic I/R injury.
