Acute mesenteric ischemia is an abdominal emergency with a mortality rate of up to 60-80%. Even though numerous modalities and substances have been studied to reduce gut ischemia/reperfusion (I/R)-induced mortality, none have been entirely successful. As such, the development of effective strategies for preventing and treating circulatory collapse and organ injury after gut I/R is critical for the improvement of patient outcome under such conditions. The market potential for gut I/R treatment is estimated at $2-5 billion per year in the U.S. alone. We have recently demonstrated that administration of rat adrenomedullin (AM), a recently-discovered potent vasodilatory peptide, in combination with its novel specific binding protein (i.e., AMBP-1), at the beginning of reperfusion attenuated tissue injury and inflammatory responses in a rat model of gut I/R induced by superior mesenteric artery occlusion (SMAO). One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for gut I/R is the potential immunogenicity of rat proteins in humans. Although we have shown that administration of rat AM plus human AMBP-1 at the beginning of reperfusion is protective, it remains unknown whether a combination of human AM and human AMBP-1 is also beneficial and, if so, whether delayed administration of AM/AMBP-1 (which is more clinically relevant) reduces gut I/R-induced mortality. We therefore hypothesize that administration of human AM/AMBP-1, even after reperfusion, improves cardiovascular function, attenuates organ injury and inflammation responses, and reduces mortality following gut I/R injury. 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 resuscitation approach in reducing mortality after gut I/R. The optimal dosage(s) of human AM/AMBP-1 will be determined by assessing 1) the effect of a dose-response of AM/AMBP-1 on cardiovascular function, tissue injury and inflammatory responses after gut I/R; 2) the effect of a dose-response of AM/AMBP-1 on gut I/R-induced mortality; and 3) the pharmacokinetics of AM and AMBP-1 in normal animals and after gut I/R. 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 gut I/R injury. ? ? ?
