Sepsis continues to be the most common cause of death in surgical intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis and septic shock has increased significantly. More than 750,000 patients develop severe sepsis each year with an overall mortality rate of 28.6% in the US alone. The average costs per case are $22,100, with annual total costs of more than $16 billion nationally. Although activated protein C is the only FDA-approved therapeutic agent for sepsis, its use is limited to non-surgical patients due to the adverse effects on coagulation. Thus, there is a great need for an effective novel treatment for surgical sepsis. The market potential for sepsis treatment is estimated at $10-25 billion/year in the US alone. We have recently shown that early injection of rat adrenomedullin (AM), a recently identified potent vasodilatory peptide, in combination with its novel specific binding protein (i.e., AMBP-1) reduced tissue injury and mortality in sepsis. However, it remains unknown if human AM plus human AMBP-1 is also beneficial and, if so, whether the delayed administration reduces mortality in sepsis. We therefore hypothesize that administration of human AM/AMBP-1 even late after the onset of sepsis attenuates inflammatory responses and reduces mortality. The primary goal of this project is to demonstrate the feasibility of further development and commercialization of human AM/AMBP-1 as a novel therapeutic agent in reducing sepsis-induced mortality by determining the beneficial effects of dose-response of human AM/AMBP-1 in sepsis. The rat cecal ligation and puncture (CLP) model of sepsis will be used. After administration of various doses of AM/AMBP-1 at 10 h after CLP (i.e., the beginning of severe sepsis), blood samples will be collected for assessment of tissue injury indicators (i.e., liver enzymes, lactate, creatinine) and proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, HMGB-1), and tissue samples harvested for histology. In addition, a 10-day survival study will be conducted following CLP and surgical removal of the necrotic cecum. The proposed studies should provide useful feasibility information that will allow us to further develop AM/AMBP-1 as an effective novel therapeutic agent for treatment of surgical sepsis. Our ultimate goal (Phase II SBIR and beyond) is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective therapy of septic patients, especially those who develop sepsis following trauma, hemorrhage, or major surgery.
