Sepsis remains a serious clinical problem causing thousands of deaths each year. Therapy for the treatment of sepsis has not progressed due to a lack of understanding of the basic inflammatory processes. The previous prevailing hypothesis postulated that patients with sepsis had too much inflammation, therefore blocking the inflammatory mediators would decrease organ injury and death. As information was gathered it became clear that this hypothesis represented an oversimplification of the complex inflammatory events. This application will study 2 hypotheses using the clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). The first hypothesis states that death during the first 5 days after CLP is due to an exaggerated immune response and will be tested by 3 specific aims. The first specific aim will block inflammatory mediators to improve survival. This represents more than just an extension of the previous failed clinical trials since we will attempt combination immunotherapy and inhibit newly described cytokines such as interleukin 18. The second specific aim will tailor the anti-inflammatory therapy based on the individual response. Rather than providing exactly the same therapy to each animal, the therapy will be directed by rapidly quantitating the level of inflammation and then providing the appropriate therapy. The third specific aim will attempt to improve outcome by increasing the local neutrophil recruitment to the site of inflammation, the peritoneum. While neutrophils may cause organ injury, they are also a critical component of the innate immune response for the control of the invading bacteria. Our second hypothesis states that deaths which occur beyond 5 days post CLP are the result of the immunosuppressed state of the animal. The fourth specific aim will test this hypothesis by providing exogenous cytokines (tumor necrosis factor, IL-1, IL-18) to the animals and attempt to boost their immune response. These exogenous cytokines will be given by subcutaneous injection. Alternatively, inducible gene therapy will also be given using the novel tetracycline inducible vectors. For each of the specific aims we will not only test if they are effective but also determine the mechanism of how they improve survival. Successful completion of our studies will provide the basic knowledge about the inflammatory response in sepsis, knowledge needed to reduce the impact of sepsis.
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