This program project will define the immunological events which are important in the organ injury and death which accompanies sepsis. The underlying hypothesis may be stated as: An inappropriate inflammatory response increases organ injury and lethality. A combination of animal models and patient samples will be studied. The application consists of 4 projects and 3 cores. The first project is directed by Dr. Remick and will examine the hypothesis: Early septic deaths are due to excessive inflammation while later deaths result from immunosuppression. This will be tested in mice which have been subjected to cecal ligation and puncture (CLP) and by examining whole blood from trauma patients. The second project will be directed by Dr. Nemzek and will explore the immunopathology of a """"""""2 hit"""""""" model of organ injury induced by non-lethal CLP plus acid aspiration. The specific hypothesis is that: Sepsis modulates the lung injury produced after acid aspiration by control of neutrophil function and/or recruitment by altering chemokine production and CXCR2 expression. This will also be examined in trauma patients in the unit who experience gastric aspiration. Dr. Su will supervise the third project which examines another """"""""2 hit"""""""" model of liver injury followed by CLP. The hypothesis for this project is: Deaths result from dysregulation of the macrophage response to bacteria. This dysregulation will be further studied in the whole blood of patients with acute cholestatic liver disease. The final project will be directed by Dr. Opp and will investigate sickness behavior in mice after CLP. The specific hypothesis is: Brain responses to sepsis are critical determinants of outcome. The studies will be extended by evaluating brain responses in septic patients. These projects are supported by 3 cores which centralize functions common to the projects. This prevents duplication of effort and fosters communication between the projects. The first is the patient recruitment and clinical data core under the direction of Dr. Wahl. This core will be responsible for identifying the patients and collecting the clinical information. All of the cytokines will be measured in the second core under the direction of Dr. Remick. This core will also collect the patient specimens and perform the whole blood stimulation experiments. This core has substantial expertise in the area of precise measurement of cytokines. The last core is the biostatistics core lead by Dr. Gillespie who will be responsible for expert advice on experimental design and data analysis. This program project application combines the expertise of 4 investigators to study the cytokine response to injury and infection in an integrated and comprehensive approach. Successful completion our goals will define both basic mechanisms of disease and potential targets for therapeutic intervention.
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