Trauma and hemorrhage elicit an acute inflammatory response. This process involves migration and activation of leukocytes, secretion of cytokines, and the production of free radicals. Together, these changes may result in severe organ dysfunction and death. We have developed a mathematical model that describes the mediators of acute inflammation, and is calibrated in mice subjected to endotoxemia, surgical trauma, and hemorrhagic shock. This model was further calibrated in human endotoxemia. Though informed by circulating mediators, this model expresses the physiological derangement experienced by individual organs in terms of a global tissue dysfunction equation. The close correlation between the output of the mathematical model of inflammation and experimental data suggests that a common inflammatory response underlies diverse shock states, raising the possibility of modeling the inflammatory process in vivo. We hypothesize that a validated and calibrated mathematical model of inflammation and its pathologic consequences will be useful for predicting outcome in patients suffering from traumatic/hemorrhagic shock. We will test this hypothesis in two Specific Aims.
In Aim 1, we will augment our mathematical model in rodents, including elements of adaptive immunity, and simulate therapeutic interventions. We will modify our model to include natural killer (NK) cells, NKT cells, mast cells, dendritic cells, and TH1 and TH2 cells. We will modify how we model reactions of nitric oxide, examine the roles of HMG-B1 and hyaluronic acid as pro-inflammatory alarm molecules, and model the impact of MAP kinase inhibitors. Furthermore, the mathematical model will inform and will be informed by the hypotheses presented in Projects I-IV. For example, we hypothesize that we can predict the optimal timing and dosage of anti-lL-6, Ringer's Ethyl Pyruvate solution, and NAD in rodent models of shock/trauma. We will carry out detailed time course studies in mice to validate and calibrate this model and the proposed interventions.
In Aim 2, we will adapt the mathematical model of trauma/hemorrhage-induced inflammation to humans and create a platform for integration into individualized clinical decision-making. In a prospective clinical study of 500 trauma patients, we will obtain data on the course of inflammation and organ dysfunction as well as cytokine gene polymorphisms needed for our mathematical model, in addition to clinical data that will be used to construct a series of statistical models. Selected interventions from Aim 1 will be tested in simulated clinical trials. We will also create a platform, based on the mathematical model, for integration into individualized clinical decision-making in shock/trauma. The research proposed herein will impact both basic and translational research on the inflammatory process of shock/trauma.
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