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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
2P50GM053789-08
Application #
6861601
Study Section
Special Emphasis Panel (ZGM1-TB-6 (04))
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$247,385
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Zettel, Kent; Korff, Sebastian; Zamora, Ruben et al. (2017) Toll-Like Receptor 4 on both Myeloid Cells and Dendritic Cells Is Required for Systemic Inflammation and Organ Damage after Hemorrhagic Shock with Tissue Trauma in Mice. Front Immunol 8:1672
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Yang, Yong; Zhang, Peng; Zhao, Yanfeng et al. (2016) Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer. Cancer Biol Ther 17:515-25
Yang, Weng-Lang; Sharma, Archna; Wang, Zhimin et al. (2016) Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. Sci Rep 6:26571
Vodovotz, Yoram (2016) Reverse Engineering the Inflammatory ""Clock"": From Computational Modeling to Rational Resetting. Drug Discov Today Dis Models 22:57-63
Yang, Jie; Zhao, Yanfeng; Zhang, Peng et al. (2016) Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS. Cell Death Dis 7:e2363

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