T cells play a central role in the defense against invading pathogens. Trauma impairs T cell function and increases the risk of infections and sepsis. Hypertonicity corresponding to the levels found in trauma patients after resuscitation with hypertonic saline (HS) enhances T cell function, suggesting that HS resuscitation could be used to counteract post-traumatic immunosuppression and sepsis. The present proposal is aimed at defining the underlying mechanisms and determining the conditions under which HS resuscitation could be used to effectively support T cell function in trauma victims. The following specific points will be addressed:
Aim 1 : How do T cells detect HS? The nature of the receptor(s) involved in the cellular response to HS will be examined. Emphasis will be placed on shrinkage-induced membrane deformation, ATP release, and the roles of P2 and P1 receptors in the feedback mechanism whereby HS enhances T cell functions.
Aim 2 : How does HS enhance normal T cell function? The intracellular signaling mechanisms whereby HS increases T cell function will be investigated. Emphasis will be placed on the involvement of PI3-kinase, the small GTPases Rac and Cdc42, MKK3 and 6, MAPK p38, and the nuclear factor NFAT5 in the upregulation of IL-2 gene expression by HS.
Aim 3 : How does HS improve the function of suppressed T cells? The conditions under which HS can be used to counteract trauma-induced T cell suppression will be studied with cells exposed to anti-inflammatory factors that are known to suppress T cells in trauma patients. Specifically, temporal requirements for optimal enhancement of T cell function by HS and the underlying molecular mechanisms will be studied. The proposed studies are important in elucidating the mechanisms through which HS modulates T cell function and in determining the potential clinical usefulness and limitations of HS resuscitation. The anticipated results are particularly significant in light of the growing clinical interest in HS resuscitation as a novel therapeutic approach in prevention of post-traumatic complications such as multiple organ failure and sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM051477-06
Application #
6572935
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1996-06-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$289,232
Indirect Cost
Name
University of California San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sumi, Yuka; Ledderose, Carola; Li, Linglin et al. (2018) Plasma Adenylate Levels are Elevated in Cardiopulmonary Arrest Patients and May Predict Mortality. Shock :
Lee, Albert H; Ledderose, Carola; Li, Xiaoou et al. (2018) Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1? Production, and the Host Immune Response to Infection. Crit Care Med 46:e1183-e1189
Ledderose, Carola; Liu, Kaifeng; Kondo, Yutaka et al. (2018) Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest 128:3583-3594
Li, Xiaoou; Kondo, Yutaka; Bao, Yi et al. (2017) Systemic Adenosine Triphosphate Impairs Neutrophil Chemotaxis and Host Defense in Sepsis. Crit Care Med 45:e97-e104
Ledderose, Carola; Bao, Yi; Kondo, Yutaka et al. (2016) Purinergic Signaling and the Immune Response in Sepsis: A Review. Clin Ther 38:1054-65
Ledderose, Carola; Bao, Yi; Ledderose, Stephan et al. (2016) Mitochondrial Dysfunction, Depleted Purinergic Signaling, and Defective T Cell Vigilance and Immune Defense. J Infect Dis 213:456-64
Ledderose, Carola; Woehrle, Tobias; Ledderose, Stephan et al. (2016) Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling? Purinergic Signal 12:439-51
Qi, Baochang; Yu, Tiecheng; Wang, Chengxue et al. (2016) Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate. J Exp Clin Cancer Res 35:161
Ledderose, Carola; Hefti, Marco M; Chen, Yu et al. (2016) Adenosine arrests breast cancer cell motility by A3 receptor stimulation. Purinergic Signal 12:673-685
Bao, Yi; Ledderose, Carola; Graf, Amelie F et al. (2015) mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. J Cell Biol 210:1153-64

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