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.
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