Neutrophils (PMNs) can cause organ damage after trauma. We found that physiologically relevant levels of hypertonic saline (HS) can inhibit human PMNs in vitro, suggesting that HS resuscitation could be used to prevent organ damage in trauma patients. Recent reports have shown that HS resuscitation can indeed prevent hemorrhage-induced organ damage in animal models. However, HS is not only able to inhibit PMNs, but it can also augment PMN functions under specific circumstances. Therefore, HS could aggravate tissue damage in certain clinical situations. Considering the heightened interest in hypertonic resuscitation fluids, the conditions under which HS can inhibit or augment PMNs must be determined to provide the best care for trauma patients. This is the goal of the present proposal, which addresses the following three questions: How do PMNs detect HS? The nature of the receptors involved in osmotic signaling and their downstream pathways will be studied. Emphasis will be placed on the rules of heterotrimeric G protein-coupled receptors, mechanoreceptors, and stretch-activated ion channels. How does HS interfere with PMN activation? The mechanism whereby HS-signals block activation signaling will be studied using superoxide formation of fMLP-stimulated cells as a model. Emphasis will be placed on the cross-talk between HS-signaling and the activation pathway leading to superoxide formation. Can HS prevent PMN activation after trauma? The effect of HS on PMNs isolated from trauma patients and on normal cells stimulated with trauma patient plasma will be studied by treating the cells in vitro with clinically relevant HS doses. This will show under which conditions HS can be used to best control PMNs in trauma patients and when HS must not be used to avoid possible negative side effects. This project will identify the mechanisms whereby extracellular tonicity regulates PMN functions. This work will benefit trauma patients by assessing the value of HS resuscitation to prevent organ damage and by suggesting how HS resuscitation could be modified to improve its clinical value.
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