Trauma is the major cause of death and disability in modern armed conflict as well as in almost every terrorist attack. Less well known, trauma is the most common cause of civilian death below age 45. Between birth and age 36, trauma exceeds all other causes of death combined. Many patients survive injury initially only to suffer prolonged critical illness or die later when trauma and shock trigger neutrophil (PMN) inflammation and dysfunction that leads to organ failure or sepsis. Thus PMN-mediated inflammation after shock is a key national defense as well as public health problem. During our last grant support period, we showed that inflammation after trauma reflects aberrant regulation of calcium ion (Ca2+) entry from the environment into PMN. These pathways depend in part on the agonist-initiated emptying of cell Ca2+ stores and are therefore generally termed store-operated calcium entry (SOCE). We further showed that in PMN, SOCE is mediated by cellular synthesis of a lipid second messenger, sphingosine 1-phosphate (S1P) in response to Ca2+ store emptying. Related lipids act similarly, and can stimulate PMN activation whether produced intra- or extra-cellular. We have also demonstrated that PMN SOCE occurs through a complex system of Ca2+ entry channels which are composed of """"""""Transient Receptor Potential"""""""" channel proteins (TRPC). Since SOCE is a key regulator of PMN Ca2+ and is abnormally regulated in PMN after injury, these findings suggested the hypothesis that pharmacologic modulation of both S1P synthesis and SOCE-specific Ca2+ channels might prevent PMN-mediated inflammatory sequellae of shock and trauma. Further work has now shown that inhibition of SOCE by a variety of strategies can act to diminish PMN-mediated inflammation and lung injury in complex animal models mimicking clinically relevant trauma and shock treatment scenarios. The present proposal seeks to extend our prior work from the stage of a clinical promising application of our prior basic molecular biologic observations, to the stage of a well-understood treatment strategy ready for clinical implementation both on the battlefield and in civilian trauma practice. We propose to do this by achieving the four following Specific Aims: 1. Determine how to use SOCE inhibition to prevent organ injury after traumatic shock 2. Determine the side effects and complications of SOCE inhibition after shock. 3. Determine the effects of injury on intracellular S1P/SOCE signaling 4. Determine the mechanisms by which circulating S1P activates PMN after trauma. ? ?
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