A dysregulated systemic inflammatory response following trauma appears to contribute to post-injury multiple organ failure (MOF). Neutrophils (PMNs) are implicated as primary effector cells in organ injury and ultimately MOF. We and others have recognized, however, that PMN apoptosis is a healthy and essential homeostatic process. Dysregulated (i.e., delayed) apoptosis may permit extended PMN- mediated inflammation and promote tissue injury by allowing the persistence of PMNs that are primed for cytotoxicity; on the other hand, premature PMN death may facilitate infection, resulting in sepsis. In collaboration with our Trauma Registry (Project I.A) we have identified prolonged postinjury PMN survival. Characterization of PMN apoptosis in the postinjury period is critical to determine a) who is at risk for dysregulated apoptosis; b) how dysregulated apoptosis affects patient outcome; and 3) how we may modulate PMN apoptosis. The global hypothesis is that dysregulated PMN apoptosis promotes postinjury MOF. In this Project II, the specific aims are as follows: 1. To relate PMN apoptosis to injury severity, gender, genetic predisposition, and age (with Projects I.A, I.B. and I.C). 2. To relate PMN apoptosis to clinical outcomes (e.g., infections, MOF, mortality) (with Project I.A). 3. To elucidate the dominant signaling pathway in postinjury PMN apoptosis (with Projects IV, V, and IX. 4. To determine the ability of various transfusion strategies to modulate dysregulated PMN apoptosis following trauma (with Project IX). The characterization of PMN apoptosis may provide insight into a therapeutic window in which the process may be restored to healthy levels, thereby promoting resolution of postinjury hyperinflammation and prevention of postinjury MOF.
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