TRAUMA PRIMES CELLS

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This current application is conceived as an extension of our funded 1998 Trauma Center application. Our GLOBAL HYPOTHESIS is that we can devise THERAPY FOR TRAUMA PRIMES CELLS. During the past two years, we have enjoyed gratifying recruitment of patients into our Trauma/MOF Registries (ADULTS-Project IA and Children-Project 1C) and we postulate that polymorphisms in the promoter region of stress- response genes influence the susceptibility to post-injury MOF (Project 1B). Activated neutrophils have traditionally been linked to post-injury systemic inflammation and we postulate an exacerbation of this injury due to delayed neutrophil apoptosis (Project II). Cells/organs/patient ischemia is the hallmark of any major injury and we wish to explore this altered cellular bioenergic profile as signal dictating post-traumatic events (Project III). We expand our previous interrogation of signaling mechanisms to an examination of mechanisms of hyperosmolar therapy (Project IV). Liposomal delivery of HSP72 inhibits Mphi TNF production. We further propose that HSP72 suppresses TNF receptor mediated amplification of Mphi inflammatory response and that targeted deliver of HSP72 controls post-injury myocardial inflammation (Project V). Lung dysfunction is acknowledged by an early victim in the sequential cascade of post-injury organ failure. We propose pulmonary vasomotor dysfunction to be the origin of this clinically frightening problem (Project VI). TNF (although immunologically healthy) is now recognized for its post-injury depressive potential. We propose both mechanisms of and therapy against interleukin-18 as an even more proximal "out of control" cytokine (Project VII). Two years ago, we proposed kinase/phosphatase signaling as the backbone of post-injury cellular message transmission. We now postulate that sarcolemmal signal endocytosis onto a cytoskeletal scaffolding regulates the sequence and magnitude of post-injury information transfer (Project VIII). To our surprise, blood transfusion (which we had happily translated as a surrogate for shock) proved to be an independent predictor of post- traumatic MOF. We now postulate that the oxygen carrying hemoglobin is good; but, the red cell membrane lipid bits are bad. We propose to decipher which membrane lipid parts cause trouble (Project IX) and further we will conduct clinical anti-cytokine trials (Projects VI and VII) (no funding requested) and a resuscitative trial with a hemoglobin based oxygen carrier (no funding requested) which we hope will bypass a problem (blood transfusion) that we identified in our early Trauma Registry (Project IA).