Multiple organ failure (MOF) is the leading cause of late post-injury mortality. We propose that the cellular response to an inflammatory stimulus can be influenced by a prior injury to the host animal or patient. Thus, the initial injury """"""""primes"""""""" cells to exhibit an amplified response to a subsequent insult. This phenomenon is best exemplified by the """"""""priming"""""""" of neutrophils. We postulate that injury """"""""primes"""""""" cells. this priming may amplify the cellular response to a subsequent stimulus in either a constructive or destructive fashion. Indeed, trauma initiates a race between physiologically protective or destructive programs, the clinical result of which is dictated by the magnitude and sequence of each insult. This Trauma Research Center is composed of 5 independent projects all relating to the first clinical core project. In the clinical core, we propose to quantify the magnitude of initial patient injury. Following initial resuscitation, we plan to examine the hypermetabolic """"""""primed"""""""" patient to determine whether a second inflammatory insult during this vulnerable period predicts MOF (Project 1). The hypermetabolic state will be investigated in animals to determine whether inflammatory mediators can sensitize (protect) and/or desensitize (injure) beta- adrenergic receptor coupled myocardial function (Project 2). The gut has been invoked as an organ central to the development of MOF. We propose that post-injury mesenteric ischemia/reperfusion promotes remote organ injury by serving as a """"""""priming"""""""" bed for circulating neutrophils (Project 3). The intense sympathetic stimulation associated with trauma may """"""""prime"""""""" cellular metabolism to promote tolerance to subsequent ischemic/inflammatory insult (Project 4). Ultimately, cells """"""""primed"""""""" by injury express a common program of genes which relate to protection and recovery (Project 5). Concurrent with our development as a Trauma Research Center, we propose to function as a Trauma Research Training Center.
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