Cell-Based Approaches to the Treatment of Clinical Shock

While the rapid institution of supportive physiologic (organ level) therapies has been highly successful in treating the severely injured, significant number of trauma casualties die as the result of the sequelae of shock. Additionally, the high rate of salvage of idnividuals who would otherwise succumb to an initial insult has created a new constellation of medical problems of which few treatements are available, e.g., ARDS, multi-system organ failure. Current therapies for acute shock states are directed at an organ system-based approach, i.e., supportive physiologic care, as a bridge until definitive surgical or mecial care can be provided. However, during these initial (crucial) periods of time within the so-called golden hour, significant cellular injury goes both undetected and untreated, adversely affecting both acute and long term outcome. To address this problem, preliminary studies on cell based approaches to the treatemen tof one cellular etiology of shock, i.e., hypoxia, are described. Strategies that promote energy synthesis in the absence of oxygen were employed successfully to prevent cellular injury in an isolated liver model of schok subjected to 1 hour of normothermic anoxia. Based on these findings, it is suggested that such treatements may be of utility to other organ systems and other causes of shock. The studies detailed herein focus on: 1. elucidating the cytoprotective mechanisms of such compounds and 2. the development of a set of therapeutic agents capable of treating shock states at the cellular level. Preliminary data is included that suggests that the design of agents directed at the cellular energetic axis may allow for a state of cellular hibernation (suspended animation) during injury intervals, the medical effect of which would be to lengthen the golden hour. Anticipated Benefits: 1) the implementation of a cellular based strategy to complement existing physiologic based treatments of traumatic injury resulting in shock; 2) an improvement in the design of medical diagnositc to detect underlying cellular injury during shock states