This Proposal represents a joint effort among several investigators interested in the sequence of events that are precipitated by certain types of injury (sepsis, endotoxin, burn, etc.). We envisage the sequence of events following injury as consisting of the transduction of the noxious stimulus to chemical signals, the transport of these mediators to susceptible organs, interactions with the cell membrane resulting in transmembrane signaling, and the generation of intracellular messengers. The latter act on various regulatory mechanisms and alter cell metabolism as well as impair cell function. The altered cell metabolism contributes to negative energy balance which impinges on cell function. The end result, if severe enough, is to bring about the failure of a single or multiple organs. It is the aim of the proposed program project to test specific hypotheses aimed at different parts of this sequence of events, to discover common mediator(s) and pathways in the trauma-induced sequence, and to eventually reverse the damage and prevent organ failure. The investigators will interrelate with each other very closely by studying different aspects of this sequence on the same experimental models using varied, yet complementary approaches to test their individual hypotheses. The novelty of our approach is in our application of up-to-date new concepts from the field of mediation of secretory, hormonal and neural events to the understanding of derangements following trauma, sepsis and burn injury. We will combine these studies with a detailed investigation of the alterations affecting carbohydrate, lipid and protein metabolism, in order to uncover the etiology of the pathophysiologic changes and subsequently attempting to reverse them by rational therapeutic approaches.
