We propose that one of the keys to understanding organ injury resulting from hemorrhagic shock is to characterize the earliest molecular events leading to the initiation and promotion of inflammatory changes in hemorrhagic shock. Most previous studies have examined the net effect of shock phase resuscitation on parameters or inflammation and organ damage. In contrast to these previous approaches, we divide the molecular events of hemorrhagic shock into two distinct phases; the shock phase and the post-resuscitation phase. In our most over-arching hypothesis, we propose that changes in gene expression during shock regulate post-resuscitation inflammatory changes and contribute to direct organ damage and dysfunction. In support of this hypothesis, we have shown that several key genes are up-regulated early during shock, including the inducible nitric oxide synthase (iNOS) and cyclooxygenase- 2 (COX-2). We also have demonstrated that the up-regulation of iNOS during shock activates inflammatory signaling pathways and contributes to end-organ damage and dysfunction post-resuscitation. Another major aspect of our overall hypothesis is that the duration and severity of the shock phase determine the degree of phenotypic changes and hence the intensity of the inflammatory response following resuscitation. Data generated within the individual projects over the first two- and-a- half years of funding support our hypothesis. Project (Dr. Billiar) has shown that iNOS and COX-2 are up-regulated during shock and that NF- kappaB activation, IL-6 expression, and PMN influx are largely iNOS- dependent. This project will explore the mechanism of iNOS up- regulation during shock and the mechanisms of NO-mediated pro- inflammatory signaling post-resuscitation. Dr. Bauer has shown that both iNOS and COX-2 are responsible for shock-induced gut dysmotility through mechanisms involving PMN influx, IL-6, and vasoactive intestine peptide (VIP). He will establish the mechanisms by which iNOS and COX-2 are responsible for shock-induced gut dysmotility. Dr. Fink (Project IV) is a newcomer to the center, and brings expertise in the mechanisms of gut mucosal barrier function. His findings suggest that iNOS up-regulation in the mucosal leads to mucosal damage and loss of barrier function. He will pursue the mechanisms of iNOS-induced mucosal damage. Dr. Pitt has identified a key interaction between NO and metallothionine (MT) in mesenteric vessels during shock. NO displaces zinc from MT and Dr. Pitt will explore the role of NO in metal ion homeostasis in vascular dysfunction in HS. Under the umbrella of our overall hypothesis, all four projects study common major themes. iNOS up-regulation during shock has a major impact on organ function and damage. The actions of NO are determined, in part, through interaction with superoxide, COX-2, and MT. The pursuit of common themes presents many opportunities for collaboration and interaction. As in the past, we will continue to take full advantage of these opportunities. Based on our progress to date, there is ample evidence that we have established a productive synergy between the project leaders. This has been facilitated not only by common hypotheses and themes but also collaborative experiments, joint conferences, and shared resources.
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