Shock causes disproportionate splanchnic vasoconstriction in trauma patients that persists despite adequate volume resuscitation. Typically, these patients require anesthetics or sedation for their ventitatory support in the ICU and analgesics for pain control. Frequently, gut dysfunction results due to activation of cytotoxic and inflammatory mediators through changes in expression of pro and anti-inflammatory gene products. However, we still have significant gaps in our understanding of the molecular programs activated that in turn orchestrate the pattern, timing, and magnitude of expression of these injurious genes. It is our contention that some of the currently used agents in the ICU amplify gut dysfunction through changes in molecular signalling events that influence the expression of injurious and protective genes that contribute to gut injury and multiple organ dysfunction syndrome. It is the PROJECT HYPOTHESIS that shock causes gastric dysfunction through changes in molecular stress response factors and that these changes can be therapeutically modulated. The current research proposal will characterize these molecular signalling events and identify the gene products that determine the fate of the injured stomach following shock to develop potential therapeutic strategies that may improve gastric function in the ICU setting.
The specific aims to prove or disprove this hypothesis are as follows.
The first aim will characterize the molecular events that occur in the stomach following shock.
The second aim will characterize the effects of the anesthetic ketamine as well as other anesthetics and sedatives on shock induced gastric dysfunction and molecular stress response genes.
The third aim will examine the effects of cyclo-oxygenase inhibition and other analgesics on shock induced gastric dysfunction and molecular stress response genes. The results of the proposed studies could result in potential therapeutic agents that would abrogate gastric dysfunction following shock with a resultant decrease in the need for expensive stress gastritis prophylactic agents, allow for gastric feeding to proceed unabated, and reduce ICU length of stay and ICU mortality.
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