THE ROLE OF THE GUT IN MULTIPLE ORGAN FAILURE (MOF)

Abstract

The gut is both the instigator and victim of MOF. Our current global hypothesis is that novel therapeutic interventions can modulate gut inflammation and dysfunction related to MOF to improve patient outcome. Project 1 is identifying the key molecular events by which therapeutic interventions differentially modulate protective anti-inflammation over injurious pro-inflammation. In the intensive care unit (ICU) the Clinical Core has standardized shock resuscitation (resus) and identified that crystalloid resus causes problematic gut edema. Project 2 is studying gut edema and its effects on gut function. Project 3 is examing the mechanism by which hypertonic saline resus limits ischemia reperfusion induced gut inflammation. A minority supplement is studying novel adjuncts in this model. In the ICU the Clinical Core has standardized early enteral nutrition (EEN) but has identified that after severe shock EEN can cause devastating nonocclusive bowel necrosis. A K-08 project is investigating how intraluminal nutrients can protect against IR inflammation. Additionally, the Clinical Core has identified that gastroparesis is an obstacle in EEN and that the stomach remains alkinalized in the early postinjury period. Project 4 is studying how sedative doses of ketamine instead of morphine can limit gastric inflammation, alkinalization and gastroparesis. A clinical trial is proposed. A 2nd K08 is studying the role of matrix metalloproteinases in sepsis induced gastric inflammation. In the ICU the Clinical Core has observed that bile reflux contributes to stress gastritis. Project 5 is exploring how novel phospholipids can maintain the hydrophobic barrier which protects against bile reflux induced inflammation. Through collaborative multidisciplinary efforts the UTHMS TRC is improving our basic understanding of how the gut contributes to adverse outcome in critical illness and is providing an environment in which to train the next generation of clinical scientists. NIGMS P50 GM38529, T32GM08792, K08 GM62975, K08 GM070812.