Protective Mechanisms of CO in Intestinal Inflammation

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DESCRIPTION (provided by applicant): Postoperative ileus, the impaired intestinal contractility following abdominal surgery, continues to be a major clinical problem, extending hospital stay and contributing to medical complications. We and others have observed that operative procedures initiate pro-inflammatory molecular events within the muscle layer of the G.I. tract which underlie the development of intestinal dysmotility. Furthermore, differences in the onset and resolution of inflammation have been identified in the small bowel and colon. The role of anti-inflammatory mechanisms in the resolution of inflammation and restoration of function are still ill-defined. We hypothesize that the early induction of anti-inflammatory pathways, or providing the endproducts of these pathways, could be exploited therapeutically to limit inflammation and reduce or prevent the functional and molecular manifestations of postoperative ileus. The inducible isoform of the enzyme heme oxygenase, HO-1, is a ubiquitous stress response protein that is highly induced by a variety of stress-related conditions. Studies report that early induction of HO-1, or exposure by inhalation to very low concentrations of CO, a normal byproduct of HO-1 activity, is highly protective against inflammatory injury. The proposed studies will establish signaling mechanisms by which CO-induced anti-inflammatory pathways protect the gut from the functional and molecular manifestations of inflammation. CO exposure constitutes a novel and non-invasive technique to determine how regional differences in pro- and anti-inflammatory signaling events are regulated, findings that have important implications for clinical management strategies, not just for intestinal inflammation, but also other organ systems. Specific aims: AIM 1: Determine whether exposure to CO prior to colonic surgery will attenuate colonic dysmotility. AIM 2: Determine effects of CO exposure on pro- and anti-inflammatory mediator expression (transcription, translation, enzyme activity) in the colon. AIM 3: Identify the mechanistic pathways by which CO alters pro- and anti-inflammatory signaling, and identify regional differences.