Protective Mechanisms of CO in Intestinal Inflammation

描述（由申请人提供）：术后肠梗阻（腹部手术后肠道收缩力受损）仍然是一个主要的临床问题，会延长住院时间并导致医疗并发症。我们和其他人观察到，手术过程会引发胃肠道肌肉层内的促炎分子事件。肠道运动障碍发展的基础。此外，小肠和结肠中炎症的发生和消退也存在差异。抗炎机制在炎症消退和功能恢复中的作用仍不明确。我们假设抗炎途径的早期诱导，或提供这些途径的最终产物，可以在治疗上用于限制炎症并减少或预防术后肠梗阻的功能和分子表现。血红素加氧酶的诱导型异构体 HO-1 是一种普遍存在的应激反应蛋白，可被多种应激相关条件高度诱导。研究报告称，早期诱导 HO-1，或通过吸入极低浓度的 CO（HO-1 活性的正常副产品），对炎症损伤具有高度保护作用。拟议的研究将建立信号传导机制，CO诱导的抗炎途径可保护肠道免受炎症的功能和分子表现的影响。 CO暴露是一种新颖的非侵入性技术，可确定促炎和抗炎信号事件的区域差异如何受到调节，这些发现对临床管理策略具有重要意义，不仅适用于肠道炎症，也适用于其他器官系统。具体目标： 目标 1：确定结肠手术前暴露于 CO 是否会减轻结肠动力障碍。目标 2：确定 CO 暴露对结肠中促炎和抗炎介质表达（转录、翻译、酶活性）的影响。目标 3：确定 CO 改变促炎和抗炎信号传导的机制途径，并确定区域差异。

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.