Protective Mechanisms of CO in Intestinal Inflammation

描述(申请人提供)：术后肠梗阻，腹部手术后肠道收缩功能受损，仍然是一个主要的临床问题，延长住院时间，并导致医疗并发症。我们和其他人已经观察到，手术过程在胃肠道肌层内启动促炎分子事件，这是肠道运动障碍发展的基础。此外，在小肠和结肠中发现了炎症的发生和消退的差异。抗炎机制在炎症消退和功能恢复中的作用仍不明确。我们推测，早期诱导抗炎通路，或提供这些通路的最终产物，可以在治疗上用于限制炎症，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亚型HO-1是一种普遍存在的应激反应蛋白，在各种应激相关条件下高度诱导。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)暴露于其中，对炎症损伤具有高度保护作用。拟议的研究将建立信号机制，通过CO诱导的抗炎途径保护肠道免受炎症的功能和分子表现的影响。一氧化碳暴露是一种新的非侵入性技术，可以确定促炎和抗炎信号事件的区域差异是如何调节的，这一发现不仅对肠道炎症，而且对其他器官系统的临床管理策略都具有重要意义。具体目标：目标1：确定结肠手术前暴露于一氧化碳是否会减轻结肠运动障碍。目的2：探讨一氧化碳暴露对大鼠结肠促炎和抗炎介质表达(转录、翻译、酶活性)的影响。目的3：确定一氧化碳改变促炎和抗炎信号的机制，并确定地区差异。

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.