Triggering Mechanisms of Post-Operative Ileus

描述(由申请人提供)： 术后肠梗阻(POI)发生于每年超过1000万次腹部手术后，是如此常见，以至于肠梗阻被认为是一种公认的医源性后果，是肠道对手术创伤的一种生理反应。术后并发症的重要性已被广泛认识，其经济负担估计为每年10亿美元。其原因似乎涉及三个主要机制：早期神经源性活动增强，术后药物治疗，以及本实验室建立的新机制-局部肠道炎症反应。我们已经证明，POI肠梗阻的延长是由肠道分子炎症反应引起的，它包括：i。激活致密的巨噬肌细胞网络，II。)转录因子的磷酸化和细胞因子、趋化因子和平滑肌抑制物质(iNOS和COX-2)的上调，III.)血管黏附分子的表达增加，随后白细胞重新聚集并渗入环状肌层，并进一步释放/分泌各种有效的白细胞产物。这些事件一起成功地延迟了胃肠道的传输，降低了局部神经肌肉功能，并激活了神经源性抑制通路，从而持续抑制了整个胃肠道的运动。在短短五年的时间里，这项工作现在被认为是腹部手术后POI的主要原因。然而，这些先前的研究没有解决术后肠梗阻的触发因素--简单地说：外科医生的手触发了什么导致炎症反应的发展？我们现在建议研究POI的双分子触发假说：1)物理操作肠壁，释放花生四烯酸，导致炎症性二十烷酸信号和，2。细胞外基质产物(透明质酸和纤维连接蛋白片段)的物理破坏和释放，以及随后的CD44介导的炎症信号。

DESCRIPTION (provided by applicant): Postoperative ileus (POI), occurring after over 10 million abdominal surgeries per year, is so common that ileus is thought to be an accepted iatrogenic consequence and a "physiological" reaction of the bowel to operative trauma. The significance of postoperative morbidity is widely acknowledge, and its economic burden has been estimated at $1 billion per year. Three main mechanisms appear to be involved in its causation: early enhanced neurogenic activity, postoperative medications and the novel mechanism established by this laboratory - a local enteric inflammatory response. We have shown that the prolonged phase of POI ileus is caused by an enteric molecular inflammatory response that consists of: i.) activation of a dense network of muscularis macrophages, ii.) phosphorylation of transcription factors and upregulation of cytokines, chemokines and smooth muscle inhibitory substances (iNOS and COX-2), iii.) an increased expression of vascular adhesion molecules with the subsequent recruitment and extravasation of leukocytes into the circular muscle layer and the further release/secretion of various potent leukocytic products. Together these events succeed in delaying gastrointestinal transit, decrease local neuromuscular function, and activate neurogenic inhibitory pathways that suppress motility along the entire gastrointestinal tract for sustained periods. In just five years, this body of work is now acknowledged to be the principle cause of POI following abdominal surgery. These previous studies, however, have not addressed the "TRIGGER" for postoperative ileus - simply stated: what does the surgeon's hand trigger that results in the development of the inflammatory response? We now propose to investigate a dual molecular TRIGGER hypothesis for POI: 1.) physical manipulation of the intestinal wall with release of arachidonic acid resulting in inflammatory eicosanoid signaling and, 2.) physical disruption and release of extracellular matrix products (hyaluronic acid and fibronectin fragments) with subsequent CD44-mediated inflammatory signaling.