Triggering Mechanisms of Post-Operative Ileus

描述（由申请人提供）： 术后肠梗阻（POI），发生在每年超过1000万次腹部手术后，是如此常见，肠梗阻被认为是一种公认的医源性后果和肠道对手术创伤的“生理”反应。术后发病率的重要性已被广泛承认，其经济负担估计为每年10亿美元。三个主要机制似乎涉及其因果关系：早期增强的神经原性活动，术后药物和本实验室建立的新机制-局部肠道炎症反应。我们已经表明，POI肠梗阻的延长期是由肠分子炎症反应引起的，所述肠分子炎症反应由以下组成：i.）激活肌层巨噬细胞的致密网络，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和考克斯-2）的上调，iii.）血管粘附分子的表达增加，随后白细胞募集和外渗到环形肌层中，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胃肠道转运，降低局部神经肌肉功能，并激活神经源性抑制通路，从而持续抑制沿着整个胃肠道的运动。在短短五年内，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“触发器”-简单地说：外科医生的手触发了什么导致炎症反应的发展？我们现在提出研究POI的双分子触发假说：1）。物理操纵肠壁释放花生四烯酸，导致炎症性类二十烷酸信号传导，以及，2.）细胞外基质产物（透明质酸和纤连蛋白片段）的物理破坏和释放，随后是CD 44介导的炎症信号传导。

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.