Triggering Mechanisms of Post-Operative Ileus

术后肠梗阻的触发机制

• 批准号: 7077751
• 负责人: ANTHONY J BAUER
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077751
• 关键词: arachidonate; cell migration; enteric nervous system; fibronectins; gastrointestinal motility /pressure; hyaluronate; inflammation; intestine obstruction; intestines; laboratory mouse; leukocyte adhesion molecules; macrophage; neuromuscular function; neuroregulation; pathologic process; postoperative complications; postoperative state; smooth muscle

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.

描述（由申请人提供）：