Mechanisms of Postoperative Ileus

术后肠梗阻的机制

• 批准号: 8258634
• 负责人: YVETTE FRANCE TACHE
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258634
• 关键词: Abdomen; Abdominal Pain; Affinity; Agonist; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Area; Autonomic nervous system; Brain; Brain Stem; CRF receptor type 1; CRF receptor type 2; Cell Nucleus; Cerebral Ventricles; Chewing Gum; Colon; Conscious; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Development; Disease; Excision; Experimental Models; Gastrointestinal Motility; Gastroparesis; Gene Expression; Grant; Health Care Costs; Hospitals; Hypothalamic structure; Ileus; Immune; Immunohistochemistry; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Intestines; Intravenous; Laboratories; Laparotomy; Lasers; Lateral; Ligands; Link; Liquid substance; Malignant Neoplasms; Medical Research; Meta-Analysis; Methods; Mission; Modality; Molecular Probes; Monitor; Motor; Nausea; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Operative Surgical Procedures; Opiates; Opioid Receptor; Outcome; Palpation; Pathogenesis; Pathway interactions; Patient Care; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Play; Polymerase Chain Reaction; Pontine structure; Postoperative Period; Preventive; Process; Progress Reports; Protein Isoforms; RNA Splicing; Rattus; Recovery; Recruitment Activity; Regulation; Research; Research Priority; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Signal Pathway; Signal Transduction; Small Intestines; Stomach; Stress; System; Testing; Therapeutic Intervention; Thyrotropin-Releasing Hormone; Time; Transgenic Mice; Trauma; United States; Up-Regulation; Vagus nerve structure; Variant; Veterans; Vomiting; War; Work; arm; bariatric surgery; base; cell motility; cholinergic; combat; corticotropin releasing factor-binding protein; gastrointestinal system; hormone analog; improved; insight; interest; laser capture microdissection; macrophage; motility disorder; mouse model; nerve supply; novel; novel strategies; pressure; psychological stressor; public health relevance; receptor; research study; response; sensor; sham feeding; somatostatin analog; stressor; tool; urocortin

DESCRIPTION (provided by applicant): ABSTRACT The long-term objective is to open new strategies to reduce the development of postoperative ileus (POI) occurring after abdominal surgery involving manipulation of the bowel by increasing the understanding of neuro-immune mechanisms in rodent experimental models of POI. Besides causing significant discomfort to patients (bloating, nausea, emesis, and abdominal pain), POI hampers recovery and constitutes the most common reason for delaying discharge from the hospital after surgery, thus incurring a substantial socio- economical burden. Recent reviews of treatment modalities point out the lack of efficient preventive therapy and our poor understanding of pathophysiological mechanisms. We will test the hypothesis, based on data obtained during the last granting period and novel preliminary data, that abdominal surgery recruits stress- related mechanisms, most prominently corticotropin releasing factor (CRF) receptor 2 (CRF2) system in the brain and the gut, which contributes to orchestrate alterations in extrinsic and myenteric neuronal activity and local inflammatory response leading to impairment of gut propulsive motor function. This will be achieved by 1) characterizing the expression of CRF ligands (CRF and urocortins, Ucns), CRF receptors and their splice variants at selective brain nuclei regulating autonomic outflow to the colon and establishing the functional relevance of brain CRF2 receptors in colonic POI using pharmacological approach; 2) assessing the up- regulation of Ucns/CRF2 system within the colon and related increased release of nitric oxide from neurons and resident macrophages, thereby decreasing colonic motility; 3) establishing that activation of brain CRF pathways in response to abdominal surgery induces stimulation of sympathetic outflow and inhibition of vagal activity and counteracting these autonomic changes improves POI by restoring myenteric neuronal activity and curtailing the local inflammatory response. The approaches to achieve these aims will dwell on new technical advances recently made in our laboratories including key molecular probes to assess gene expression of rodent CRF ligands and CRF1 and CRF2 receptors and novel receptor variants that we have cloned, the use of laser captured microdissected brain nuclei, the ability to monitor increase in neuronal activity in the brain and myenteric neurons using functional Fos immunohistochemistry along with real-time monitoring of colonic motility with novel non-invasive methods of Mikrotip pressure sensor in conscious rodents, pharmacological tools (selective CRF receptor subtype agonists and antagonists) and transgenic mouse models . The characterization of CRF/Ucns signaling pathways in the brain and the gut that contribute to POI induced by abdominal surgery will enable us to uncover novel mechanisms in the pathogenesis of POI. This experimental research is relevant to the VA patient care mission as part of the medical research priority area that relates to stress, trauma and disorders of the gastrointestinal system, which is particularly pertinent as an increasing number of combat veterans deployed in war zone suffered traumatic injuries that required surgery. PUBLIC HEALTH RELEVANCE: NARRATIVE This research directed to uncover mechanisms underlying the pathogenesis of postoperative ileus linked with abdominal surgery is relevant to the patient care mission as part of the medical research priority area that relates to stress, trauma and disorders of the gastrointestinal system, which is particularly pertinent as a number of veterans deployed in war zone undergo injuries requiring surgery and the high incidence of veterans undergoing abdominal surgery for removal of malignancies, bariatric surgery or other conditions.

描述（由申请人提供）： 摘要 长期目标是通过增加对 POI 啮齿动物实验模型中神经免疫机制的了解，开辟新的策略，以减少涉及肠道操作的腹部手术后发生的术后肠梗阻 (POI) 的发生。除了给患者带来明显不适（腹胀、恶心、呕吐和腹痛）外，POI 还会阻碍康复，并成为术后延迟出院的最常见原因，从而造成巨大的社会经济负担。最近对治疗方式的回顾指出，缺乏有效的预防性治疗以及我们对病理生理机制的了解不足。我们将根据上次资助期间获得的数据和新的初步数据来检验这一假设，即腹部手术会招募压力相关机制，最显着的是大脑和肠道中的促肾上腺皮质激素释放因子（CRF）受体2（CRF2）系统，它有助于协调外在和肌间神经元活动以及局部炎症反应的改变，从而导致肠道推进受损 运动功能。这将通过以下方式实现：1) 表征 CRF 配体（CRF 和尿皮质素，Ucns）、CRF 受体及其剪接变体在调节自主神经流向结肠的选择性脑核中的表达，并使用药理学方法建立结肠 POI 中脑 CRF2 受体的功能相关性； 2)评估结肠内Ucns/CRF2系统的上调以及相关的神经元和驻留巨噬细胞释放一氧化氮的增加，从而降低结肠蠕动； 3) 确定腹部手术后大脑 CRF 通路的激活会刺激交感神经流出并抑制迷走神经活动，并抵消这些自主神经变化，通过恢复肌间神经元活动和减少局部炎症反应来改善 POI。实现这些目标的方法将重点关注我们实验室最近取得的新技术进展，包括评估啮齿动物 CRF 配体和 CRF1 和 CRF2 受体基因表达的关键分子探针以及我们克隆的新型受体变体、使用激光捕获显微解剖脑核、使用功能性 Fos 免疫组织化学监测大脑和肌间神经元中神经元活动增加的能力 在有意识的啮齿动物、药理学工具（选择性 CRF 受体亚型激动剂和拮抗剂）和转基因小鼠模型中，使用 Mikrotip 压力传感器的新型非侵入性方法实时监测结肠运动。大脑和肠道中导致腹部手术诱发 POI 的 CRF/Ucns 信号通路的特征将使我们能够揭示 POI 发病机制的新机制。这项实验研究与退伍军人管理局的患者护理任务相关，是与压力、创伤和胃肠系统疾病相关的医学研究优先领域的一部分，随着越来越多部署在战区的退伍军人遭受需要手术的创伤，这一点尤其重要。 公共卫生相关性： 叙述性这项研究旨在揭示与腹部手术相关的术后肠梗阻的发病机制，与患者护理任务相关，作为与压力、创伤和胃肠系统疾病相关的医学研究优先领域的一部分，这一点尤其重要，因为许多部署在战区的退伍军人遭受需要手术的伤害，而且退伍军人接受腹部手术的发生率很高。 用于切除恶性肿瘤、减肥手术或其他病症。