Mechanisms of Postoperative Ileus

术后肠梗阻的机制

• 批准号: 7688268
• 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/7688268
• 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啮齿动物术后肠梗阻(POI)动物模型神经免疫机制的了解，为减少腹部手术后肠梗阻(POI)的发展开辟新的策略。POI除了会给患者带来严重的不适(腹胀、恶心、呕吐和腹痛)外，还会阻碍康复，并构成手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。最近对治疗方法的回顾指出，缺乏有效的预防性治疗，而且我们对病理生理机制的了解很少。我们将基于上一次授权期内获得的数据和新的初步数据来检验这一假设，即腹部手术招募了与应激相关的机制，最突出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，该系统有助于协调外部和肌间神经活动的变化，以及导致肠道推进运动功能受损的局部炎症反应。为此，将通过1)鉴定CRF配体(CRF和urocortins，UCNs)、CRF受体及其剪接变体在调节自主神经流出到结肠的选择性脑核的表达，并利用药理学方法确定脑CRF2受体在结肠POI中的功能相关性；2)评估UCNs/CRF2系统在结肠内的上调以及相关的神经元和常驻巨噬细胞释放一氧化氮的增加，从而降低结肠的动力；3)建立腹部手术后激活脑CRF通路可刺激交感神经流出和抑制迷走神经活动并抵消这些自主神经变化，通过恢复肌神经活性和抑制局部炎症反应来改善POI。实现这些目标的方法将重点介绍我们实验室最近取得的新技术进展，包括用于评估啮齿动物CRF配体和CRF1和CRF2受体基因表达的关键分子探针，我们克隆的新型受体变体，利用激光捕获的显微解剖大脑核的应用，利用功能性Fos免疫组织化学监测大脑和肌间神经元活动增加的能力，以及通过Mikrotop压力传感器等新型非侵入性方法实时监测清醒啮齿动物的结肠运动的能力，药理工具(选择性CRF受体亚型激动剂和拮抗剂)以及转基因小鼠模型。CRF/UCNs在脑和肠道中参与腹部手术后POI的信号通路的特征将使我们能够揭示POI的发病机制。这项实验研究与退伍军人管理局患者护理任务有关，是与压力、创伤和胃肠道系统紊乱有关的医学研究优先领域的一部分，尤其与部署在战区的越来越多的退伍军人遭受需要手术的创伤有关。 公共卫生相关性： 简介本研究旨在揭示与腹部手术相关的术后肠梗阻的发病机制，作为与压力、创伤和胃肠系统紊乱相关的医学研究优先领域的一部分，与患者护理任务相关，这一点尤其相关，因为部署在战区的许多退伍军人都受到了需要手术的伤害，而且为移除恶性肿瘤、减肥手术或其他情况而接受腹部手术的退伍军人的发病率很高。