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理解，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）的发展。除了引起患者的显著不适（腹胀、恶心、呕吐和腹痛）之外，POI妨碍恢复并且构成手术后延迟出院的最常见原因，从而引起实质性的社会经济负担。最近的治疗方式的审查指出，缺乏有效的预防性治疗和我们的病理生理机制的认识不足。我们将基于在最后一次授权期间获得的数据和新的初步数据来检验这一假设，即腹部手术招募应激相关机制，最显著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（CRF 2）系统，其有助于协调外在和肌间神经元活动的改变以及导致肠道推进运动功能受损的局部炎症反应。这将通过1）表征CRF配体的表达来实现（CRF和尿皮质素，Ucns），CRF受体及其剪接变体在选择性脑核中调节自主流出到结肠，并使用药理学方法建立脑CRF 2受体在结肠POI中的功能相关性; 2）评估结肠内Ucns/CRF 2系统的上调以及相关的从神经元和驻留巨噬细胞释放一氧化氮的增加，从而降低结肠运动性; 3）确定响应于腹部手术的脑CRF通路的激活诱导交感神经流出的刺激和迷走神经活性的抑制，并且抵消这些自主变化通过恢复肌间神经元活性和减少局部炎症反应来改善POI。实现这些目标的方法将详述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CRF 1和CRF 2受体的基因表达的关键分子探针，以及我们克隆的新型受体变体，使用激光捕获的显微切割脑核，使用功能性Fos免疫组织化学沿着与真实的-在清醒啮齿动物、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对结肠运动进行时间监测。CRF/Ucns信号通路在大脑和肠道中的特征，有助于腹部手术引起的POI将使我们能够发现新的机制，在POI的发病机制。这项实验研究是相关的VA病人护理使命的一部分，医学研究的优先领域，涉及压力，创伤和胃肠系统疾病，这是特别相关的，因为越来越多的战斗退伍军人部署在战区遭受创伤性损伤，需要手术。 公共卫生关系： 叙述本研究旨在揭示与腹部手术相关的术后肠梗阻发病机制的潜在机制，与患者护理使命相关，作为医学研究优先领域的一部分，其涉及应激、创伤和胃肠系统疾病，这一点尤其重要，因为许多部署在战区的退伍军人受伤需要手术，而且退伍军人接受腹部手术的发生率很高恶性肿瘤切除手术、减肥手术或其他病症。