Pathogenesis of gut dysfunction in bowel obstruction and after obstruction is resolved

肠梗阻时及梗阻解除后肠道功能障碍的发病机制

• 批准号: 9149191
• 负责人: Xuan-Zheng Peter Shi
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149191
• 关键词: Abdomen; Abdominal Pain; Accounting; Acute; Acute Abdomen; Admission activity; Adult; Afferent Neurons; American; Brain-Derived Neurotrophic Factor; Cations; Child; Chronic; Colon; Congenital Megacolon; Constipation; Defecation; Development; Dinoprostone; Distal; Fecal Incontinence; Functional disorder; Gene Expression; Genetic Transcription; Goals; Health; Hospitals; Hypersensitivity; Immune Sera; Intervention; Intestinal Obstruction; Intestines; Left; Length of Stay; Malignant - descriptor; Measures; Mechanical Stress; Mechanics; Mediator of activation protein; Megacolon; Modeling; Molecular; Muscle function; Nerve; Nerve Growth Factors; Neuronal Plasticity; Neurons; Obstruction; Operative Surgical Procedures; Oral; Pain; Pathogenesis; Patients; Play; Pre-Clinical Model; Production; Prostaglandins; Rattus; Resolution; Role; Site; Smooth Muscle Myocytes; Spinal Ganglia; Surgeon; Symptoms; TRPV1 gene; Testing; Therapeutic; Time; Up-Regulation; Visceral; Voltage-Gated Potassium Channel; Woman; Work; base; cell motility; constriction; cost; cyclooxygenase 2; effective therapy; follow-up; gastrointestinal; gastrointestinal symptom; improved; in vitro Model; in vivo; inhibitor/antagonist; new therapeutic target; novel; novel strategies; prevent; prophylactic; protein kinase D; receptor; response; voltage

 DESCRIPTION (provided by applicant): Bowel obstruction (BO) is a significant health challenge in adults and children, and accounts for more than 300,000 hospital admissions in the US per year. Abdominal pain and motility dysfunction are two main concerns in the conservative management of BO, especially in inoperable and malignant BO. About 57% of BO patients are treated by surgery. The current surgical approach is to release blockage or remove the distal constrictive segment, but to leave alone the distended segment in the gut. However, after the surgery, many patients suffer long-term gut dysfunction such as abdominal discomfort, pain and constipation. The pathogenesis of gut dysfunction in BO and after its release remains poorly understood. There is no effective treatment for the condition that impacts millions of patients. We hypothesize that mechanical stress-induced gene expression (mechano-transcription) in gut smooth muscle cells (SMC) in the distended segment not only plays a critical role in abdominal pain and motility dysfunction during BO, but exerts prolonged effects on bowel function through its secondary effects on gene expression in colonic sensory neurons and SMC. To test the hypothesis, we will focus on two aspects of gut dysfunction, i.e., abdominal pain in Aim 1 and motility dysfunction in Aim 2. In Aim 1, we propose that mechanical stress-induced expression of pain mediators nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in colonic SMC sensitize colonic sensory neurons and contribute to pain during BO. NGF increases the expression and function of transient receptor potential cation channel subtype V1 (TRPV1) and voltage-gated Na+ channel, whereas BDNF down-regulates the expression and function of voltage-gated K+ channel in colonic sensory neurons. Some of the secondary changes (i.e., up-regulation of TRPV1) in sensory neurons are long-lasting, and account for persistent visceral hypersensitivity after BO is released. In Aim 2, we will investigate the mechanisms of motility dysfunction during BO and after BO is resolved. We found for the first time that protein kinase D (PKD) is profoundly involved in the cellular response to mechanical stress. We will test the working hypothesis that mechano-transcription in colonic SMC plays a critical role in motility dysfunction not only during BO via PKD1-dependent induction of cyclooxygenase-2 (COX-2), but also after BO is resolved through prostaglandin E2 (PGE2)- dependent up-regulation of microsomal PGE synthase-1 (mPGES-1). We will use in vivo and in vitro models to define these novel mechanisms. In summary, our study suggests that the once distended oral segment in BO is where mechano-transcription occurs, and is the cause of long-term gut dysfunction. Proposed studies will identify potential prophylactic and therapeutic treatments towards the dysfunction. Inhibition of mechano-transcription during BO (i.e. NGF antiserum and PKD1 inhibitor) may not only improve pain and motility function in BO, but also prevent long-term gut dysfunction, whereas targeting secondary effects (i.e. TRPV1 and mPGES-1) following the release of BO is a potential treatment for long-term gut dysfunction.

 描述（由申请人提供）：肠梗阻 (BO) 是成人和儿童面临的一项重大健康挑战，每年导致美国超过 300,000 人入院。腹痛和运动功能障碍是 BO 保守治疗中的两个主要问题，特别是对于无法手术的恶性 BO。约57%的BO患者通过手术治疗。目前的手术方法是解除阻塞或切除远端收缩段，但保留肠道内扩张的段。然而，手术后，许多患者会出现长期的肠道功能障碍，如腹部不适、疼痛和便秘。 BO 及其释放后肠道功能障碍的发病机制仍知之甚少。对于影响数百万患者的疾病，目前尚无有效的治疗方法。我们假设扩张段肠道平滑肌细胞 (SMC) 中机械应力诱导的基因表达（机械转录）不仅在 BO 期间的腹痛和运动功能障碍中发挥关键作用，而且还通过其对结肠感觉神经元和 SMC 基因表达的二次影响对肠功能产生长期影响。为了检验这一假设，我们将重点关注肠道功能障碍的两个方面，即目标 1 中的腹痛和目标 2 中的运动功能障碍。在目标 1 中，我们提出机械应力诱导的结肠 SMC 中疼痛介质神经生长因子 (NGF) 和脑源性神经营养因子 (BDNF) 的表达使结肠感觉神经元敏感并导致 BO 期间的疼痛。 NGF 增加瞬时受体电位阳离子通道亚型 V1 (TRPV1) 和电压门控 Na+ 通道的表达和功能，而 BDNF 下调结肠感觉神经元中电压门控 K+ 通道的表达和功能。感觉神经元中的一些继发变化（即 TRPV1 的上调）是持久的，并且是 BO 释放后持续的内脏超敏反应的原因。在目标 2 中，我们将研究 BO 期间和 BO 解决后运动功能障碍的机制。我们首次发现蛋白激酶 D (PKD) 与细胞对机械应力的反应密切相关。我们将检验以下工作假设：结肠 SMC 中的机械转录不仅在 BO 期间通过 PKD1 依赖性环加氧酶 2 (COX-2) 诱导，而且在 BO 通过前列腺素 E2 (PGE2) 依赖性微粒体 PGE 合酶 - 1 (mPGES-1) 上调解决后在运动功能障碍中发挥关键作用。我们将使用体内和体外模型来定义这些新机制。总之，我们的研究表明，BO 中曾经扩张的口腔部分是机械转录发生的地方，并且是长期肠道功能障碍的原因。拟议的研究将确定针对功能障碍的潜在预防和治疗方法。 BO期间的机械转录抑制（即NGF抗血清和PKD1抑制剂）不仅可以改善BO的疼痛和运动功能，还可以预防长期肠道功能障碍，而针对BO释放后的二次效应（即TRPV1和mPGES-1）是长期肠道功能障碍的潜在治疗方法。