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: 9334200
• 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/9334200
• 关键词: Abdomen; Abdominal Pain; 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; Hospital Costs; Hospitals; Hypersensitivity; Impairment; Intervention; Intestinal Obstruction; Intestines; 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; PTGS2 gene; 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; cell motility; constriction; cyclooxygenase 2; effective therapy; follow-up; gastrointestinal; gastrointestinal symptom; improved; in vitro Model; in vivo; inhibitor/antagonist; mouse PGE synthase 1; new therapeutic target; novel; novel strategies; prevent; prophylactic; protein kinase D; public health relevance; 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.

 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.