Reflexes and Supraesophageal Consequences of Reflux Disease

反流病的反射和食管上后果

• 批准号: 7458670
• 负责人: BRENDAN J CANNING
• 金额: $ 31.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-21 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458670
• 关键词: ASIC channel; Acids; Address; Asthma; Capsaicin; Cavia; Chemicals; Chronic; Chronic Obstructive Airway Disease; Coughing; Disease; Epithelium; Esophageal; Esophagus; Gastroesophageal reflux disease; Gene Expression; Hyperalgesia; Immunohistochemistry; In Vitro; Ion Channel; Lung; Lung diseases; Mechanics; Mechanoreceptors; Microinjections; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Neurons; Nociceptors; Nucleus solitarius; Pain; Pathway interactions; Peripheral; Physiological; Play; Process; Property; Receptor Activation; Reflex action; Reflux; Relative (related person); Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Stimulus; Symptoms; Techniques; Tissues; afferent nerve; central sensitization; extracellular; in vivo; information gathering; insight; interdisciplinary approach; nerve supply; neurochemistry; novel therapeutics; patch clamp; receptor; respiratory reflex; response; single cell analysis

DESCRIPTION (provided by applicant): Supraesophageal complications are a major component of gastroesophageal reflux disease (GERD). GERD, for example, is a leading cause of chronic cough. GERD is also a frequently observed co-morbidity of asthma and COPD that worsens the symptoms associated with these pulmonary disorders. We hypothesize that refluxate initiates coughing and other airway defensive reflexes by two disparate mechanisms. First, aspiration of refluxate activates an airway afferent nerve subtype we have recently identified leading directly to coughing. Terminating beneath the epithelium of the extrapulmonary airways, the "cough receptors" are exquisitely sensitive to punctuate mechanical stimuli and acid and ideally situated and responsive to regulate coughing upon aspiration. Second, we propose that pulmonary reflexes such as cough may be amplified by reflux, independent of aspiration. We have recently identified 3 subtypes of nociceptors innervating the esophagus that are activated by noxious mechanical and chemical stimuli including acid. We hypothesize that transmitters released from the central terminals of these nociceptors will act to sensitize reflexes initiated by activation of airway vagal afferent nerves (i.e. central sensitization regulated by esophageal and airway afferent nerves). We have shown this directly, as capsaicin selectively administered to the esophagus does not evoke cough but markedly sensitizes the cough reflex evoked by cough receptor stimulation. In Aims 1 and 2 of this proposal, we will further characterize the electrophysiological and neurochemical properties of the vagal afferents innervating the esophagus and assess the relative capacity of these subtypes to regulate the cough reflex. In Aim 3, retrograde neuronal tracing and pharmacological analyses using microinjection will be used to define the pathways, transmitters and mechanisms by which esophageal afferent nerve activation sensitizes the cough reflex. Finally, in Aim 4, we will use patch clamp and extracellular recording techniques along with in vivo pharmacological analyses to determine the ion channels regulating cough receptor activation by acid and refluxate. The multidisciplinary approach of the planned experimentation should provide important insights into the mechanisms underlying the supraesophageal consequences of GERD. This research may also help identify novel therapeutic strategies for treating both GERD and chronic cough.

描述（由申请人提供）：食管上并发症是胃食管反流疾病（GERD）的主要组成部分。例如，GERD是慢性咳嗽的主要原因。 GERD也是经常观察到的哮喘和COPD的合并症，这会使与这些肺部疾病相关的症状恶化。我们假设回流通过两种不同的机制启动咳嗽和其他气道防御反射。首先，回流的抽吸激活了我们最近直接导致咳嗽的气道传入神经亚型。 “咳嗽受体”终止于肺外气道的上皮下的上皮下，对标点的机械刺激和酸非常敏感，并且理想位置且反应迅速，以调节抽吸时的咳嗽。其次，我们提出，肺反射（例如咳嗽）可以通过反流（与抽吸无关）扩增。我们最近确定了3个亚型的伤害感受器，这些亚型神经食管被包括有害的机械和化学刺激激活，包括酸。我们假设从这些伤害感受器的中央末端释放的发射机将起作用，以使气道迷走神经神经激活引发的反射（即，由食管和气道传入神经调节的中心敏化）。我们已经直接表明了这一点，因为辣椒素选择性地给予食管并未引起咳嗽，但明显地敏感了咳嗽受体刺激引起的咳嗽反射。在该提案的目标1和2中，我们将进一步表征神经化的迷走神经传入的电生理和神经化学特性，并评估这些亚型调节咳嗽反射的相对能力。在AIM 3中，使用显微注射的逆行神经元跟踪和药理学分析将用于定义食管传入神经激活敏感咳嗽反射的途径，发射器和机制。最后，在AIM 4中，我们将使用斑块夹和细胞外记录技术以及体内药理学分析来确定通过酸和流动性转化调节咳嗽受体激活的离子通道。计划的实验的多学科方法应为GERD上po骨上方后果的基础机制提供重要的见解。这项研究还可能有助于确定治疗GERD和慢性咳嗽的新型治疗策略。