Reflexes and Supraesophageal Consequences of Reflux Disease

描述（由申请方提供）：食管上并发症是胃食管反流病（GERD）的主要组成部分。例如，GERD是慢性咳嗽的主要原因。GERD也是一种常见的哮喘和COPD合并症，它掩盖了与这些肺部疾病相关的症状。我们假设反流液通过两种不同的机制引发咳嗽和其他气道防御反射。首先，反流物的吸入激活了我们最近发现的直接导致咳嗽的气道传入神经亚型。终止于肺外气道的上皮下方，“咳嗽受体”对间断的机械刺激和酸非常敏感，并且理想地定位和响应于在吸入时调节咳嗽。第二，我们提出肺反射，如咳嗽，可能会被反流放大，独立于吸入。我们最近已经确定了3种神经支配食管的伤害感受器亚型，它们被有害的机械和化学刺激（包括酸）激活。我们假设，从这些伤害感受器的中央末梢释放的递质将起作用，以敏化由气道迷走传入神经激活引发的反射（即由食管和气道传入神经调节的中枢敏化）。我们已经直接证明了这一点，因为辣椒素选择性地给予食管不会引起咳嗽，但会显著地使咳嗽受体刺激引起的咳嗽反射敏感。在本提案的目标1和2中，我们将进一步表征支配食管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。在目标3中，使用显微注射的逆行神经元追踪和药理学分析将用于定义食管传入神经激活使咳嗽反射敏感的途径、递质和机制。最后，在目标4中，我们将使用膜片钳和细胞外记录技术沿着体内药理学分析来确定调节酸和回流物引起的咳嗽受体活化的离子通道。计划的实验的多学科方法应提供重要的见解的机制，胃食管反流病的食管上的后果。这项研究也可能有助于确定治疗GERD和慢性咳嗽的新治疗策略。

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.