Reflexes and Supraesophageal Consequences of Reflux Disease

描述(申请人提供)：食道上并发症是胃食道反流病(GERD)的主要组成部分。例如，GERD是慢性咳嗽的主要原因。GERD也是哮喘和COPD的常见并存，会加重与这些肺部疾病相关的症状。我们假设，反流物通过两种不同的机制启动咳嗽和其他呼吸道防御反射。首先，吸入回流液会激活我们最近发现的一种呼吸道传入神经亚型，直接导致咳嗽。“咳嗽感受器”终止于肺外呼吸道上皮下，对点状机械刺激和酸非常敏感，理想的位置和反应调节吸入时的咳嗽。其次，我们认为肺反射，如咳嗽，可能会被反流放大，而不依赖于吸入。我们最近发现了三种类型的伤害性感受器，它们可以被包括酸在内的有害机械和化学刺激所激活。我们推测，从这些伤害性感受器的中央终末释放的递质将起到敏化由呼吸道迷走传入神经激活(即，由食道和呼吸道传入神经调节的中枢敏化)的反射的作用。我们已经直接证明了这一点，因为选择性地将辣椒素注射到食道不会引起咳嗽，但显著地敏化由咳嗽感受器刺激引起的咳嗽反射。在本提案的目标1和2中，我们将进一步描述支配食道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，将使用逆行神经元示踪和微量注射的药理学分析来确定食道传入神经激活敏化咳嗽反射的途径、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以及体内药理学分析来确定调节酸和回流液激活咳嗽感受器的离子通道。计划中的实验的多学科方法应该为GERD食道上后果的潜在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.