Airway Sensory Neuroexcitability

描述(申请人提供)：呼吸系统中的绝大多数感觉神经是支气管肺C纤维。这些神经分布在整个支气管肺系统。这些神经的激活可导致刺激感和反射，包括无效咳嗽、粘液分泌增加、血管扩张和支气管痉挛。在健康的肺中，它们通常是安静的，但可以被与呼吸道炎症相关的有害刺激和过程激活，包括pH值下降和各种炎症介质的存在。因此，它们被设计为呼吸道防御系统的一部分，但当炎症变成慢性时，它们的过度激活可能会导致呼吸道疾病的症状和病理生理。尽管C纤维在健康和疾病中的相关性，但我们对C纤维在肺中的表型、它们的准确分布以及它们的激活机制的知识基础仍有很大差距。在本提案中，概述了旨在提供关于支气管肺C纤维不同表型的更详细信息的实验。我们将对C纤维在肺内的分布提供新的见解。此外，我们的研究将增加关于神经营养因子、炎症介质和质子导致肺内神经末梢的电兴奋性和动作电位放电变化的生物物理机制的新知识。为了实现我们的目标，我们将结合解剖学和各种电生理学技术，使我们能够以最先进的方式解决我们的假设。

DESCRIPTION (provided by applicant): The vast majority of sensory nerves in the respiratory system are bronchopulmonary C-fibers. These nerves are distributed throughout the bronchopulmonary system. Activation of these nerves can lead to sensation of irritation and reflexes including nonproductive cough, increases in mucus secretion, vasodilatation, and bronchospasm. They are typically quiet in a healthy lung, but can be activated by noxious stimuli and processes associated with airway inflammation including decreases in pH and the presence of various inflammatory mediators. They are thus designed as part of an airway defense system, but when the inflammation becomes chronic, their excessive activation likely contributes to the symptoms and pathophysiology of airway disease. The relevance of bronchopulmonary C-fibers in health and disease notwithstanding, there is a large gap in our knowledge base regarding C-fiber phenotypes in the lungs, their precise distribution, and the mechanisms of their activation. In the present proposal experiments are outlined that are aimed at providing more detailed information on the distinct phenotypes of bronchopulmonary C-fibers. We will provide new insights into the C-fiber distribution within the lungs. In addition our studies will add new knowledge regarding the biophysical mechanisms by which neurotrophins, inflammatory mediators, and protons lead to changes in electrical excitability and action potential discharge at nerve terminals within the lungs. To accomplish our aims we will bring to bear a combination of anatomical and various electrophysiological techniques that allow us to address our hypotheses in a state-of-the-art fashion.