Neuro-immune mechanisms in carotid body chemoreceptor response to chronic hypoxia

描述（由申请人提供）：近年来的实验揭示了暴露于特定（慢性）刺激条件下与慢性疼痛发展相关的初级传入神经元的不稳定电生理和神经化学表型。这些研究共同表明，负责功能可塑性的机制主要是由涉及循环和常驻免疫细胞及其分泌产物的新型神经免疫相互作用介导的，它们共同诱导初级感觉神经元的高兴奋性。在另一种外周感觉方式，即动脉化学感受器中，慢性缺氧（CH）形式的持续刺激会引起哺乳动物颈动脉体化学传入兴奋性的增加。先前的研究主要集中在该器官中氧敏感型I细胞的功能变化上，但未能充分阐明启动和控制这种适应性反应的分子和细胞机制。值得注意的是，神经免疫机制在化学传入敏感性增加中的可能参与从未被研究过。我们提出的研究计划评估免疫细胞和细胞因子参与化学传入途径作为化学感觉适应的机制。实验将探讨1)、CH-诱导免疫细胞侵袭和细胞因子产生的趋化传入途径；2)免疫细胞活性与化学敏感性升高的关系；3)，氧敏感性I型细胞在颈动脉体炎症反应中的作用；4)炎症诱导的I型细胞和初级化学传入神经元的表型改变，促进了高兴奋性。初步结果表明，免疫系统在调节颈动脉体对生理上相关的缺氧水平的化学适应性反应中起着独特的作用。这些研究有望对慢性阻塞性肺疾病（COPD）和慢性心力衰竭（CHF）等常见临床疾病产生影响。公共卫生相关性：研究表明，长期低水平的动脉血氧在颈动脉体的氧敏感组织中诱导炎症反应，颈动脉体是血液中溶解氧的主要传感器。此外，炎症状况显示会引起颈动脉体的超敏反应，因此随后暴露于低水平的氧气会引起异常大的反应。这种适应性调整与常见的临床状况有关，如慢性心力衰竭（CHF）和慢性阻塞性肺疾病（COPD），其中血氧水平降低。

DESCRIPTION (provided by applicant): Experiments in recent years have revealed labile electrophysiological and neurochemical phenotypes in primary afferent neurons exposed to specific (chronic) stimulus conditions associated with the development of chronic pain. These studies collectively demonstrate that the mechanisms responsible for functional plasticity are primarily mediated by novel neuro-immune interactions involving circulating and resident immune cells and their secretory products, which together induce hyperexcitability in the primary sensory neurons. In another peripheral sensory modality, namely the arterial chemoreceptors, sustained stimulation in the form of chronic hypoxia (CH) elicits increased chemoafferent excitability from the mammalian carotid body. Previous studies which focused on functional changes in oxygen-sensitive type I cells in this organ have failed to fully elucidate the molecular and cellular mechanisms which initiate and control this adaptive response. It is noteworthy that the possible involvement of neuro-immune mechanisms in increased chemoafferent sensitivity has never been investigated. Our proposed research program assesses immune cell and cytokine involvement in the chemoafferent pathway as a mechanism for chemosensory adaptation. Experiments will investigate 1), CH- induced immune cell invasion and cytokine production in the chemoafferent pathway; 2), the relationship between immune cell activity and increased chemosensitivity; 3), the role of oxygen-sensitive type I cells in initiating an inflammatory response in carotid body; and, 4), inflammation-induced phenotypic changes in type I cells and primary chemoafferent neurons which facilitate hyperexcitability. Preliminary results indicate a unique role for the immune system in regulating the chemo-adaptive response of the carotid body to physiologically relevant levels of hypoxia. These studies are expected to have implications for common clinical conditions such as chronic obstructive pulmonary disease (COPD), and chronic heart failure (CHF). PUBLIC HEALTH RELEVANCE: The research demonstrates that chronically low levels of arterial blood oxygen induce an inflammatory response in oxygen-sensitive tissue of the carotid body, the principal sensor of dissolved oxygen in blood. Furthermore, the inflammatory condition is shown to induce hypersensitivity in the carotid body, so that subsequent exposures to low levels of oxygen elicit an abnormally large response. This adaptive adjustment is relevant to common clinical conditions, such as chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD), in which blood oxygen levels decrease.