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

描述(申请人提供)：近年来的实验表明，在与慢性疼痛的发展相关的特定(慢性)刺激条件下，初级传入神经元的电生理和神经化学表型不稳定。这些研究表明，负责功能可塑性的机制主要是通过涉及循环免疫细胞和常驻免疫细胞及其分泌产物的新型神经免疫相互作用来介导的，这些相互作用共同诱导初级感觉神经元的过度兴奋。在另一种外周感觉方式，即动脉化学感受器中，慢性缺氧(CH)形式的持续刺激引起哺乳动物颈动脉小体化学传入兴奋性的增加。以前的研究集中在该器官中对氧敏感的I型细胞的功能变化，但未能完全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，神经免疫机制可能参与了化学传入敏感性的增加，但从未被研究过。我们建议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。实验将研究1)CH诱导的免疫细胞入侵和化学传入途径中细胞因子的产生；2)免疫细胞活性与化疗敏感性增加的关系；3)氧敏感的I型细胞在颈动脉小体启动炎症反应中的作用；以及4)炎症诱导的I型细胞和初级化学传入神经元的表型变化，从而促进过度兴奋。初步结果表明，免疫系统在调节颈动脉小体对生理相关水平的低氧的化学适应性反应方面具有独特的作用。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。与公共健康相关：研究表明，长期低水平的动脉血氧会在颈动脉体氧敏感组织中引发炎症反应，颈动脉体氧敏感组织是血液中溶解氧的主要感应器。此外，炎症状态可诱导颈动脉小体的超敏反应，因此随后暴露在低氧环境中会引起异常大的反应。这种适应性调整与常见的临床情况有关，如慢性心力衰竭(CHF)和慢性阻塞性肺疾病(COPD)，在这些疾病中，血氧水平下降。

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.