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

近年来的实验揭示了不稳定的电生理和神经化学表型。 特定(慢性)刺激条件下的传入神经元与慢性精神分裂症的发展相关 疼痛。这些研究共同证明，导致功能可塑性的机制是 主要由新的神经免疫相互作用介导，涉及循环和常驻免疫细胞和 它们的分泌产物，共同诱导初级感觉神经元的过度兴奋。在另一个国家 外周感觉通道，即动脉化学感受器，以慢性刺激的形式持续刺激 低氧(CH)引起哺乳动物颈动脉小体化学传入兴奋性增加。以前的研究 他们专注于这个器官中对氧敏感的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度的增加 调查过了。我们建议的研究计划评估免疫细胞和细胞因子在 化学传入途径作为化学感觉适应的机制。实验将研究1)，CH- 诱导免疫细胞侵袭和趋化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之间的关系；3)氧敏感的I型细胞在 启动颈动脉小体的炎症反应；以及，4)炎症诱导的I型表型改变 促进过度兴奋的细胞和初级化学传入神经元。初步结果显示， 免疫系统在调节颈动脉小体的化学适应性反应中的独特作用 生理上相关的低氧水平。这些研究有望对常见的临床应用产生影响。 慢性阻塞性肺疾病(COPD)和慢性心力衰竭(CHF)等疾病。

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).