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

颈动脉体化学感受器对慢性缺氧反应的神经免疫机制

基本信息

批准号：
8197205
负责人：
SALVATORE J FIDONE
金额：
$ 37.25万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-15 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197205
关键词：
Acids Afferent Neurons Animal Model Anti-Inflammatory Agents Anti-inflammatory Area Attention Blood CD8-Positive T-Lymphocytes Carotid Body Cells Chemoreceptors Chemotactic Factors Chronic Chronic Obstructive Airway Disease Clinical Development E-Selectin Endothelin Endothelin Receptor Antagonist Exposure to Face Ganglia Gene Deletion Gene Expression Genes Heart failure Human Hypersensitivity Hypoxia Imaging Techniques Immune Immune system Immunofluorescence Immunologic Inflammation Inflammatory Inflammatory Response Injury Interleukin-6 Interleukins Investigation Ion Channel Mediating Modality Molecular Monocyte Chemoattractant Protein-1 Monocyte Chemoattractant Proteins Nerve Fibers Neurons Organ Oxygen Pathway interactions Peptides Peripheral Pharmaceutical Preparations Pharmacology Phenotype Preparation Production Property Regulation Research Role Sensory Signal Transduction Spinal Ganglia Stimulus Text Time Tissues Transducers Tumor Necrosis Factor-alpha Type I Epithelial Receptor Cell Vascular Cell Adhesion Molecule-1 Vasoconstrictor Agents cell type chronic pain cytokine cytotoxic extracellular hypoxia inducible factor 1 inflammatory neuropathic pain intercellular cell adhesion molecule macrophage neurochemistry neurophysiology neutrophil novel programs research study response sensor transcription factor

项目摘要

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).

近年来的实验揭示了小学生不稳定的电生理和神经化学表型传入神经元暴露于特定的（慢性）刺激条件下与慢性痛苦这些研究共同表明，负责功能可塑性的机制是主要由涉及循环和驻留免疫细胞的新型神经免疫相互作用介导，它们的分泌产物，共同诱导初级感觉神经元的过度兴奋。在另一外周感觉模态，即动脉化学感受器，以慢性刺激的形式持续刺激。缺氧（CH）可增强哺乳动物颈动脉体化学传入兴奋性。以前的研究这些研究集中于该器官中氧敏感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化学传入敏感性的增加，研究了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通路作为化学感觉适应的机制。实验将研究1），CH- 诱导的免疫细胞侵袭和细胞因子的产生在化学传入途径; 2），免疫细胞活性和增加的化学敏感性之间的关系; 3），氧敏感性I型细胞在免疫细胞中的作用。引发颈动脉体中的炎症反应;以及，4）I型中炎症诱导的表型变化细胞和初级化学传入神经元，促进过度兴奋。初步结果显示，免疫系统在调节颈动脉体的化学适应性反应中的独特作用，生理相关的缺氧水平。这些研究有望对常见的临床例如慢性阻塞性肺病（COPD）和慢性心力衰竭（CHF）。