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

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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.