The human carotid body releases acetylcholine, ATP and cytokines during hypoxia

Abstract

New Findings r What is the central question of this study?Data on human carotid body (CB) function are limited. The aim of this study was therefore to investigate whether the human CB releases acetylcholine, ATP or cytokines during hypoxia. r What is the main finding and its importance?Using human CBs, we demonstrate hypoxia-induced acetylcholine and ATP release, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. Moreover, the human CB releases cytokines upon hypoxia and expresses cytokine receptors as well as hypoxia-inducible factor proteins HIF-1α and HIF-2α in glomus cells, indicating their role in immune signalling and oxygen sensing, respectively, in accordance with previous animal data.Studies on experimental animals established that the carotid bodies are sensory organs for detecting arterial blood O 2 levels and that the ensuing chemosensory reflex is a major regulator of cardiorespiratory functions during hypoxia. However, little information is available on the human carotid body responses to hypoxia. The present study was performed on human carotid bodies obtained from surgical patients undergoing elective head and neck cancer surgery. Our results show that exposing carotid body slices to hypoxia for a period as brief as 5 min markedly facilitates the release of ACh and ATP. Furthermore, prolonged hypoxia for 1 h induces an increased release of interleukin (IL)-1β, IL-4, IL-6, IL-8 and IL-10. Immunohistochemical analysis revealed that type 1 cells of the human carotid body express an array of cytokine receptors as well as hypoxia-inducible factor-1α and hypoxia-inducible factor-2α. Taken together, these results demonstrate that ACh and ATP are released from the human carotid body in response to hypoxia, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. The finding that the human carotid body releases cytokines in response to hypoxia adds to the growing body of information M.J.F. and L.I.E. contributed equally to this paper.

The Human Carotid Body Gene Expression and Function in Signaling of Hypoxia and Inflammation

“…Combined with the demonstration of corresponding receptors and over-expression of genes in the infl ammatory response and expression of several early and late infl ammatory mediators (Kahlin et al 2014 ;Mkrtchian et al 2012 ), we believe that fundamental prerequisites for an immune-tobrain signalling link are established in the human carotid body.…”

“…The levels of ACh and ATP returned to baseline The abbreviations are explained in the corresponding publication (Fagerlund et al 2010 ;Kahlin et al 2014 ;Mkrtchian et al 2012 ) following 15 min of re-oxygenation (Kahlin et al 2014 ).…”

“…Fresh carotid body tissue incubated in preoxygenated KRS after extraction was exposed to either brief (5-min) or prolonged (60-min) hypoxia to detect subsequent release of ACh and ATP as measured with high performance liquid chromatography (HPLC) and infl ammatory signalling molecules using a Luminometric assay, respectively and as described earlier (Kahlin et al 2014 ).…”

“…After written consent, the carotid body was removed unilaterally during sevofl urane and opioid-based general anesthesia at normoxia and normocarbia as provided by mechanical ventilation during the whole surgical procedure (Fagerlund et al 2010 ;Kahlin et al 2014 ;Mkrtchian et al 2012 ).…”

“…The release of a multitude of cytokines was monitored from human carotid body slices exposed to prolonged hypoxia for 1 h. Release of the cytokines IL-1β, IL-4, IL-6, IL-8 and IL-10 was induced by prolonged hypoxia (Kahlin et al 2014 ).…”