Introduction and aim: Metabolic diseases are regarded as a leading cause of mortality and morbidity worldwide. Carotid bodies (CBs), which were traditionally considered oxygen-sensitive organs, are also metabolic sensors that play a role in the development of metabolic disorders [1-3]. In metabolic disease states the CB activity is increased and the abolishment of its activity improves metabolic function [1-3]. Inflammatory cytokines are among the factors that can contribute to CB dysfunction in dysmetabolic states [4]. Indeed, the presence of inflammatory cytokines and their corresponding receptors in the CB have been reported [1,4]. In this study, we investigated the contribution of CB to the ventilatory responses induced by pro-inflammatory cytokines, as well as the effect of pro-inflammatory cytokines on CB function.

Methods: Two groups of Wistar rats were used: a control group fed with a standard diet (CTL) and a high-fat (HF) group fed with a diet rich in lipids (60% energy from fat) for 3 weeks. The animals were anesthetized with pentobarbital sodium (60mg/kg i.p.) and at the end of the experimental protocol were killed with an overdose of the same anesthetic. The effect of IL-6 on ventilation was tested by administering IL-6 (0.5 and 5 ng/ml) into the femoral vein in CTL animals with and without carotid sinus nerve (CSN) resection and on the release of adenosine from isolated CBs [5]. To quantify adenosine release, CBs were incubated in normoxia (20% O2 + 5% CO2, balanced N2) in the presence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; an inhibitor of adenosine deaminase, 2.5 μM) for 10 min, followed by incubation during 30 min with IL-6 (1ng/ml) in normoxic conditions. Adenosine levels were quantified by HPLC with UV detection. TNF-α levels and the receptors for IL-1β and IL-6 of CTL and HF animals were evaluated by immunohistochemistry. One-way ANOVA with Dunnett's comparison test and Student’s t-test was used. Experiments followed the 2010/63/EU European Union Directive and were approved by NMS Ethics Committee and the Portuguese Authority for Animal Health.

Results: In control animals, IL-6 enhanced basal ventilation, an effect abolished by CSN resection. Moreover, in CTL animals, IL-6 increased by 87% (p<0.05) the adenosine release from the CB. HF diet intake for 3 weeks, increased by 80% (p<0.01) and 46% (p<0.01), respectively, the TNF-α immunoreactivity and IL-1β receptor in CB, compared to CTL animals. Additionally, the immunoreactivity for the IL-6 receptor remained unaltered. 

Conclusion: We conclude that the CB plays a crucial role mediating IL-6’s effect on ventilation, an effect that can involve the stimulation of adenosine release from the CB. Additionally, HF diet intake promotes inflammation within the CB. Taken together, these results suggest that pro-inflammatory cytokines may contribute to CB dysfunction in metabolic diseases.