ReviewInflammation in the carotid body during development and its contribution to apnea of prematurity☆
Introduction
Premature birth is associated with immaturity and instability of the respiratory network, which manifests as frequent apneas that often are associated with chronic intermittent hypoxia (CIH) (Di Fiore et al., 2010). Apnea of prematurity is considered a developmental disorder that occurs in infants born before 34 weeks gestational age and usually resolves by term gestation (Henderson-Smart, 1981). However, for infants born less than 28 weeks gestation, apnea is associated with profound episodes of hypoxemia and bradycardia that often persist past term gestation (Eichenwald et al., 1997, Hofstetter et al., 2008). These infants need prolonged respiratory support, take longer to achieve oral feedings, have a greater incidence of retinopathy of prematurity (Di Fiore et al., 2010), and have greater risk of adverse neurodevelopmental outcomes (Pillekamp et al., 2007). CIH increases free radical production and contributes to the pathogenesis of adverse outcomes [reviewed in (Martin et al., 2011)]. Similar to any disorder, there is a spectrum of severity; infants with the most severe apnea (longer duration and greater magnitude of hypoxemia) have the greatest morbidity and cost of care. Furthermore, infants with the most severe apnea often have worse lung disease with reduced functional residual capacity (Tourneux et al., 2008), which contributes to rapidly developing hypoxemia during apnea. Paradoxically, the frequency and severity of apnea of prematurity often progressively increases during the first weeks of life when the infant's lung disease is improving. Moreover, apnea can occur in infants with minimal to no lung disease (Martin et al., 2011).
Several factors can worsen apnea; a major one is acute infection, which markedly increases the frequency and severity of apnea. Inflammatory mediators affect both peripheral and central structures that control breathing; the sum of which is respiratory depression in premature infants and neonatal animals (Froen et al., 2002, Hofstetter et al., 2008). Thus, apnea is often one of the first presenting symptoms of bacterial or viral infections in premature, former premature and term infants (Hofstetter et al., 2008, Pickens et al., 1989, Stock et al., 2010). Oxygen stress and bacterial toxins cause inflammation in key central and peripheral structures that regulate breathing. We will focus this review on the role of inflammation/infection in modifying the structure and function of the carotid body, a small but major organ that dynamically changes ventilation. Since little has been published on this topic, we will present preliminary data from our laboratory showing the effect of lipopolysaccharide (LPS) on alterations in structure and function of the carotid body in newborn rats. Further, we will compare and contrast the “inflammatory response” within the carotid body induced by infection versus that induced by chronic sustained hypoxia or CIH on the cellular and integrated hypoxic stimulus-response of the carotid body during development.
Section snippets
Apnea of prematurity
Apnea and periodic breathing are universal features of breathing in infants born prematurely and are observed most frequently in infants born at the lowest gestational age (Henderson-Smart and Cohen, 1986, Hofstetter et al., 2008). The duration and type of apnea with and without oxyhemoglobin desaturations [(O2 desaturations), detected by pulse oximetry] and bradycardia classifies apneas as physiological or pathological (Hunt et al., 2004, Ramanathan et al., 2001). Short central apneas <10 s
Brief overview of the structure and function of the carotid body during development
Because of its rapid stimulus response on breathing, the carotid body is likely to contribute significantly to breathing instability and thus apnea that occurs in premature infants (Al-Matary et al., 2004). Therefore, modifications of carotid body structure and function can have a profound influence on breathing stability. The carotid body contains specialized cells (type1 or glomus cells), which are multimodal sensors that are excited by decreases in oxygen tension, pH and perhaps glucose, and
Inflammation and carotid body function
While surgical carotid body denervation cannot be done experimentally in human infants, premature infants are commonly exposed to factors that could modify the carotid body resulting in absence of hypoxic chemosensitivity acutely and chronically. For example, when infants have an inflammatory or infectious illness, the frequency and duration of apneic episodes substantially increases (Hofstetter et al., 2008). In response to infection, pro-inflammatory cytokines such as interleukin (IL)-1β and
Conclusion
This review has focused on the level of sensitivity of the carotid body and its possible relationship to apnea of prematurity. The carotid body has the greatest blood flow per gram of tissue in the body and remains the first line defense to reflexly increase ventilation in response to hypoxia, induce arousal and terminate apnea; although, it should be emphasized that multiple inputs from the peripheral and central nervous systems are constantly being integrated and processed which modulates the
Acknowledgements
The authors would like to thank Ms. Idil Tuncali for her help with preparing the table and figures.
References (130)
- et al.
Increased peripheral chemoreceptor activity may be critical in destabilizing breathing in neonates
Seminars in Perinatology
(2004) - et al.
Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata
Respiratory Physiology and Neurobiology
(2011) Developmental plasticity of the hypoxic ventilatory response after perinatal hyperoxia and hypoxia
Respiratory Physiology and Neurobiology
(2005)The role of CO(2) and central chemoreception in the control of breathing in the fetus and the neonate
Respiratory Physiology and Neurobiology
(2010)- et al.
A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity
Journal of Pediatrics
(2010) - et al.
Chronic hyperoxia alters the expression of neurotrophic factors in the carotid body of neonatal rats
Respiratory Physiology and Neurobiology
(2011) - et al.
Lipopolysaccharide signaling in the carotid chemoreceptor pathway of rats with sepsis syndrome
Respiratory Physiology and Neurobiology
(2011) - et al.
Transmitter diversity in carotid body afferent neurons: dopaminergic and peptidergic phenotypes
Neuroscience
(1992) - et al.
Important role of carotid chemoreceptor afferents in control of breathing of adult and neonatal mammals
Respiration Physiology
(2000) - et al.
Peripheral arterial chemoreceptors and sudden infant death syndrome
Respiratory Physiology and Neurobiology
(2007)
Role of chemoreceptors in effects of chronic hypoxia
Comparative Biochemistry and Physiology. Part A: Molecular and Integrative Physiology
An inflammatory pathway to apnea and autonomic dysregulation
Respiratory Physiology and Neurobiology
Lethal respiratory disturbance in neonatal rats after arterial chemoreceptor denervation
Life Sciences
Cardiorespiratory events detected by home memory monitoring and one-year neurodevelopmental outcome
Journal of Pediatrics
Airway closure during mixed apneas in preterm infants: is respiratory effort necessary?
Journal of Pediatrics
Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth
Respiratory Physiology and Neurobiology
Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells
Neurochemistry International
Oxygen and glucose sensing by carotid body glomus cells
Current Opinion in Neurobiology
Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants
Journal of Pediatrics
Ibuprofen blocks time-dependent increases in hypoxic ventilation in rats
Respiratory Physiology and Neurobiology
The influence of chronic hypoxia upon chemoreception
Respiratory Physiology and Neurobiology
NO and CO as second messengers in oxygen sensing in the carotid body
Respiration Physiology
Induction of mixed apneas by inhalation of 100% oxygen in preterm infants
Journal of Applied Physiology
Intrapulmonary lipopolysaccharide exposure upregulates cytokine expression in the neonatal brainstem
Acta Paediatrica
Time-dependent effect of hypoxia on carotid body chemosensory function
Journal of Applied Physiology
Developmental plasticity of the hypoxic ventilatory response in rats induced by neonatal hypoxia
Journal of Physiology
Chronic hyperoxia alters the early and late phases of the hypoxic ventilatory response in neonatal rats
Journal of Applied Physiology
Mechanisms of hypoxia-induced periodic breathing during sleep in humans
Journal of Physiology
Increase in carotid body sensitivity during sustained hypoxia
Biological Signals
Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia
Journal of Applied Physiology
Normalization of the blunted ventilatory response to acute hypoxia in congenital cyanotic heart disease
New England Journal of Medicine
Postnatal maturation of respiration in intact and carotid body – chemodenervated lambs
Journal of Applied Physiology
Mechanisms of carotid chemoreceptor resetting after birth. In vitro studies
Advances in Experimental Medicine and Biology
Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential new model of Parkinson's disease
Frontiers in Bioscience
The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-alpha, IL-1beta and IFN-gamma
Journal of Neurochemistry
Effect of hyperoxic exposure during early development on neurotrophin expression in the carotid body and nucleus tractus solitarii
Journal of Applied Physiology
Age-dependent vulnerability to carotid chemodenervation in piglets
Journal of Applied Physiology
Chemoreflexes in breathing
Physiological Reviews
Predominant role of peripheral chemoreceptors in the termination of apnea in maturing newborn lambs
Journal of Applied Physiology
Cardiorespiratory events in preterm infants referred for apnea monitoring studies
Pediatrics
Low oxygen saturation target range is associated with increased incidence of intermittent hypoxemia
Journal of Pediatrics
Developmental changes in membrane properties of chemoreceptor afferent neurons of the rat petrosal ganglia
Journal of Neurophysiology
Developmental aspects of oxygen sensing by the carotid body
Journal of Applied Physiology
Developmental changes in hypoxia-induced catecholamine release from rat carotid body, in vitro
Journal of Physiology
Prolonged apnea and impaired survival in piglets after sinus and aortic nerve section
Journal of Applied Physiology
The blunted ventilatory response to hypoxia in cyanotic congenital heart disease
New England Journal of Medicine
Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks
Pediatrics
Arterial partial pressure of oxygen required to achieve 90% saturation of hemoglobin in very low birth weight newborns
Pediatrics
Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor are required simultaneously for survival of dopaminergic primary sensory neurons in vivo
Journal of Neuroscience
Chemoafferent degeneration and carotid body hypoplasia following chronic hyperoxia in newborn rats
Journal of Physiology
Cited by (44)
Control of Breathing
2023, Avery's Diseases of the NewbornPredicting apneic events in preterm infants using cardio-respiratory and movement features
2021, Computer Methods and Programs in BiomedicineCyclooxygenase and nitric oxide synthase pathways mediate the respiratory effects of TNF-α in rats
2021, Respiratory Physiology and NeurobiologyVentilatory and carotid body responses to acute hypoxia in rats exposed to chronic hypoxia during the first and second postnatal weeks
2020, Respiratory Physiology and NeurobiologyImpact of inflammation on developing respiratory control networks: rhythm generation, chemoreception and plasticity
2020, Respiratory Physiology and NeurobiologyMechanistic actions of oxygen and methylxanthines on respiratory neural control and for the treatment of neonatal apnea
2020, Respiratory Physiology and NeurobiologyCitation Excerpt :The pathophysiological consequences (specifically associated with intermittent hypoxemia (IH), reviewed in this special issue: Di Fiore and Vento) of recurrent neural apnea can be further exacerbated by insufficient pulmonary development, which constrains gas exchange and compromises blood gas homeostasis. The respiratory and physiological stability of the preterm infant can be confounded by numerous other co-morbidities, which can include infection, congenital abnormalities, malnourishment, and prior in utero exposure to drug and alcohol abuse, to name a few (Di Fiore et al., 2013; Gauda et al., 2013). Many preterm infants require some form of respiratory support ranging from pharmacological, which could include supplemental O2, to more aggressive interventions including continuous positive pressure support and even tracheal intubation (Di Fiore et al., 2016b, a).
- ☆
This paper is part of a special issue entitled “Development of the Carotid Body”, guest-edited by John L. Carroll, David F. Donnelly and Aida Bairam.