Review
Inflammation in the carotid body during development and its contribution to apnea of prematurity

https://doi.org/10.1016/j.resp.2012.08.005Get rights and content

Abstract

Breathing is a complex function that is dynamic, responsive, automatic and often unstable during early development. The carotid body senses dynamic changes in arterial oxygen and carbon dioxide tension and reflexly alters ventilation and plays an essential role in terminating apnea. The carotid body contributes 10–40% to baseline ventilation in newborns and has the greatest influence on breathing in premature infants who characteristically have unstable breathing leading to apnea of prematurity. In this review, we will discuss how both excessive and minimal contributions from the carotid body destabilizes breathing in premature infants and how exposures to hypoxia or infection can lead to changes in the sensitivity of the carotid body. We propose that inflammation/infection during a critical period of carotid body development causes acute and chronic changes in the carotid body contributing to a protracted course of intractable and severe apnea known to occur in a subset of premature infants.

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.

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