Respiratory Physiology & Neurobiology 185 (2013) 120–131 Contents lists available at SciVerse ScienceDirect Respiratory Physiology & Neurobiology jou rn al h om epa ge: www.elsevier.com/locate/resphysiol Review Inflammation in the carotid body during development and its contribution to apnea of prematurity  Estelle B. Gauda a,∗ , Machiko Shirahata b , Ariel Mason a , Luis E. Pichard b , Eric W. Kostuk b , Raul Chavez-Valdez a a Department of Pediatrics, Division of Neonatology, The Johns Hopkins School of Medicine, Baltimore, MD, USA b Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA a r t i c l e i n f o Article history: Accepted 2 August 2012 Keywords: Infection Hypoxia Hyperoxia Chemoreceptors a b s t r a c t 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. © 2012 Published by Elsevier B.V. 1. 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 pro- duction 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  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. ∗ Corresponding author at: Johns Hopkins Hospital, Neonatology Research Labo- ratories, CMSC 6-104, 600 N, Wolfe Street, Baltimore, MD 21287-3200, USA. Tel.: +1 410 614 7232. E-mail address: egauda@jhmi.edu (E.B. Gauda). severe apnea often have worse lung disease with reduced func- tional 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 infec- tion, 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 tox- ins 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 con- trast 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. 1569-9048/$ – see front matter © 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.resp.2012.08.005