Ariel Mason

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

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.

Effect of hyperoxic exposure during early development on neurotrophin expression in the carotid body and nucleus tractus solitarii

Synaptic activity can modify expression of neurotrophins, which influence the development of neuronal circuits. In the newborn rat, early hyperoxia silences the synaptic activity and input from the carotid body, impairing the development and function of chemoreceptors. The purpose of this study was to determine whether early hyperoxic exposure, sufficient to induce hypoplasia of the carotid body and decrease the number of chemoafferents, would also modify neurotrophin expression within the nucleus tractus solitarii (nTS). Rat pups were exposed to hyperoxia (fraction of inspired oxygen 0.60) or normoxia until 7 or 14 days of postnatal development (PND). In the carotid body, hyperoxia decreased brain-derived neurotrophic factor (BDNF) protein expression by 93% (P = 0.04) after a 7-day exposure, followed by a decrease in retrogradely labeled chemoafferents by 55% (P = 0.004) within the petrosal ganglion at 14 days. Return to normoxia for 1 wk after a 14-day hyperoxic exposure did not reverse this effect. In the nTS, hyperoxia for 7 days: 1) decreased BDNF gene expression by 67% and protein expression by 18%; 2) attenuated upregulation of BDNF mRNA levels in response to acute hypoxia; and 3) upregulated p75 neurotrophic receptor, truncated tropomyosin kinase B (inactive receptor), and cleaved caspase-3. These effects were not observed in the locus coeruleus (LC). Hyperoxia for 14 days also decreased tyrosine hydroxylase levels by 18% (P = 0.04) in nTS but not in the LC. In conclusion, hyperoxic exposure during early PND reduces neurotrophin levels in the carotid body and the nTS and shifts the balance of neurotrophic support from prosurvival to proapoptotic in the nTS, the primary brain stem site for central integration of sensory and autonomic inputs.

The Effect of Development on the Pattern of A1 and A2a-Adenosine Receptor Gene and Protein Expression in Rat Peripheral Arterial Chemoreceptors

1995; Montoro et al., 1996; Wyatt et al., 1995). Reduction of K+ conductance in response to hypoxia is the signal that triggers Type I cell depolarization, Ca entry, and secretion of neurotransmitters that bind to receptors on the first order sensory nerve endings of the carotid sinus nerve with cell bodies in the petrosal ganglion {(Gonzalez et al., 1994;Gonzalez et al., 1992). These first order sensory neurons (chemoafferents) project to second order neurons within the nucleus tractus solitarii (nTS), which send projections to the muscles of respiration. While the cascade of molecular and cellular events occurs in multiple CB preparations from multiple mammalian species, key aspects of the cascade are still unknown, particularly identification of the specific oxygen sensor within the Type I cell that initiates the cascade and the specific excitatory neurotransmitter systems that are involved in chemoexcitation. Furthermore, in multiple immature mammalian species, including human infants, hypoxic chemosensitivity matures during the first several weeks of postnatal life. Specific mechanisms mediating that maturation are unknown. Adenosine (ADO) is an ubiquitous molecule that is released from metabolically active cells by facilitated diffusion or is generated extracellularly by degradation of released ATP (Zimmermann & Braun, 1996). ADO levels increase in response to hypoxia. ADO modifies cellular function by binding to specific cell-surface receptors. All four identified ADO-Rs (A1-R, A2a-R, A2bR, and A3-R) are members of the superfamily of G protein-coupled receptors (GPCRs). A1and A3-Rs interact with pertussis toxin-sensitive G proteins (Gi and Go), inhibit adenylyl cyclase (AC), and hyperpolarize cells by G proteincoupled K channels, whereas A2aand A2b-Rs interact with G proteins and