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Caffeine, a nonspecific adenosine receptor (AR) antagonist is widely used to treat apnea of prematurity. Because adenosine modulates multiple biologic processes including inflammation, we hypothesized that AR blockade by caffeine would increase cytokine release from neonatal monocytes. Using cord blood monocytes (CBM), we investigated 1) the changes in AR mRNA profile by real time quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) and protein expression (western blot) after in vitro culture, caffeine or lipopolysaccharide (LPS) exposure, and 2) the modulation of cytokine release and cyclic adenosine monophosphate (cAMP) production by enzyme-linked immunosorbent assay (ELISA) induced by caffeine and specific AR antagonists: DPCPX(A1R), ZM241385(A2aR), MRS1754(A2bR), and MRS1220(A3R). After 48 h in culture, A2aR and A2bR gene expression increased 1.9 (p = 0.04) and 2.5-fold (p = 0.003), respectively. A1R protein expression directly correlated with increasing LPS concentrations (p = 0.01), with minimal expression preexposure. Only caffeine (50 µM) and DPCPX (10 nM) decreased tumor necrosis factor-alpha (TNF-a) release from LPS activated-CBM by 20 and 25% (p = 0.01) and TNF-a gene expression by 30 and 50%, respectively, in conjunction with a =2-fold increase in cAMP (p < 0.05). AR blockade did not modulate other measured cytokines. The induction of A1R after LPS exposure suggests an important role of this receptor in the control of inflammation in neonates. Our findings also suggest that caffeine, via A1R blockade, increases cAMP production and inhibits pretranscriptional TNF-a production by CBM.

Caffeine, a nonspecific adenosine receptor (AR) antagonist is widely used to treat apnea of prematurity. Because adenosine modulates multiple biologic processes including inflammation, we hypothesized that AR blockade by caffeine would increase cytokine release from neonatal monocytes. Using cord blood monocytes (CBM), we investigated 1) the changes in AR mRNA profile by real time quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) and protein expression (western blot) after in vitroculture, caffeine or lipopolysaccharide (LPS) exposure, and 2) the modulation of cytokine release and cyclic adenosine monophosphate (cAMP) production by enzyme-linked immunosorbent assay (ELISA) induced by caffeine and specific AR antagonists: DPCPX(A1R), ZM241385(A2aR), MRS1754(A2bR), and MRS1220(A3R). After 48 h in culture, A2aR and A2bR gene expression increased 1.9 (p0.04) and 2.5-fold (p0.003), respectively. A1R protein expression directly correlated with increasing LPS concentrations (p0.01), with minimal expression preexposure. Only caffeine (50 M) and DPCPX (10 nM) decreased tumor necrosis factor-alpha (TNF-) release from LPS activated-CBM by 20 and 25% (p0.01) and TNF- gene expression by 30 and 50%, respectively, in conjunction with a ≥2-fold increase in cAMP (p< 0.05). AR blockade did not modulate other measured cytokines. The induction of A1R after LPS exposure suggests an important role of this receptor in the control of inflammation in neonates. Our findings also suggest that caffeine, viaA1R blockade, increases cAMP production and inhibits pretranscriptional TNF- production by CBM.

To document mechanisms contributing to upper airway collapse, we compared the electromyographic activity of the genioglossus (GG) and diaphragm (DIA) during spontaneous mixed and obstructive apnea and during induced end-expiratory airway occlusion in 11 premature infants. In addition to ventilation and esophageal pressure measurements, we obtained DIA and GG electromyograms (EMG) from subcostal and sublingual surface electrodes, respectively. Amplitude of the DIA EMG and the frequency of occurrence of the GG EMG were determined for1) the breath preceding apnea or occlusion, 2) the initial and last obstructed inspiratory efforts, and 5) the first breath at resolution of both apnea and occlusion. During spontaneous apnea with airway obstruction amplitude of the DIA, EMG decreased on the initial obstructed inspiratory effort and did not exceed that of the breath preceding apnea until reestablishment of flow. In contrast, during end-expiratory airway occlusion, the amplitude of the DIA EMG increased both during and at release of occlusion. In 18 ± 6 of the spontaneous apneic episodes, GG EMG was present with the breath preceding apnea and this frequency did not increase significantly until resolution of the apnea. During induced airway occlusion, GG EMG was not present with the breath preceding occlusion but its frequency did increase to 58 ± 8 and 42 ± 8 with the last occluded inspiratory effort and the first breath after release of occlusion, respectively. The decreased presence of the GG EMG from the last occluded effort to the breath at release of occlusion (58 ± 8 versus 42 ± 8, p<0.05) was probably due to the greater mechanoreceptormediated inhibition associated with reestablishment of flow. This study thus demonstrates markedly different respiratory muscle responses to spontaneously occurring obstructed inspiratory efforts during apnea as compared to experimentally induced airway occlusion in preterm infants.

The ability to maintain pharyngeal patency is compromised in infants who have apneic episodes associated with airway obstruction. Since the genioglossus (GG) muscle is thought to be important in maintaining pharyngeal patency, we measured the GG EMG with sublingual surface electrodes during unobstructed breathing and in response to end-expiratory airway occlusion. Studies were performed in nine premature infants with mixed and obstructive apnea and in eight nonapneic control infants. Phasic GG EMG was usually absent during normal tidal breathing in both groups of infants, however, GG activity typically appeared during airway occlusion. The response of the GG muscle during airway occlusion differed between control and apneic infants. During the first three occluded inspiratory efforts, control infants had 42 ± 5, 74 ± 5, and 80 ± 5 (mean ± SEM) of their occlusions associated with a GG EMG response, respectively. In contrast, apneic infants had significantly fewer (13 ± 4, 38 ± 9, and 52 ± 9) occlusions associated with a GG EMG response. There was a delay in onset of the GG EMG when compared to the onset of the diaphragm EMG and initial negative esophageal pressure swing, but this delay decreased with each subsequent appearance of the GG EMG in both infant groups. Infants with mixed and obstructive apnea thus have decreased activation of their GG in response to occlusion which may reflect their inability to recruit dilating muscles of the upper airway during spontaneous airway obstruction.

Sleep-disordered breathing (SDB) is a constellation of breathing disorders that occur during sleep. Obstructive sleep apnea (OSA), the most common form, is characterized by complete or partial airway obstruction, hypoventilation, and central apneas, all of which lead to recurrent episodes of hypoxia, hypercapnia, sleep fragmentation, and elevated sympathetic tone. OSA occurs throughout the life span and is associated with significant cognitive, metabolic, and cardiovascular consequences that impair the quality of life. Building on observations that the upper airway collapses during sleep, obesity increases the risk of upper airway obstruction, and this obstruction leads to periods of hypoxia and reoxygenation that cause oxidative stress, researchers used large and small animal models to study the genetic predeterminants of OSA, the neuromechanical control of the upper airway during development and aging, and the metabolic consequences of oxidative stress. From the early canine models of experimentally induced upper airway obstruction to the current rodent models of intermittent hypoxia, the information now available has significantly improved scientists’ understanding of the pathogenesis of OSA and its consequences, leading to better care for individuals with sleep-disordered breathing.

The symptoms of opiate withdrawal in infants are defined as neonatal abstinence syndrome (NAS). NAS is a significant cause of morbidity in term and preterm infants. Factors, such as polysubstance abuse, inadequate prenatal care, nutritional deprivation, and the biology of the developing central nervous system contribute to the challenge of evaluating and treating opiate-induced alterations in the newborn. Although research on the effects of opiates in neonatal animal models is limited, the data from adult animal models have greatly contributed to understanding and treating opiate tolerance, addiction, and withdrawal in adult humans. Yet the limited neonatal data that are available indicate that the mechanisms involved in these processes in the newborn differ from those in adult animals, and that neonatal models of opiate withdrawal are needed to understand and develop effective treatment regimens for NAS. In this review, the behavioral and neurochemical evidence from the literature is presented and suggests that mechanisms responsible for opiate tolerance, dependence, and withdrawal differ between adult and neonatal models. Also reviewed are studies that have used neonatal rodent models, the authors preliminary data based on the use of neonatal rat and mouse models of opiate withdrawal, and other neonatal models that have been proposed for the study of neonatal opiate withdrawal.