Adverse Effects of Nicotine and Interleukin-1β on Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome

Frøen, J. Frederik; Akre, Harriet; Stray‐Pedersen, Babill; Saugstad, Ola Didrik

doi:10.1542/peds.105.4.e52

Cited by 77 publications

(57 citation statements)

References 33 publications

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“…These findings are in accordance with other studies demonstrating that IL-1␤ depresses respiration and adversely affects recovery from apnea induced by laryngeal stimulation (6,7). However, the specific pathway by which IL-1␤ acts cannot be determined with our methods.…”

Section: Discussionsupporting

confidence: 92%

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

et al. 2003

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IL-1␤ has been proposed to be an important mediator linking infection, apnea, and sudden infant death syndrome. We hypothesized that IL-1␤ acts in this capacity by depressing brainstem respiratory neurons via a prostaglandin-dependent pathway. For studying the effects of IL-1␤ on respiration as well as the mechanism underlying its actions, 7-d-old rats received an initial injection (i.p.) of NaCl or a cyclooxygenase inhibitor (indomethacin, 10 mg/kg) followed by a second injection (i.p.) at 30 min of NaCl, recombinant rat IL-1␤ (10 g/kg), or lipopolysaccharide (LPS; 100 g/kg). Respiration during normoxia and in response to anoxia (100% N 2 ) was examined at 60 min after the second injection using flow and barometric plethysmography. Animals given IL-1␤ breathed more slowly and died more often after anoxia. LPS also reduced the rats' ability to autoresuscitate and survive an anoxic challenge. Indomethacin prevented the depressive effects during normoxia and the adverse effects on survival. For investigating drug-induced changes in central respiratory activity, IL-1␤ (1.0 or 1.25 ng/mL) and prostaglandin E 2 (5 or 20 g/L) was applied to the brainstem-spinal cord preparation of 0-to 4-d-old rats. Whereas IL-1␤ exerted no effect on respiration measured at the C4 ventral root during a 60-min period, prostaglandin E 2 reversibly inhibited respiratory activity. These findings suggest that IL-1␤ does not inhibit respiratory neurons directly but may depress breathing and hypoxic defense via a prostaglandin-mediated mechanism. Abbreviations BBB, blood-brain barrier COX-2, cyclooxygenase-2 f R , respiratory frequency LPS, lipopolysaccharide NTS, nucleus of the solitary tract PGE 2 , prostaglandin E 2 RVLM, rostral ventrolateral medulla Infection, hypoxia, and apnea each have been implicated in the pathogenesis of sudden infant death syndrome, and it has been postulated that the proinflammatory cytokine IL-1␤ may serve as the critical link between them (1, 2). IL-1␤ is released during an acute-phase immune response and subsequently induces multiple effects within the CNS, including the initiation of fever, sleep, and neuropeptide release [for review, see (3)]. Previous studies indicated that this immunomodulator may also alter respiration and autoresuscitation, yet the mechanism underlying such effects must be further elucidated (4 -7). Systemic administration of IL-1␤ has been shown to induce time-and dose-dependent expression of early immediate genes in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), both of which contain neurons important for respiratory control and the latter houses the central pattern generator for breathing (8,9). Because of its size and lipophilic properties, IL-1␤ does not diffuse readily across the blood-brain barrier (BBB) (10). However, IL-1␤ may still communicate with the brain across the BBB via active transport passage, through circumventricular organs, vagal afferent stimulation, and via second messenger induction at the BBB [for review, see (11)].We propose ...

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Section: Discussionsupporting

confidence: 92%

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

et al. 2003

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“…N lambs had more sighs, and these efforts appeared less efficient in restoring a sustained rise in HR and regular breathing. Sighing and gasping are considered to be key elements in successful cardiorespiratory recovery (27), and our findings of less-efficient sighs support other reports that nicotine exposure impairs the ability to autoresuscitate in situations such as repeated hypoxic exposures or LCR-induced apnea after IL-1B pretreatment (15,28,29).…”

Section: Lcr Response and Sympathetic Activitysupporting

confidence: 89%

Impaired Cardiorespiratory Recovery after Laryngeal Stimulation in Nicotine-Exposed Young Lambs

Sundell

2003

Pediatric Research

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The hypothesis that postnatal nicotine exposure weakens cardiorespiratory recovery from reflex apnea and bradycardia was tested in eight lambs continuously infused with nicotine from the day of birth at a dose of 1 to 2 mg·kg Ϫ1 ·d Ϫ1 . Eight age-matched lambs infused with saline served as controls. Apnea and bradycardia were elicited by laryngeal stimulation with 1 mL of water (laryngeal chemoreflex) both during air breathing [0.21 fraction of inspired oxygen (FiO 2 )] and mild hypoxia (0.10 FiO 2 ) at a mean postnatal age of 5 Ϯ 1, 14 Ϯ 1, and 28 Ϯ 1 d. Ventilation, heart rate, and blood pressure were similar in the two groups at rest. In response to laryngeal chemoreflex stimulation, nicotine-treated lambs had a more pronounced decrease in ventilation (p Ͻ 0.05), longer reflex apnea (p Ͻ 0.001 in 0.21 FiO 2 ; p Ͻ 0.01 in 0.10 FiO 2 ), and greater reflex bradycardia (p Ͻ 0.01). During reflex apnea, sighs were less efficient in restoring heart rate to prestimulation level, and a greater decrease in heart rate was observed before sighs in nicotine-treated lambs. These effects were most apparent at 5 d of age, when nicotine-treated lambs also had lower ventilation during hypoxia (p Ͻ 0.05). The response to hyperoxia was comparable in the two groups at all ages. The ability to terminate laryngeal chemoreflex-induced apnea is attenuated in young lambs continuously exposed to nicotine. This attenuation is present both in normoxia and in hypoxia and is accompanied by reduced effects from sighing on cardiac autoresuscitation. Laryngeal stimulation with fluids potentially harmful to the airways induces a graded and reproducible reflex response consisting of laryngeal constriction, swallowing, and apnea followed by hypoventilation (1). The inhibition of respiration is accompanied by a cardiovascular response consisting of bradycardia, peripheral vasoconstriction, and redistribution of blood flow (2, 3). This response may be particularly strong in young mammals and lead to cardiovascular collapse and death (4). Termination of LCR apnea relies on mechanisms similar to those that modulate the cardiorespiratory response to hypoxia, i.e. sympathetic activation, increased alertness, and augmented peripheral chemoreceptor and baroreceptor sensory discharge. The clinical importance of these escape and defense mechanisms are supported by observations that infants who are at risk for life-threatening events are also less able to recover from LCR-induced reflex apnea and bradycardia (5,6) In this study, we tested the hypothesis that long-term postnatal exposure to nicotine attenuates and prolongs recovery from apnea and bradycardia in response to LCR stimulation. This notion was based on our previous observations that postnatal nicotine exposure leads to an attenuation of cardiorespiratory defense mechanisms to hypoxia (7). We therefore assumed that nicotine, which has effects on both sympathetic regulation and the ventilatory response to hypoxia, could adversely affect cardiorespiratory recovery from induced apnea.

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“…4). Previous studies indicate that this immunomodulator also alters respiration and autoresuscitation (5)(6)(7)(8)(9)(10). IL-1␤ induces expression of the immediate-early gene c-fos in respiration-related regions of the brainstem such as the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) (11).…”

mentioning

confidence: 99%

The induced prostaglandin E ₂ pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

Hofstetter

Saha

Siljehav

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

125

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Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1␤ may serve as a critical mediator between these events. To determine the mechanism by which IL-1␤ depresses respiration, we examined a prostaglandin E2 (PGE2)-dependent pathway in newborn mice and human neonates. IL-1␤ and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1␤ reduced respiratory frequency during hyperoxia and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, PGE2 induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE 2 exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE2 exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE 2 in the cerebrospinal fluid, and elevated central PGE2 was associated with an increased apnea frequency. We conclude that IL-1␤ adversely affects breathing and its control by mPGES-1 activation and PGE2 binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality.A pnea and sudden infant death syndrome (SIDS) represent major medical concerns in the neonatal population, and infection may play a crucial role in their pathogenesis. Apnea is a common presenting sign of infection in neonates, and mild viral or bacterial infection precedes death in the majority of SIDS victims (1, 2). Proinflammatory cytokines such as IL-1␤ may serve as key mediators between these events (3). IL-1␤ is produced during an acute phase immune response to infection and inflammation and evokes a variety of sickness behaviors (for a review, see ref. 4). Previous studies indicate that this immunomodulator also alters respiration and autoresuscitation (5-10). IL-1␤ induces expression of the immediate-early gene c-fos in respiration-related regions of the brainstem such as the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) (11). However, IL-1␤ is a large lipophobic protein that does not readily diffuse across the blood-brain barrier (BBB). Furthermore, the NTS and RVLM do not appear to express IL-1 receptor mRNA (12), and IL-1␤ does not alter brainstem respiration-related neuronal activity in vitro (5). Thus, it is likely that an indirect mechanism underlies the central respiratory effects of IL-1␤.IL-1␤ binds to IL-1 receptors on vascular endothelial cells of the BBB and induces cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) activity (for a review, see ref.13). COX-2 catalyzes the formation of prostaglandin H 2 (PGH 2 ) from arachidonic acid, and mPGES-1 subsequently catalyzes the synthesis of prostaglandin E 2 (PGE 2 ) from PGH 2. PGE 2 is then released into the brain parenchyma where it recently has been sho...

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Adverse Effects of Nicotine and Interleukin-1β on Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome

Cited by 77 publications

References 33 publications

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

Impaired Cardiorespiratory Recovery after Laryngeal Stimulation in Nicotine-Exposed Young Lambs

The induced prostaglandin E ₂ pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

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Adverse Effects of Nicotine and Interleukin-1β on Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome

Cited by 77 publications

References 33 publications

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

Impaired Cardiorespiratory Recovery after Laryngeal Stimulation in Nicotine-Exposed Young Lambs

The induced prostaglandin E 2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

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The induced prostaglandin E ₂ pathway is a key regulator of the respiratory response to infection and hypoxia in neonates