Changes in apnea and autoresuscitation in piglets after intravenous and intrathecal interleukin-1β injection

Stoltenberg, Lauritz; Sundar, Tom; Almaas, Runar; Storm, Hanne; Rognum, Torleiv O.; Saugstad, Ola Didrik

doi:10.1515/jpme.1994.22.5.421

Cited by 31 publications

(28 citation statements)

References 34 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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“…[12][13][14][15][16] These characteristics are separately known to enhance, produce, and prolong apneas, and interfere with normal autoresuscitation after apnea. 9,11,[17][18][19] Early in life, the infant is more susceptible to apnea by laryngeal stimulation 11 and hypoxia during apnea, 20 and probably responds inadequately to mild hypoxia by increased periodic breathing. [21][22][23] Potential additive adverse effects when combined with nicotine as demonstrated in this study, could prove detrimental, and SIDS victims have often been exposed to nicotine before death.…”

Section: Discussionmentioning

confidence: 99%

“…33 Its effects on apnea have been demonstrated and discussed previously. 9 IL-1␤ has been found elevated in SIDS, although elevated interleukin-6 (IL-6) is a more common finding. 34 This is probably caused by an earlier peak in release and rapid return to baseline values of IL-1␤ during immune reaction, while IL-6 has a more delayed and sustained release.…”

Section: Discussionmentioning

confidence: 99%

“…6 Interleukines are released during infections, and interleukin-1␤ (IL-1␤) has been shown to prolong apnea and interfere with the subsequent autoresuscitation. 9 We have tested the hypothesis that postnatal exposure to tobacco constituents and infections might adversly affect an infant's ability to cope with an apneic episode by investigating the acute effects of nicotine and IL-1␤ on apnea by laryngeal reflex stimulation, and on the subsequent autoresuscitation. …”

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confidence: 99%

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

et al. 2000

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ABSTRACT. Objectives. Maternal cigarette smoking is established as a major dose-dependent risk factor for sudden infant death syndrome (SIDS). Both prenatal and postnatal exposures to constituents of tobacco smoke are associated with SIDS, but no mechanism of death attributable to nicotine has been found. Breastfeeding gives a substantial increase in absorbed nicotine compared with only environmental tobacco smoke when the mother smokes, because the milk:plasma concentration ratio of nicotine is 2.9 in smoking mothers. Furthermore, many SIDS victims have a slight infection and a triggered immune system before their death, thus experiencing a release of cytokines like interleukin-1␤ (IL-1␤) that may depress respiration. Because apneas in infancy are associated with SIDS, we have tested the hypothesis that postnatal exposure to tobacco constituents and infections might adversely affect an infant's ability to cope with an apneic episode. This is performed by investigating the acute effects of nicotine and IL-1␤ on apnea by laryngeal reflex stimulation and on the subsequent autoresuscitation.Design. Thirty 1-week-old piglets (؎1 day) were sedated with azaperone. A tracheal and an arterial catheter were inserted during a short halothane anesthesia. The piglets were allowed a 30-minute stabilization period before baseline values were recorded and they were randomized to 4 pretreatment groups (avoiding siblings in the same group): 1) immediate infusion of 10 pmol IL-1␤ intravenously/kg (IL-1␤ group; n ‫؍‬ 8); 2) slow infusion of 5 g nicotine intravenously/kg 5 minutes later (NIC group; n ‫؍‬ 8); 3) both IL-1␤ and NIC combined (NIC ؉ IL-1␤ group; n ‫؍‬ 6); or 4) placebo by infusion of 1 ml .9% NaCl (CTR group; n ‫؍‬ 8). Fifteen minutes later, apnea was induced by insufflation of .1 ml of acidified saline (pH ‫؍‬ 2) in the subglottic space 5 times with 5-minute intervals, and variables of respiration, heart rate, blood pressure, and blood gasses were recorded.Results. Stimulation of the laryngeal chemoreflex by insufflation of acidified saline in the subglottic space produced apneas, primarily of central origin. This was followed by a decrease in heart rate, a fall in blood pressure, swallowing, occasional coughs, and finally autoresuscitation with gasping followed by rapid increase in heart rate, rise in blood pressure, and (in the CTR group) an increase of respiratory rate. Piglets pretreated with nicotine had more spontaneous apneas, and repeated spontaneous apneas caused an inability to perform a compensatory increase of the respiratory rate after induced apnea. This resulted in a lower SaO 2 than did CTR at 2 minutes after apnea (data shown as median ABBREVIATIONS. SIDS, sudden infant death syndrome; IL-1␤, interleukin-1␤; CRP, C-reactive protein; IL-6, interleukin-6; IL-1␤ group, 10 pmol IL-1␤ intravenously/kg; NIC group, 5 g nicotine intravenously/kg; NIC ϩ IL-1␤ group, both IL-1␤ and NIC combined; CTR group, placebo. M aternal cigarette smoking is established as a major dose-dependent risk factor for sudden infan...

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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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Changes in apnea and autoresuscitation in piglets after intravenous and intrathecal interleukin-1β injection

Abstract: Intravenous and intrathecal injection of IL-1 beta prolong the duration of apnea and modifies autoresuscitation.

Cited by 31 publications

References 34 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

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

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

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Changes in apnea and autoresuscitation in piglets after intravenous and intrathecal interleukin-1β injection

Abstract: Intravenous and intrathecal injection of IL-1 beta prolong the duration of apnea and modifies autoresuscitation.

Cited by 31 publications

References 34 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

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

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