Tolerance to low-dose endotoxin in awake sheep

Whyte, Richard I.; Warren, H. Shaw; Greene, E.; Glennon, M.; Robinson, Dwight R.; Zapol, Warren M.

doi:10.1152/jappl.1989.66.6.2546

Cited by 17 publications

(13 citation statements)

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“…Previous studies have shown that tolerance develops with repeated doses of endotoxin over a period of days (15)(16)(17). However, we found no marked differences between the three LPS treatments in both the temperature and cortisol responses.…”

Section: Discussioncontrasting

confidence: 79%

“…Pregnenolone, progesterone, and allopregnanolone were measured in plasma and the brain. Experiments were repeated three times between 12 and 20 d of age to allow us to determine whether the responses were attenuated by repeated exposure to LPS, as has been observed in adult animals (15)(16)(17). Our results show that large changes in peripheral and central concentrations of allopregnanolone and increased sleep occur on exposure to LPS in the newborn lamb, with no evidence of tolerance.…”

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confidence: 53%

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Endotoxin Increases Sleep and Brain Allopregnanolone Concentrations in Newborn Lambs

et al. 2002

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Infection has been identified as a risk factor for sudden infant death syndrome (SIDS). Synthesis of allopregnanolone, a neuroactive steroid with potent sedative properties, is increased in response to stress. In this study, we investigated the effect of endotoxin (lipopolysaccharide, LPS) on brain and plasma allopregnanolone concentrations and behavior in newborn lambs. LPS was given intravenously (0.7 g/kg) at 12 and 15 d of age (n ϭ 7), and resulted in a biphasic febrile response (p Ͻ 0.001), hypoglycemia, lactic acidemia (p Ͻ 0.05), a reduction in the incidence of wakefulness, and increased nonrapid eye movement sleep and drowsiness (p Ͻ 0.05) compared with saline-treated lambs (n ϭ 5). Plasma allopregnanolone and cortisol were significantly (p Ͻ 0.05) increased after LPS treatment. These responses to LPS lasted 6 -8 h, and were similar at 12 and 15 d of age. Each lamb was then given LPS at 20 d of age and killed 3 h posttreatment to obtain samples of the brain. Allopregnanolone concentrations were increased (p Ͻ 0.05) in all brain areas except the cerebellum and diencephalon. We suggest that LPS-induced increase of allopregnanolone in the brain may contribute to somnolence in the newborn, and may be responsible for the reduced arousal thought to contribute to the risk of SIDS in human infants. Infection is a stress often faced by neonates and has been proposed as a risk factor in SIDS. The potential mechanism(s) by which infection could increase susceptibility to SIDS remain unclear. It is likely, however, that a SIDS death results from the coincidence of a number of events that together create a period of increased risk (1). We propose that one of the mechanisms involved is the increased production of sedative neuroactive steroids in response to infection, and that these steroids contribute to the lethargy and increased sleep associated with infection in neonates.The pathology of infection and its effects on sleep-wake states has been extensively studied (2-4). Together with fever and other "acute phase" changes (such as increased cytokine production and cortisol levels), increased somnolence is one of the cardinal responses to infection in adults. Several components of the body's response to infection, including increased production of cytokines and prostaglandins, have been shown to induce sleep. Muramyl peptides and LPS associated with the cell wall of bacteria have also been shown to be somnifacient (5, 6). Although sleepiness may have an adaptive role that promotes rest and conserves energy, the combination of infection and somnolence in the newborn, with its high metabolic rate and low pulmonary oxygen stores, may increase the susceptibility of the infant to episodes of periodic breathing, sleep-associated apnea, and SIDS by ablating essential cardiorespiratory responses to hypoxia and asphyxia.Neuroactive steroids are a group of steroids that influence CNS function and, in the adult, can be produced in the brain from cholesterol, or in peripheral organs such as the adrenal cortex and gonads. Progest...

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Section: Discussioncontrasting

confidence: 79%

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confidence: 53%

Endotoxin Increases Sleep and Brain Allopregnanolone Concentrations in Newborn Lambs

et al. 2002

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“…All of these responses were attenuated after subsequent LPS treatments, but fetuses remained mildly hypoxemic at the conclusion of the 5-d protocol. Attenuation of responses to repeated LPS exposure has been described previously (34,35), and may be due to down-regulation of the LPS receptor CD14 (36). The fetal hypoxemia and metabolic acidosis after LPS are likely due to placental dysfunction as LPS, albeit at higher doses, increases umbilico-placental vascular resistance (37).…”

Section: Discussionmentioning

confidence: 97%

White Matter Injury after Repeated Endotoxin Exposure in the Preterm Ovine Fetus

Duncan

2002

Pediatric Research

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Intrauterine infection has been linked to neurologic injury in preterm infants. However, a reproducible model of white matter injury in the preterm fetus in a long gestation species that can be monitored in utero is currently unavailable. Thus, our objective was to determine the effects of bacterial endotoxin (lipopolysaccharide, LPS) on physiologic and inflammatory responses and brain structure in the preterm ovine fetus. At 0.7 of gestation, six catheterized fetuses received three to five intravenous injections of LPS (1 g/kg) over 5 d; seven fetuses served as controls. Fetal responses were monitored and brain tissue examined 10 -11 d after the initial LPS injection. After LPS on d 1 and 2, fetuses became transiently hypoxemic and hypotensive and blood IL-6 levels were increased, but these responses were smaller or absent after subsequent LPS exposures. Neural injury was observed in all LPS-exposed fetuses, most prominently in the cerebral white matter. Injury ranged from diffuse subcortical damage to periventricular leukomalacia, and in the brainstem the cross-sectional area of the corticospinal tract was reduced by 30%. Thus, repeated exposure of the preterm ovine fetus to LPS causes neuropathology resembling that of cerebral palsy and provides a robust model for exploring the etiology, prevention, and treatment of white matter damage. It has been hypothesized that infection during pregnancy, for example, bacterial vaginosis, urinary tract infection, or chorioamnionitis, can lead to preterm fetal brain injury (1-4). Furthermore, it has been hypothesized that such injury might result from an inflammatory cascade initiated via mediators from the mother, placenta, or membranes (3). These hypotheses have been supported by clinical evidence that maternal infection is associated with both preterm birth and neonatal neurologic injury (5), and with increased levels of pro-inflammatory cytokines in amniotic fluid (6) and fetal blood (7). White matter damage is the most common form of brain injury and includes necrosis and cystic lesions in white matter adjacent to the lateral ventricles, usually referred to as PVL. The proinflammatory cytokines TNF-␣ (8) and IL-6 (9) have been identified within PVL (8)

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“…Similar to the ablated effect on TNF-and IL-6, the response of both activin A and follistatin was reduced following LPS treatment of an identical dose administered 5 days after an initial challenge. The nature of how these proteins form part of the tolerance mechanism has not been elucidated; tolerance is readily demonstrable in mature sheep (Whyte et al 1989) and is also presumed to occur in immature animals. Of interest will be to establish if the diminished release of activin/follistatin is subject to a recovery in responsiveness, as in rats there is an initial refractory period to repeated LPS stimulation which disappears after some weeks and after which a full response to LPS is observed again (Sanchez-Cantu et al 1989).…”

Section: Discussionmentioning

confidence: 99%

Effects of age and pregnancy on the circulatory activin response of sheep to acute inflammatory challenge by lipopolysaccharide

McClure

O’Connor

Hayward

et al. 2005

Journal of Endocrinology

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The release of activin A in response to intravenous injection of the bacterial cell-wall component lipopolysaccharide (LPS) was investigated in an ovine model of acute inflammatory challenge in newborn and adult sheep, and in non-pregnant and pregnant ewes. Neonatal lambs (<20 days of age) showed a quantitatively similar response in terms of circulating concentrations of activin A, its binding protein follistatin and the cytokine interleukin-6 compared with adult ewes challenged with an equivalent dose (300 ng/kg bodyweight) of LPS. The fever response and plasma tumour necrosis factor-release in response to LPS, however, were significantly (P<0·01) less in lambs than in the adult group. Pregnant ewes in the last trimester of gestation had similar responses to LPS, in all aspects measured, compared with their non-pregnant counterparts, apart from an ablated fever response. Although the adult and neonatal sheep responded to LPS, a similar response was not apparent in the fetal circulation, possibly due to a protective effect of the placenta. A 10-fold increase in the dose of LPS (from 300 ng to 3 µg/kg bodyweight) given to neonatal lambs elicited an increase in several cytokine responses measured, with a significant (P<0·05) increase in follistatin release. In contrast, the amount of activin released by the increased dose of LPS was similar to that invoked by the lower dose. The effect of tolerance to LPS was investigated by giving a second challenge of LPS 5 days after the initial injection. In all animals studied, there was an ablated (P<0·05) response to the subsequent LPS injection, apart from a similar temperature-response profile. These data provide further evidence that activin A concentrations in the bloodstream are acutely responsive to inflammatory challenge in postnatal life and suggest that the response forms a significant component of the innate immune system.

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Tolerance to low-dose endotoxin in awake sheep

Cited by 17 publications

References 0 publications

Endotoxin Increases Sleep and Brain Allopregnanolone Concentrations in Newborn Lambs

Endotoxin Increases Sleep and Brain Allopregnanolone Concentrations in Newborn Lambs

White Matter Injury after Repeated Endotoxin Exposure in the Preterm Ovine Fetus

Effects of age and pregnancy on the circulatory activin response of sheep to acute inflammatory challenge by lipopolysaccharide

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