Outside-in? Acute fetal systemic inflammation in very preterm chronically catheterized sheep fetuses is not driven by cells in the fetal blood

Kemp, Matthew W.; Molloy, Timothy J.; Usuda, Haruo; Woodward, Eleanor; Miura, Yoshio; Payne, Matthew S.; Ireland, Demelza J.; Jobe, Alan H.; Kallapur, Suhas G.; Stock, Sarah; Spiller, O. Brad; Newnham, John P.; Saito, Masatoshi

doi:10.1016/j.ajog.2015.09.076

Cited by 21 publications

(23 citation statements)

References 38 publications

(34 reference statements)

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“…Thirty-two date-mated ewes carrying singleton fetuses at 116 days of gestational age (term, approximately 150 days) were acclimatized to a large animal surgical facility for 10 days before undergoing a recovery surgical procedure of 50 minutes in duration to place bilateral maternal jugular and unilateral fetal jugular catheters as previously described. 22 There were no interoperative fetal losses.…”

Section: Methodsmentioning

confidence: 94%

“…Microarray analysis of total messenger ribonuclease acid from fetal lung right lower lobe was as performed previously. 22 Prior to analysis, all ribonuclease acid samples underwent quality control assessment for purity and integrity and had a RNA integrity number value of between 8.2 and 9.5. For each sample, 100 ng of total ribonuclease acid was amplified using a WTPlus kit (Affymetrix, Santa Clara, CA) following the manufacturer's instructions.…”

Section: Measurement Of Transcript Expression Changes In the Fetal Lungmentioning

confidence: 99%

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Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate

Kemp

Saito

Usuda

et al. 2016

American Journal of Obstetrics and Gynecology

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Constant maternal betamethasone infusions delivering substantially lower fetal and maternal betamethasone maximal concentrations than those achieved with current clinical treatment protocols were associated with dose-dependent changes in glucocorticoid-response markers in the fetal lung. Further studies to determine the minimally efficacious dose of steroids for improving outcomes in preterm infants should be viewed as a priority.

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Section: Methodsmentioning

confidence: 94%

Section: Measurement Of Transcript Expression Changes In the Fetal Lungmentioning

confidence: 99%

Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate

Kemp

Saito

Usuda

et al. 2016

American Journal of Obstetrics and Gynecology

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“…Whereas our group previously demonstrated that intra-amniotic LPS stimulated fetal lung and skin inflammation in extreme preterm sheep [34], we determined in this study how the extremely premature sheep lung responded to chronic U . parvum exposure.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

et al. 2017

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BackgroundChorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.MethodsOvine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.ResultsLPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.

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“…For the pharmacokinetics studies, time-mated ewes had recovery surgery for placement of double lumen maternal jugular and single lumen fetal jugular catheters at 114–116 days of gestation as described previously. 16 Animals were allowed to recover for 48 hours and then were assigned to receive intramuscular treatments of Beta-P 0.125 mg/kg, Beta-Ac 0.125 mg/kg, or Beta-Ac 0.5 mg/kg. We chose the dose of Beta-P of 0.125 mg/kg because this is the amount of Beta-P in a dose of Beta-P+Beta-Ac 0.25 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep

Schmidt

Kemp

Rittenschober-Böhm

et al. 2018

American Journal of Obstetrics and Gynecology

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BackgroundAntenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure.ObjectiveThe purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep.Study DesignGroups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours.ResultsAll betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg.ConclusionA single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.

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Outside-in? Acute fetal systemic inflammation in very preterm chronically catheterized sheep fetuses is not driven by cells in the fetal blood

Cited by 21 publications

References 38 publications

Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate

Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate

Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep

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