Induction of Necrotizing Funisitis by Fetal Administration of Intravenous Granulocyte-Colony Stimulating Factor and Intra-Amniotic Endotoxin in Premature Fetal Sheep

Watanabe, Tatsuya; Matsuda, Tadashi; Hanita, Takushi; Okuyama, Kazuhiko; Cho, Kazutoshi; Kobayashi, Kunihiko; Kobayashi, Yoshiyasu

doi:10.1203/pdr.0b013e31815991bf

Cited by 14 publications

(22 citation statements)

References 19 publications

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“…The preparations for this experiment were very similar to those used in our previous studies (13)(14)(15)(16). In brief, a total of five Suffolk ewes with timed pregnancies underwent surgery between 120 and 130 d of gestation.…”

Section: Animal Preparationmentioning

confidence: 99%

Novel modification of an artificial placenta: pumpless arteriovenous extracorporeal life support in a premature lamb model

et al. 2012

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Background: Previous studies aimed at developing an artificial placenta have had limited success. We hypothesized that the introduction of a high-performance membranous oxygenator to a pumpless artificial placenta could prolong the survival time of premature lambs. Methods: Immediately after delivery of the fetuses, the umbilical vessels were cannulated and connected to the pumpless artificial placenta. Both the fetuses and the circuit were submerged in a warm saline bath. results: Five fetuses survived for 18.2 ± 3.2 (mean ± seM) h after attachment to the artificial placenta, which maintained fetal circulation. circuit blood flow was positively correlated with mean arterial pressure and negatively correlated with blood lactate levels. Milrinone administration transiently decreased lactate levels, although dopamine administration unexpectedly induced a marked increase in the lactate levels despite an elevated arterial pressure and improved circuit blood flow. conclusIon: We prolonged the survival of fetal lambs using a high-performance membranous oxygenator with a small priming volume. The increased systemic resistance induced by vasoconstrictors may increase the circuit blood flow excessively, resulting in circulation failure in systemic organs; therefore, vasodilators may be more useful than vasoconstrictors for maintaining organ blood flow within this circuit.d espite progress in neonatal intensive care, effective treatments for premature low-birth-weight infants with cardiopulmonary abnormalities are lacking. The use of an artificial placenta has been proposed, but previous studies have had limited success, possibly because the circuit volume was too large and the resistance of the circuit was too high (1-5). A more compact circuit may be a solution; in 2009, Reoma et al. reported a 4-h survival period using a pumpless artificial placenta for the first time (6). However, the fetuses could not survive for longer than 4 h because of fetal circulatory deterioration. The authors concluded that prolonging the survival time any further was difficult without the assistance of a roller pump.Is it impossible to prolong the survival time using a pumpless artificial placenta? The goal of our study was to prolong survival time by improving the following two points. First, we developed a high-performance membranous oxygenator jointly with the group of A. Funakubo, who is a pioneer in the development of the membranous oxygenator (7,8). Our membranous oxygenator enabled a reduction in priming volume of 40%, as compared with that used in Reoma's experiment (6), while maintaining membrane surface area. Second, we administered a vasodilator to the fetuses to maintain circulation in systemic organs. Table 1 compares the values obtained in Reoma's experiments (6) with those obtained in our study. The fetuses in our experimental group had a shorter gestational age, a lower birth weight, and a longer survival time than those in Reoma's experiment. In this study, five fetuses were successfully connected to the artificial placenta,...

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Section: Animal Preparationmentioning

confidence: 99%

Novel modification of an artificial placenta: pumpless arteriovenous extracorporeal life support in a premature lamb model

et al. 2012

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“…No significant differences in the gestational days of the hemorrhagic insult and the withdrawn blood volume were noted between the hemorrhage and inflammatory hemorrhage groups. All the fetuses in the inflammation and inflammatory hemorrhage groups showed necrotizing funisitis, in which numerous PMNLs had infiltrated from the vascular space toward the amniotic cavity, and had accumulated and degenerated within the epithelial layers (Watanabe et al 2007;Saito et al 2009). No fetuses in the sham and hemorrhage groups had funisitis.…”

Section: Discussionmentioning

confidence: 93%

“…All the fetuses in the inflammatory insult group received daily intravenous infusions of 40 µg of G-CSF (Neutrogin® R; Chugai Co. Ltd, Tokyo, Japan) solubilized in 2 mL of saline from 105-109 days of gestation. G-CSF has been shown to increase polymorphonuclear leukocytes (PMNLs) counts in the circulating blood (Watanabe et al 2007). …”

Section: Experimental Protocol For Inflammatory Insult Groupsmentioning

confidence: 99%

“…Fetuses were then exposed to 20 mg of endotoxin (Escherichia coli 055:B5 endotoxin; Sigma Chemical Co., St. Louis, MO) solubilized in 5 mL of saline administered into the amniotic cavity once on 107 days of gestation to activate the PMNLs and induce inflammation around the amniotic cavity (Watanabe et al 2007). In the sham group, no inflammatory insult was performed and as a result, none of these fetuses had PVL (Table 1 and Fig.…”

Section: Experimental Protocol For Inflammatory Insult Groupsmentioning

confidence: 99%

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Cerebral Ischemia or Intrauterine Inflammation Promotes Differentiation of Oligodendroglial Precursors in Preterm Ovine Fetuses: Possible Cellular Basis for White Matter Injury

Kitanishi

Matsuda

Watanabe

et al. 2014

Tohoku J. Exp. Med.

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White matter injury in premature infants is known to be major cause of long-term neurocognitive disability, but the pathogenic mechanism remains unclear, hampering our ability to develop preventions. Periventricular leukomalacia is a severe form of white matter injury. In the present study, we explored the effects of cerebral ischemia and/or intrauterine inflammation on the development of oligodendroglia in the cerebral white matter using chronically instrumented fetal sheep. Each fetus received one of three insults: hemorrhage, inflammation and their combination. In the hemorrhage group, 40% of the fetoplacental blood volume was acutely withdrawn, and 24 hours after removal, the blood was returned to the fetus. The inflammation group received intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin and thus suffered from necrotizing funisitis and chorioamnionitis. The inflammatory hemorrhage group underwent acute hemorrhage under the inflammatory state. The sham group received no insults. Importantly, periventricular leukomalacia was not detected in the sham and the inflammation groups. Differentiating oligodendroglia at various developmental stages were identified by immunohistochemical analysis with specific antibodies. No difference in the density of oligodendroglial progenitors was detected among the four groups, whereas oligodendroglial precursors were significantly reduced in the three insult groups, compared to sham control. Moreover, the density of immature oligodendroglia was higher in the inflammation group and the inflammatory hemorrhage group, while the density of mature oligodendroglia was highest in the hemorrhage group. We propose that cerebral ischemia or intrauterine inflammation induces the differentiation of oligodendroglial precursors in preterm fetuses, eventually resulting in their exhaustion.

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“…bolus injections of G-CSF have not been utilized before. Hence, we hypothesized that our novel and relatively simple experimental model that does not require chronic maternal or fetal instrumentation would be able to produce exacerbated inflammation in utero, at least to an extent of that observed in previous experiments (1,2,3,5,6,7) .…”

Section: Introductionmentioning

confidence: 96%

Inflammation-mediated fetal injury by maternal granulocyte-colony stimulating factor and high-dose intraamniotic endotoxin in the caprine model

Sezi̇k

Köker

Özmen

et al. 2019

tjod

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Objective: To define a novel experimental model with maternal intravenous (i.v.) granulocyte-colony stimulating factor (G-CSF) followed by a single- and high-dose of 20 mg intra-amniotic (IA) endotoxin to induce fetal brain injury in the preterm fetal goat. Materials and Methods: Pregnant goats (n=4) were given 50 microg/day G-CSF into the maternal jugular vein through gestational days 110-115 (term, 150 days). At gestational day 115, 20 mg of IA endotoxin was administered. Following preterm delivery at day 120 by cesarean section umbilical cord, fetal lung and brain tissues were harvested for histopathology, immunohistochemistry, and electron microscopy. Inflammatory markers were evaluated in the amniotic fluid and fetal plasma. Results: Necrotizing funisitis with abundant leukocyte infiltration and fetal brain injury was induced in all the fetuses in the experimental group. Conclusion: Maternal i.v. G-CSF for 5 days followed by 20 mg of IA endotoxin is a feasible caprine model to exacerbate intrauterine inflammation.

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Induction of Necrotizing Funisitis by Fetal Administration of Intravenous Granulocyte-Colony Stimulating Factor and Intra-Amniotic Endotoxin in Premature Fetal Sheep

Abstract: ABSTRACT:The purpose of the present study was to determine whether experimental intrauterine inflammation could induce necrotizing funisitis, a severe, chronic inflammation of the umbilical cord.

Cited by 14 publications

References 19 publications

Novel modification of an artificial placenta: pumpless arteriovenous extracorporeal life support in a premature lamb model

Novel modification of an artificial placenta: pumpless arteriovenous extracorporeal life support in a premature lamb model

Cerebral Ischemia or Intrauterine Inflammation Promotes Differentiation of Oligodendroglial Precursors in Preterm Ovine Fetuses: Possible Cellular Basis for White Matter Injury

Inflammation-mediated fetal injury by maternal granulocyte-colony stimulating factor and high-dose intraamniotic endotoxin in the caprine model

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