5 results on '"Wolfs, Tim G. A. M."'
Search Results
2. Global Hypoxia-Ischemia Induced Inflammation and Structural Changes in the Preterm Ovine Gut Which Were Not Ameliorated by Mesenchymal Stem Cell Treatment
- Author
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Nikiforou, Maria, Willburger, Carolin, de Jong, Anja E, Kloosterboer, Nico, Jellema, Reint K, Ophelders, Daan R M G, Steinbusch, Harry W M, Kramer, Boris W, and Wolfs, Tim G A M
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- 2016
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3. Multipotent adult progenitor cells for hypoxic-ischemic injury in the preterm brain.
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Jellema, Reint K., Ophelders, Daan R. M. G, Zwanenburg, Alex, Nikiforou, Maria, Delhaas, Tammo, Andriessen, Peter, Mays, Robert W., Deans, Robert, Germeraad, Wilfred T. V., Wolfs, Tim G. A. M., and Kramer, Boris W.
- Subjects
PROGENITOR cells ,ISCHEMIA ,PREMATURE labor ,PREMATURE infants ,MESENCHYMAL stem cells ,GESTATIONAL age ,STEM cell transplantation ,CEREBRAL anoxia-ischemia ,ANIMAL experimentation ,ANIMAL populations ,BIOLOGICAL models ,SHEEP ,THERAPEUTICS - Abstract
Background: Preterm infants are at risk for hypoxic-ischemic encephalopathy. No therapy exists to treat this brain injury and subsequent long-term sequelae. We have previously shown in a well-established pre-clinical model of global hypoxia-ischemia (HI) that mesenchymal stem cells are a promising candidate for the treatment of hypoxic-ischemic brain injury. In the current study, we investigated the neuroprotective capacity of multipotent adult progenitor cells (MAPC®), which are adherent bone marrow-derived cells of an earlier developmental stage than mesenchymal stem cells and exhibiting more potent anti-inflammatory and regenerative properties.Methods: Instrumented preterm sheep fetuses were subjected to global hypoxia-ischemia by 25 min of umbilical cord occlusion at a gestational age of 106 (term ~147) days. During a 7-day reperfusion period, vital parameters (e.g., blood pressure and heart rate; baroreceptor reflex) and (amplitude-integrated) electroencephalogram were recorded. At the end of the experiment, the preterm brain was studied by histology.Results: Systemic administration of MAPC therapy reduced the number and duration of seizures and prevented decrease in baroreflex sensitivity after global HI. In addition, MAPC cells prevented HI-induced microglial proliferation in the preterm brain. These anti-inflammatory effects were associated with MAPC-induced prevention of hypomyelination after global HI. Besides attenuation of the cerebral inflammatory response, our findings showed that MAPC cells modulated the peripheral splenic inflammatory response, which has been implicated in the etiology of hypoxic-ischemic injury in the preterm brain.Conclusions: In a pre-clinical animal model MAPC cell therapy improved the functional and structural outcome of the preterm brain after global HI. Future studies should establish the mechanism and long-term therapeutic effects of neuroprotection established by MAPC cells in the developing preterm brain exposed to HI. Our study may form the basis for future clinical trials, which will evaluate whether MAPC therapy is capable of reducing neurological sequelae in preterm infants with hypoxic-ischemic encephalopathy. [ABSTRACT FROM AUTHOR]- Published
- 2015
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4. Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.
- Author
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Ophelders, Daan R M G, Gussenhoven, Ruth, Lammens, Martin, Küsters, Benno, Kemp, Matthew W, Newnham, John P, Payne, Matthew S, Kallapur, Suhas G, Jobe, Allan H, Zimmermann, Luc J, Kramer, Boris W, and Wolfs, Tim G A M
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PROTEIN metabolism ,METABOLISM ,ANIMAL experimentation ,BIOLOGICAL models ,BRAIN injuries ,CANDIDA albicans ,CANDIDIASIS ,ENCEPHALITIS ,ENZYME-linked immunosorbent assay ,GRANULOCYTE-colony stimulating factor ,INTERLEUKIN-3 ,INTERLEUKINS ,NERVE tissue proteins ,PREGNANCY ,PROTEINS ,RECOMBINANT proteins ,RESEARCH funding ,SHEEP ,TUMOR markers ,DNA-binding proteins ,FLUORESCENT dyes ,PRENATAL exposure delayed effects ,DISEASE complications - Abstract
Background: Intra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.Methods: Pregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.Results: Intra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.Conclusions: Intra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury. [ABSTRACT FROM AUTHOR]- Published
- 2016
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5. Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep.
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Jellema RK, Lima Passos V, Zwanenburg A, Ophelders DR, De Munter S, Vanderlocht J, Germeraad WT, Kuypers E, Collins JJ, Cleutjens JP, Jennekens W, Gavilanes AW, Seehase M, Vles HJ, Steinbusch H, Andriessen P, Wolfs TG, and Kramer BW
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- Animals, Animals, Newborn, Female, Fetus immunology, Fetus pathology, Immunity, Innate, Microglia immunology, Microglia pathology, Pregnancy, Sheep, Brain immunology, Brain pathology, Cell Movement immunology, Hypoxia-Ischemia, Brain immunology, Hypoxia-Ischemia, Brain pathology
- Abstract
Background: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI., Methods: Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis., Results: Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function., Conclusions: Our data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE.
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- 2013
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