
Daan OpheldersMaastricht University | UM · Department of Pediatrics
Daan Ophelders
PhD
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59
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Introduction
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January 2021 - present
January 2017 - December 2020
September 2011 - December 2016
Publications
Publications (59)
Introduction
Preterm infants close to viability commonly require mechanical ventilation (MV) for respiratory distress syndrome. Despite commonly used lung‐sparing ventilation techniques, rapid lung expansion during MV induces lung injury, a risk factor for bronchopulmonary dysplasia. This study investigates whether ventilation with optimized lung e...
Background: Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative...
Inflammation is a physiological state where immune cells evoke a response against detrimental insults. Finding a safe and effective treatment for inflammation associated diseases has been a challenge. In this regard, human mesenchymal stem cells (hMSC), exert immunomodulatory effects and have regenerative capacity making it a promising therapeutic...
Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms...
Phosphodiesterase (PDE) inhibition has been identified in animal studies as a new treatment option for neonatal lung injury, and as potentially beneficial for early lung development and function. However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental effects and promote lung inflammation in the...
During mechanical ventilation of the neonate the main goal is to stabilize respiratory function of the often premature lungs. Ventilating the patient without inflicting harm is then the subordinated next goal. Ideally the arterial partial pressure of CO2 lays within a normocapnic range and fluctuations are kept minimal. By closely monitoring CO2 an...
Systemic and cerebral inflammation following antenatal infection (e.g. chorioamnionitis) and dysregulation of the blood brain barrier (BBB) are major risk factors for abnormal neonatal brain development. Administration of multipotent adult progenitor cells (MAPCs) represents an interesting pharmacological strategy as modulator of the peripheral and...
Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamic...
Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of an...
Background:
Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we exami...
Involvement of the cerebellum in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) in preterm infants is increasingly recognized. We aimed to assess the neuroprotective potential of intravenously administered multipotent adult progenitor cells (MAPCs) in the preterm cerebellum. Instrumented preterm ovine fetuses were subjected to transie...
With a worldwide incidence of 15 million cases, preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and economic burden Preterm infants are predisposed to lifelong neurological disorders due to the immaturity of the brain. The risks are inversely proportional to maturity at birth. In the majority of extr...
Abstract Background Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes. Methods We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using th...
Background Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes.
Methods We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using three diffe...
Background: Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes.
Methods: We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using three dif...
Background:
Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhi...
The conclusion of our recent paper that performance of the STAN device in clinical practice is potentially limited by high false-negative and high false-positive STAN-event rates and loss of ST waveform assessment capacity during severe hypoxemia, evoked comments by Kjellmer, Lindecrantz and Rosén. These comments can be summarized as follows: 1) ST...
Autologous fat transfer (AFT) is limited by post-operative volume loss due to ischemia-induced cell death in the fat graft. Previous studies have demonstrated that electrical stimulation (ES) promotes angiogenesis in a variety of tissues and cell types. In this study we investigated the effects of ES on the angiogenic potential of adipose-derived s...
Blood-brain barrier (BBB) disruption is associated with hypoxia-ischemia (HI) induced brain injury and life-long neurological pathologies. Treatment options are limited. Recently, we found that mesenchymal stem/stromal cell derived extracellular vesicles (MSC-EVs) protected the brain in ovine fetuses exposed to HI. We hypothesized that Annexin A1 (...
Background:
Antenatal infection (i.e., chorioamnionitis) is an important risk factor for adverse neurodevelopmental outcomes after preterm birth. Destructive and developmental disturbances of the white matter are hallmarks of preterm brain injury. Understanding the temporal effects of antenatal infection in relation to the onset of neurological in...
Introduction
The inconclusive clinical results for ST-waveform analysis (STAN) in detecting fetal hypoxemia may be caused by the signal processing of the STAN-device itself. We assessed the performance of a clinical STAN device in signal processing and in detecting hypoxemia in a fetal sheep model exposed to prolonged umbilical cord occlusion (UCO)...
Background:
Vitamin A (VA) is crucial for lung growth and development. In premature infants, inadequate VA levels are associated with an increased risk of bronchopulmonary dysplasia (BPD). Intramuscular VA supplementation has been shown to decrease the incidence of BPD, but is not widely used in the clinical setting due to concerns about feasibili...
Background
Poractant alfa (Curosurf®) and Bovactant (Alveofact®) are two animal-derived pulmonary surfactants preparations approved for the treatment of neonatal respiratory distress syndrome (nRDS). They differ in their source, composition, pharmaceutical form, and clinical dose. How much these differences affect the acute pulmonary response to tr...
Chorioamnionitis is associated with adverse neurodevelopmental outcomes in preterm infants. Ureaplasma spp. are the microorganisms most frequently isolated from the amniotic fluid of women diagnosed with chorioamnionitis. However, controversy remains concerning the role of Ureaplasma spp. in the pathogenesis of neonatal brain injury. We hypothesize...
Significance:
Bone marrow-derived mesenchymal stromal cells (MSCs) show promise in treating hypoxic-ischemic injury of the preterm brain. Study results suggest administration of extracellular vesicles, rather than intact MSCs, is sufficient to exert therapeutic effects and avoids potential concerns associated with administration of living cells. T...
Perinatal asphyxia, a condition of impaired gas exchange during birth, leads to fetal hypoxia-ischemia (HI) and is associated with postnatal adverse outcomes including intestinal dysmotility and necrotizing enterocolitis (NEC). Evidence from adult animal models of transient, locally-induced intestinal HI has shown that inflammation is essential in...
Objectives:
NSAIDs are used to relieve pain and decrease inflammation by inhibition of cyclooxygenase (COX)-catalyzed prostaglandin (PG) synthesis. PGs are fatty acid mediators involved in cartilage homeostasis, however the action of their synthesizing COX-enzymes in cartilage differentiation is not well understood. In this study we hypothesized t...
Background:
Current methods for assessing perinatal hypoxic conditions did not improve infant outcomes. Various waveform-based and interval-based ECG markers have been suggested, but not directly compared. We compare performance of ECG markers in a standardised ovine model for fetal hypoxia.
Methods:
69 fetal sheep of 0.7 gestation had ECG recor...
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...
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 br...
Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-ind...
Hyperoxia and hypoxia influence morbidity and mortality of preterm infants. Automated closed-loop control of the fraction of inspired oxygen (FiO2) has been shown to facilitate oxygen supplementation in the NICU, but has not yet been tested during preterm resuscitation. We hypothesized that fully automated FiO2 control based on predefined oxygen sa...
Surfactant replacement therapy is the gold standard treatment of neonatal respiratory distress (RDS). Nebulization is a non-invasive mode of surfactant administration. We administered Poractant alfa (Curosurf) via a vibrating perforated membrane nebulizer (eFlow Neonatal Nebulizer) to spontaneously breathing preterm lambs during binasal continuous...
Chorioamnionitis results from an infection of the fetal membranes and is associated with fetal adverse outcomes notably in the intestine. Using a translational ovine model, we showed that intra-amniotic exposure to inflammatory stimuli decreased the regulatory/effector T (Treg/Teff) cell balance in the gut, which was accompanied by intestinal infla...
Background Oxygen under- and overexposure has detrimental effects on preterm infants. Controlling the oxygen saturation manually within strict targets is a notoriously difficult and time consuming task which can be facilitated by automated control.
Aims To evaluate the performance of a closed loop fraction of inspired oxygen (FiO2) controller based...
Background:
A new technique was proposed to administer surfactant to spontaneous breathing preterm infants by placing a thin catheter through the vocal cords. This technique was not studied with respect to oxygenation, gas exchange, surfactant distribution, and lung mechanics. We tested the technique of less-invasive surfactant administration (LIS...
Chorioamnionitis and antenatal glucocorticoids are common exposures for preterm infants and can affect the fetal brain, contributing to cognitive and motor deficits in preterm infants. The effects of antenatal glucocorticoids on the brain in the setting of chorioamnionitis are unknown. We hypothesized that antenatal glucocorticoids would modulate i...
The artificial placenta as a fascinating treatment alternative for neonatal lung failure has been the subject of clinical research for over 50 years. Pumpless systems have been in use since 1986. However, inappropriate dimensioning of commercially available oxygenators has wasted some of the theoretical advantages of this concept. Disproportional s...
Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of t...
Detection of human specific β-2-microglobulin DNA sequences in preterm sheep brain.
Genomic DNA was extracted from subcortical white matter of a MSC treated animal (MSC) and a saline treated animal (SAL) and analyzed by nested PCR for the presence of human β-2-microglobulin (B2M) DNA sequences. The presence of amplifiable DNA was evaluated by PCR...
Correlation plots.
(A) Density of immature preOLs was inversely related (Pearson r = -.83, P<0.001) to IBA-1 immunoreactivity in the SCWM. (B) MBP immunoreactivity was inversely related (Pearson r = -.71, P=0.002) to IBA-1 immunoreactivity in the SCWM. (C) The number of non-proliferating CD4-positive T cells harvested from the spleen was inversely...
Gating strategy proliferation assay.
(A–C) Dot plots illustrating gating strategy in the flow cytometry analysis of the proliferation assay. FSC = forward scatter, SSC = sideward scatter, 7-AAD = 7-Aminoactinomycin D (viability stain).
(TIF)
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...
Background:
The understanding of hypoxemia-induced changes in baroreflex function is limited and may be studied in a fetal sheep experiment before, during, and after standardized hypoxic conditions.
Methods:
Preterm fetal lambs were instrumented at 102 d gestation (term: 146 d). At 106 d, intrauterine hypoxia--ischemia was induced by 25 min of u...
Respiratory distress syndrome in preterm babies is caused by a pulmonary surfactant deficiency, but also by its inactivation due to various conditions, including plasma protein leakage. Surfactant replacement therapy is well established, but clinical observations and in vitro experiments suggested that its efficacy may be impaired by inactivation....
Minute and tidal volume. Recordings of the minute (A) and tidal volume (B) did not show any significantly difference between CHF 5633 treated animals and Poractant alfa treated animals for the duration of the experiment. Grey spheres = CHF 5633; Black cubes = Poractant alfa. Data expressed as mean±SEM. *p<0.05, two-way repeated-measures analysis of...
Questions
Question (1)
For sorting of ovine Tregs I am looking for a CD127 antibody. FoxP3 works for identifaction of ovine Tregs, but is not suitable for sorting.