Inflammatory response to repetitive umbilical cord occlusions with worsening acidosis in the near term ovine fetus

Department of Obstetrics and Gynecology, Lawson Health Research Institute, University of Western Ontario, London, Canada.
American journal of obstetrics and gynecology (Impact Factor: 4.7). 11/2009; 202(1):82.e1-9. DOI: 10.1016/j.ajog.2009.08.020
Source: PubMed


We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening acidosis will lead to a fetal inflammatory response.
Chronically instrumented fetal sheep underwent a series of UCOs until fetal arterial pH decreased to <7.00. Maternal and fetal blood samples were taken for blood gases/pH and plasma interleukin (IL)-1B and IL-6 levels. Animals were euthanized at 24 hours of recovery with brain tissue processed for subsequent measurement of microglia and mast cell counts.
Repetitive UCOs resulted in a severe degree of fetal acidemia. Fetal plasma IL-1B values were increased approximately 2-fold when measured at maximal fetal acidosis and again at 1-2 hours of recovery. Fetal microglia cells were increased approximately 2-fold in the white matter and hippocampus, while mast cells were increased approximately 2-fold in the choroid plexus and now evident in the thalamus when analyzed at 24 hours recovery.
Repetitive UCOs leading to severe acidemia in the ovine fetus near term will result in an inflammatory response both systemically and locally within the brain.


Available from: Martin Gerbert Frasch
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    • "Accordingly , this ancillary surveillance modality during labor could be added easily and cost-effectively to the current electronic FHR monitoring that is widely used (Liston et al. 2002). We hypothesized that fetal EEG recorded from a modified FHR scalp electrode will allow for early detection of worsening acidemia similar to our previous findings for fetal ECOG (Prout et al. 2010; Frasch et al. 2011). Consequently, in this study we subjected near-term ovine fetuses to repetitive UCO insults and compared the fetal ECOG and EEG responses during worsening acidemia . "
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    ABSTRACT: In fetal sheep, the electrocorticogram (ECOG) recorded directly from the cortex during repetitive heart rate (FHR) decelerations induced by umbilical cord occlusions (UCO) predictably correlates with worsening hypoxic-acidemia. In human fetal monitoring during labor, the equivalent electroencephalogram (EEG) can be recorded noninvasively from the scalp. We tested the hypothesis that combined fetal EEG - FHR monitoring allows for early detection of worsening hypoxic-acidemia similar to that shown for ECOG-FHR monitoring. Near-term fetal sheep (n = 9) were chronically instrumented with arterial and venous catheters, ECG, ECOG, and EEG electrodes and umbilical cord occluder, followed by 4 days of recovery. Repetitive UCOs of 1 min duration and increasing strength (with regard to the degree of reduction in umbilical blood flow) were induced each 2.5 min until pH dropped to <7.00. Repetitive UCOs led to marked acidosis (arterial pH 7.35 ± 0.01 to 7.00 ± 0.03). At pH of 7.22 ± 0.03 (range 7.32-7.07), and 45 ± 9 min (range 1 h 33 min-20 min) prior to attaining pH < 7.00, both ECOG and EEG amplitudes began to decrease ~fourfold during each FHR deceleration in a synchronized manner. Confirming our hypothesis, these findings support fetal EEG as a useful adjunct to FHR monitoring during human labor for early detection of incipient fetal acidemia. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    07/2015; 3(7). DOI:10.14814/phy2.12435
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    • "Whether inflammatory molecules besides iNOS and COX-2 are produced in the CNS during IH is not known, nor is the cellular source of these molecules, although iNOS has been attributed to neurons [11]. Microglia, CNS resident immune cells are considered to be contributors to IH-induced neuroinflammation [7], but their activities have never directly been tested in this model of IH [15], [16]. Thus, a major goal of the present studies was to determine the contributions of microglia to IH-induced neuroinflammation over time, and to elucidate the expression profile of inflammatory factor genes. "
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    ABSTRACT: Intermittent hypoxia (IH) during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2) for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells). We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.
    PLoS ONE 12/2013; 8(12):e81584. DOI:10.1371/journal.pone.0081584 · 3.23 Impact Factor
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    • "Tissue sections were incubated with an anti-IBA1 rabbit polyclonal antibody (1∶500, Wako Industries, Richmond, VA) which has been reported to be a robust marker for microglia in human and animal studies [27], [28] with detection of bound antibody obtained following incubation in Cardassian DAB Chromogen (Biocare Medical, Concord, CA). The presence of mast cells in brain tissue was determined using histological and morphological assessment techniques after tissue sections were stained in 0.1 M HCL with toluidine blue [1]. "
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    ABSTRACT: Fetal hypoxic episodes may occur antepartum with the potential to induce systemic and cerebral inflammatory responses thereby contributing to brain injury. We hypothesized that intermittent umbilical cord occlusions (UCOs) of sufficient severity but without cumulative acidosis will lead to a fetal inflammatory response. Thirty-one chronically instrumented fetal sheep at ∼0.85 of gestation underwent four consecutive days of hourly UCOs from one to three minutes duration for six hours each day. Maternal and fetal blood samples were taken for blood gases/pH and plasma interleukin (IL)-1β and IL-6 levels. Animals were euthanized at the end of experimental study with brain tissue processed for subsequent counting of microglia and mast cells. Intermittent UCOs resulted in transitory fetal hypoxemia with associated acidemia which progressively worsened the longer umbilical blood flow was occluded, but with no cumulative blood gas or pH changes over the four days of study. Fetal arterial IL-1β and IL-6 values showed no significant change regardless of the severity of the UCOs, nor was there any evident impact on the microglia and mast cell counts for any of the brain regions studied. Accordingly, intermittent UCOs of up to three minutes duration with severe, but limited fetal hypoxemia and no cumulative acidemia, do not result in either a systemic or brain inflammatory response in the pre-term ovine fetus. However, fetal IL-1B and IL-6 values were found to be well correlated with corresponding maternal values supporting the placenta as a primary source for these cytokines with related secretion into both circulations. Female fetuses were also found to have higher IL-1β levels than males, indicating that gender may impact on the fetal inflammatory response to various stimuli.
    PLoS ONE 06/2012; 7(6):e39043. DOI:10.1371/journal.pone.0039043 · 3.23 Impact Factor
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