Abstract
Intrauterine infection has been linked to neurologic injury in preterm infants. However, a reproducible model of white matter injury in the preterm fetus in a long gestation species that can be monitored in utero is currently unavailable. Thus, our objective was to determine the effects of bacterial endotoxin (lipopolysaccharide, LPS) on physiologic and inflammatory responses and brain structure in the preterm ovine fetus. At 0.7 of gestation, six catheterized fetuses received three to five intravenous injections of LPS (1 μg/kg) over 5 d; seven fetuses served as controls. Fetal responses were monitored and brain tissue examined 10–11 d after the initial LPS injection. After LPS on d 1 and 2, fetuses became transiently hypoxemic and hypotensive and blood IL-6 levels were increased, but these responses were smaller or absent after subsequent LPS exposures. Neural injury was observed in all LPS-exposed fetuses, most prominently in the cerebral white matter. Injury ranged from diffuse subcortical damage to periventricular leukomalacia, and in the brainstem the cross-sectional area of the corticospinal tract was reduced by 30%. Thus, repeated exposure of the preterm ovine fetus to LPS causes neuropathology resembling that of cerebral palsy and provides a robust model for exploring the etiology, prevention, and treatment of white matter damage.
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Abbreviations
- ABC:
-
avidin-biotin-peroxidase
- AMPA:
-
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- bpm:
-
beats per minute
- Ca2+:
-
calcium
- Cao2:
-
arterial oxygen content
- CNPase:
-
2′,3′-cyclic nucleotide 3′-phosphodiesterase
- GA:
-
gestational age
- GFAP:
-
glial fibrillary acidic protein
- H&E:
-
hematoxylin and eosin
- Hg:
-
mercury
- HR:
-
heart rate
- IR:
-
immunoreactivity
- LFB:
-
Luxol fast blue
- LPS:
-
lipopolysaccharide
- MAP:
-
mean arterial pressure
- MBP:
-
myelin basic protein
- NF:
-
nuclear factor
- Ov:
-
ovine
- Pao2:
-
partial pressure of arterial oxygen
- PVL:
-
periventricular leukomalacia
- SaO2:
-
arterial oxygen saturation
- TNF:
-
tumor necrosis factor
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Acknowledgements
The authors thank Ms. Mehrnoush Lotfi-Miri, Mr. Alex Satragno, and Mr. Philip Moss for technical assistance, Associate Professor Greg Rice for assistance with cytokine assays, and the Center for Animal Biotechnology for their kind donation of the CD45 antibody.
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Supported by the National Health and Medical Research Council of Australia, the Bonnie Babes Foundation, and the Australian Research Council.
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Duncan, J., Cock, M., Scheerlinck, JP. et al. White Matter Injury after Repeated Endotoxin Exposure in the Preterm Ovine Fetus. Pediatr Res 52, 941–949 (2002). https://doi.org/10.1203/00006450-200212000-00021
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DOI: https://doi.org/10.1203/00006450-200212000-00021
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