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J Neuroinflammation. 2016 Sep 6;13(1):238. doi: 10.1186/s12974-016-0706-4.

Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques.

Author information

1
Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
2
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
3
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
4
California National Primate Research Center and Department of Pediatrics and Cell Biology and Human Anatomy, University of California, Davis, CA, USA.
5
Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA. suhas.kallapur@cchmc.org.

Abstract

BACKGROUND:

Chorioamnionitis is associated with an increased risk of brain injury in preterm neonates. Inflammatory changes in brain could underlie this injury. Here, we evaluated whether neuroinflammation is induced by chorioamnionitis in a clinically relevant model.

METHODS:

Rhesus macaque fetuses were exposed to either intra-amniotic (IA) saline, or IA lipopolysaccharide (LPS) (1 mg) 16 or 48 h prior to delivery at 130 days (85 % of gestation) (n = 4-5 animals/group). We measured cytokines in the cerebrospinal fluid (CSF), froze samples from the left brain for molecular analysis, and immersion fixed the right brain hemisphere for immunohistology. We analyzed the messenger RNA (mRNA) levels of the pro-inflammatory cytokines IL-1β, CCL2, TNF-α, IL-6, IL-8, IL-10, and COX-2 in the periventricular white matter (PVWM), cortex, thalamus, hippocampus, and cerebellum by RT-qPCR. Brain injury was assessed by immunohistology for myelin basic protein (MBP), IBA1 (microglial marker), GFAP (astrocyte marker), OLIG2 (oligodendrocyte marker), NeuN (neuronal marker), CD3 (T cells), and CD14 (monocytes). Microglial proliferation was assessed by co-immunostaining for IBA1 and Ki67. Data were analyzed by ANOVA with Tukey's post-test.

RESULTS:

IA LPS increased mRNA expression of pro-inflammatory cytokines in the PVWM, thalamus, and cerebellum, increased IL-6 concentration in the CSF, and increased apoptosis in the periventricular area after 16 h. Microglial proliferation in the white matter was increased 48 h after IA LPS.

CONCLUSIONS:

LPS-induced chorioamnionitis caused neuroinflammation, microglial proliferation, and periventricular apoptosis in a clinically relevant model of chorioamnionitis in fetal rhesus macaques. These findings identify specific responses in the fetal brain and support the hypothesis that neuroinflammatory changes may mediate the adverse neurodevelopmental outcomes associated with chorioamnionitis.

KEYWORDS:

Apoptosis; Brain injury; Chorioamnionitis; Cytokines; Microglia; Periventricular leukomalacia; Prematurity

PMID:
27596440
PMCID:
PMC5011884
DOI:
10.1186/s12974-016-0706-4
[Indexed for MEDLINE]
Free PMC Article

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