Inflammation-induced preterm birth in a murine model is associated with increases in fetal macrophages and circulating erythroid precursors.
The presence of intrauterine inflammation has been associated with adverse neurologic outcomes in preterm infants, but the precise mechanisms of fetal brain injury remain unclear. We sought to evaluate inflammatory cell trafficking, fetal organ damage, and molecular regulation in the fetoplacental unit using an established mouse model of preterm birth associated with intrauterine inflammation. Gestational sacs were harvested 6 hours after intrauterine infusion of saline or lipopolysaccharide (LPS). Histologic, immunohistochemical, and molecular investigations were performed to identify target organ damage and the cellular phenotype of inflammatory cells and to quantify circulating inflammatory and hematopoietic mediators within the placental and fetal tissue. There was widespread increase in fetal macrophages in LPS-exposed pups, including within the leptomeninges of the brain, associated with significantly higher of interleukin 6 levels in LPS-exposed pups. Although no specific central nervous system injury (necrosis or apoptosis) was documented, liver hematomas were seen significantly more frequently in LPS-exposed pups. Circulating nucleated fetal erythrocytes were also present more frequently with LPS exposure without significantly higher erythropoietin levels than saline-exposed mice. The presence of increased macrophages, increased circulating interleukin 6 levels, and increased circulating erythroid precursors in LPS-exposed pups suggests that these are significant factors associated with potential target organ damage, such as liver hematomas, associated with intrauterine inflammation and preterm birth. The role of macrophages within the fetal leptomeninges is unclear, but they may play an important role in inflammatory-mediated brain damage, and further investigation of their significance and potential as therapeutic targets is warranted.
Department of Pathology and Laboratory Medicine, The Children's Hospital of Pennsylvania, and University of Pennsylvania, Philadelphia, PA, USA. linda-ernst@northwestern.edu
Linda M
LM
Ernst
Juan
J
Gonzalez
Ella
E
Ofori
Michal
M
Elovitz
D000818:Animals; D021461:Animals, Outbred Strains; D015415:Biomarkers / Q000378:metabolism; D001927:Brain Diseases / Q000196:embryology*; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000276:immunology*; D005260:Female; D005315:Fetal Diseases / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D047928:Premature Birth / Q000276:immunology*
D015415:Biomarkers; D015850:Interleukin-6; D008070:Lipopolysaccharides