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a Department of Pediatrics, Louisiana State University Medical Center, New Orleans, Louisiana 70112, USA
b Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
Premature labor, fetal demise, and fetal growth restriction are accompanied by indices of inflammation or infection of the uteroplacental unit. To understand whether these events are causally related, we established an animal model of fetal demise and growth restriction and evaluated the potential utility of the anti-inflammatory cytokine interleukin-10 (IL-10). We administered low-dose endotoxin (lipopolysaccharide, or LPS, 100 µg/kg, i.p.) to third trimester rats (gestational days 14–20). Control rats received normal saline. A third group received IL-10 (100 µg/kg; s.c.) concomitantly with LPS for 7 prenatal days. Cytokine gene expression (IL-10 and TNF-
) was evaluated by RT-PCR and tissue levels (TNF-) were determined by ELISA. Apoptosis was evaluated by TdT-mediated dUTP nick end labeling immunohistochemistry, and nitric oxide (NO) levels were quantified by microelectrode electrochemical detection in explants in culture media. LPS exposure resulted in 43% fetal demise and reduced the size of the surviving fetuses. Placental weight was not altered by LPS. IL-10 attenuated the LPS-induced fetal death rate (to 22%) and growth restriction (P<0.05). In normal rats, IL-10 did not affect fetus size or the incidence of resorptions, although placental size was marginally smaller. Increased uterine TNF- content and NO release and apoptosis of uterine epithelia and muscularis were hallmarks of the LPS model. All were normalized by IL-10. IL-10 may represent a new therapeutic option for the treatment of a variety of perinatal complications. Benefit may result from the suppression of TNF-- and NO-mediated cell death.—Rivera, D. L., Olister, S. M., Liu, X., Thompson, J. H., Zhang, X.-J., Pennline, K., Azuero, R., Clark, D. A., Miller, M. J. S. Interleukin-10 attenuates experimental fetal growth restriction and demise. FASEB J. 12, 189–197 (1998)
Key Words: TNF- • nitric oxide • IL-10 • TUNEL • placenta • cellular infiltration
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