Abstract
BackgroundEarly events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero.Methodology/Principal FindingsTen chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received one of two treatments: 1) choriodecidual and intra-amniotic saline (n = 5), or 2) choriodecidual inoculation of Group B Streptococcus (GBS) 1×106 colony forming units (n = 5). Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-α, IL-8, IL-1β, IL-6) and fetal plasma (IL-8) were detected in GBS animals and correlated with lung injury (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (∼10 samples tested/animal), maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology.Conclusions/SignificanceA transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently without symptoms and before the onset of the fetal systemic inflammatory response syndrome.
Highlights
Preterm birth and the resulting neonatal morbidity and mortality represent a significant public health and economic burden to our society [1]
Bacteria induce cytokines, including interleukin-1b (IL-1b) and interleukin-8 (IL-8), which are thought to be a critical trigger of preterm labor and fetal lung injury predisposing the neonate to chronic lung disease [3,4,5]
In a pilot study in rhesus macaques, we have shown that Group B Streptococcus (GBS) inoculated into the choriodecidual space can traffic into the amniotic fluid, but required large and sometimes several inoculations [7]
Summary
Preterm birth and the resulting neonatal morbidity and mortality represent a significant public health and economic burden to our society [1]. Intra-amniotic infection has been suggested as an earlier step in the process, followed by secondary bacterial colonization of the fetal membranes (chorioamnion) resulting in chorioamnionitis [6]. If this scenario is more typical, direct administration of a drug into the amniotic fluid via amniocentesis may be required. Both microbial and host factors, as well as inoculum size, are likely to play a role in whether bacterial colonization of the choriodecidual space results in intra-amniotic infection. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero
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