Wolfs TG, Kramer BW, Thuijls G, Kemp MW, Saito M, Willems MG, Senthamarai-Kannan P, Newnham JP, Jobe AH, Kallapur SG. Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation. Am J Physiol Gastrointest Liver Physiol 306: G382-G393, 2014. First published January 23, 2014; doi:10.1152/ajpgi.00260.2013.-Intra-amniotic exposure to proinflammatory agonists causes chorioamnionitis and fetal gut inflammation. Fetal gut inflammation is associated with mucosal injury and impaired gut development. We tested whether this detrimental inflammatory response of the fetal gut results from a direct local (gut derived) or an indirect inflammatory response mediated by the chorioamnion/skin or lung, since these organs are also in direct contact with the amniotic fluid. The gastrointestinal tract was isolated from the respiratory tract and the amnion/ skin epithelia by fetal surgery in time-mated ewes. Lipopolysaccharide (LPS) or saline (controls) was selectively infused in the gastrointestinal tract, trachea, or amniotic compartment at 2 or 6 days before preterm delivery at 124 days gestation (term 150 days). Gastrointestinal and intratracheal LPS exposure caused distinct inflammatory responses in the fetal gut. Inflammatory responses could be distinguished by the influx of leukocytes (MPO ϩ , CD3 ϩ , and FoxP3 ϩ cells), tumor necrosis factor-␣, and interferon-␥ expression and differential upregulation of mRNA levels for Toll-like receptor 1, 2, 4, and 6. Fetal gut inflammation after direct intestinal LPS exposure resulted in severe loss of the tight junctional protein zonula occludens protein 1 (ZO-1) and increased mitosis of intestinal epithelial cells. Inflammation of the fetal gut after selective LPS instillation in the lungs caused only mild disruption of ZO-1, loss in epithelial cell integrity, and impaired epithelial differentiation. LPS exposure of the amnion/skin epithelia did not result in gut inflammation or morphological, structural, and functional changes. Our results indicate that the detrimental consequences of chorioamnionitis on fetal gut development are the combined result of local gut and lung-mediated inflammatory responses.endotoxin; fetal inflammatory response; necrotizing enterocolitis; sheep A FREQUENT ASSOCIATION WITH preterm delivery is chorioamnionitis, a bacterial infection of the amniotic fluid, fetal membranes, and placenta (13,28,30). Chorioamnionitis is associated with an increased risk for poor postnatal developmental outcomes (3,4,15,32). The inflammatory response to chorioamnionitis is postulated to be the proximal cause of injury to fetal organs, which increase the risk of periventricular leukomalacia (6) necrotizing enterocolitis (3, 4), and bronchopulmonary dysplasia (34, 37). Because the fetus swallows and aspirates the amniotic fluid, infection of the amniotic fluid exposes the premature lungs and intestine directly to bacteria and inflammatory products. In addition, the fetal skin and the amniotic epithelium are exposed to...

Articles Translational Investigation nature publishing groupBackground: Hyperoxia and hypoxia influence morbidity and mortality of preterm infants. Automated closed-loop control of the fraction of inspired oxygen (FiO 2 ) has been shown to facilitate oxygen supplementation in the neonatal intensive care unit (NICU), but has not yet been tested during preterm resuscitation. We hypothesized that fully automated FiO 2 control based on predefined oxygen saturation (SpO 2 ) targets was applicable in both preterm resuscitation and ventilation. Methods: Twenty-two preterm lambs were operatively delivered and intubated in a modified EXIT procedure. They were randomized to receive standardized resuscitation with either automated or manual FiO 2 control, targeting SpO 2 according to the Dawson curve in the first 10 min and SpO 2 90-95% hereafter. Automated FiO 2 control also was applied during surfactant replacement therapy and subsequent ventilation. results: Time within target range did not differ significantly between manual and automated FiO 2 control during resuscitation, however automated FiO 2 control significantly avoided hyperoxia. Automated FiO 2 control was feasible during surfactant replacement and kept SpO 2 within target range significantly better than manual control during subsequent ventilation. conclusion: In our model, fully automated FiO 2 control was feasible in rapidly changing physiologic conditions during postnatal resuscitation and prevented hyperoxia. We conclude that closed loop FiO 2 control is a promising tool for the delivery room.o xygen supplementation is one of the most common therapeutic interventions in resuscitation and neonatal intensive care of term and preterm infants (1). However, both hypoxia and hyperoxia must be avoided because of their detrimental effects on morbidity and mortality in these children. While hypoxia may lead to direct and indirect cellular damage, hyperoxia has been associated with oxygen toxicity, oxidative stress (2), and chronic diseases of preterm infants such as bronchopulmonary dysplasia (3) and retinopathy of prematurity (4).Increase in oxygenation after birth is a gradual process (5). Measurement of oxygen saturation (SpO 2 ) by pulse oximetry in the delivery room is feasible in newborn resuscitation (6) and in preterm infants within the first minutes of life (7). SpO 2 reference values of preterm infants increase within the first 10 min of life (5). This has led to SpO 2 target values incorporated in the current European Resuscitation Council guidelines on resuscitation of newborns (8). In order to avoid hyperoxia, current recommendations advise resuscitation of preterm infants with a mixture of air and oxygen, and to use fraction of inspired oxygen (FiO 2 ) between 0.21 and 0.30 (9). FiO 2 should subsequently be titrated according to SpO 2 (10,11). General use of pulse oximetry has been shown to extensively reduce O 2 -derived toxicity in preterm infants (12). However, keeping SpO 2 manually within changing saturation limits during a hectic period of resu...

Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis.

BackgroundChorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.MethodsOvine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.ResultsLPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.

Intrauterine inflammation induced a rapid and sustained splenic immune response with persistent changes in the cytokine profile. This altered immune status may drive sustained inflammation and injury in other fetal organs.