Antenatal Inflammation Research Articles

Extremely preterm fetal sheep lung responses to antenatal steroids and inflammation

The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood. We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings. Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n= 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone+ lipopolysaccharide; and (4) intraamniotic+ intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation. Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs. Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response.

Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns.

BackgroundPreterm newborns exposed to intrauterine inflammation are at increased risk of neurodevelopmental disorders. We hypothesized that adverse outcomes are more strongly associated with a combination of antenatal and postnatal inflammation than with either of them alone.MethodsWe defined antenatal inflammation as histologic inflammation in the placenta. We measured the concentrations of seven inflammation-related proteins in blood obtained on postnatal days 1, 7, and 14 from 763 infants born before 28 weeks of gestation. We defined postnatal inflammation as a protein concentration in the highest quartile on at least 2 days. We used logistic regression models to evaluate the contribution of antenatal and postnatal inflammation to the risk of neurodevelopmental disorders.ResultsThe risk of white matter damage was increased when placental inflammation was followed by sustained elevation of CRP or ICAM-1. We found the same for spastic cerebral palsy when placental inflammation was followed by elevation of TNF-α or IL-8. The presence of both placental inflammation and elevated levels of IL-6, TNF-α, or ICAM-1 was associated with an increased risk for microcephaly.ConclusionCompared to a single hit, two inflammatory hits are associated with stronger risk for abnormal cranial ultrasound, spastic cerebral palsy, and microcephaly at 2 years.

Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns

Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns

Intrauterine infection and neonatal pulmonary outcomes

There is no consensus about the relationships between chorioamnionitis and 3 pulmonary outcomes of concern for preterm infants: respiratory distress syndrome, pneumonia/sepsis, and bronchopulmonary dysplasia.Intrauterine infection increases the risk of neonatal infection including sepsis/pneumonia, also increases the incidence of bronchopulmonary dysplasia, but may reduce the incidence and severity of respiratory distress syndrome.In recent years, translational research with various animal models has been helpful to answer basic questions about the effect of antenatal inflammation on maturation and development of the fetal lung and immune system.Although the mechanisms are not entirely clear, chorioamnionitis predisposes infants to premature birth, neonatal sepsis, and other adverse outcomes.In this article, we reviewed the relationship of intrauterine infection and neonatal pulmonary morbidity. Key words: Intrauterine infection; Fetal inflammatory response syndrome; Neonatal sepsis; Pneumonia; Respiratory distress syndrome; Bronchopulmonary

Antenatal inflammation and gestational diabetes mellitus risk among pregnant African-American women

Although inflammation is associated with risk of gestational diabetes mellitus (GDM), little is known if there is an association between inflammation and GDM in African-American women, a group at higher risk for GDM complications. In the present study, we aimed to determine if selected inflammatory cytokines (i.e. TNF-α, hs-CRP, IL-6, IL-10, IL-6/IL-10 ratio, IL-1β) measured in the 2nd trimester, were associated with GDM risk in 185 pregnant African-American women. GDM was defined as a physician-documented GDM diagnosis, a fasting glucose between 92 and 125mg/dl, or evidence of glucose intolerance (defined using the 3-h glucose tolerance test). A total of 18 women (9.7%) had GDM. After covariate adjustment, C-reactive protein, measured at a mean 21.2±3.7 weeks gestation, was statistically significantly associated with GDM development (P=0.025); for every one-unit increase in log-transformed C-reactive protein, the odds of GDM increased by 5.3. Results were similar using a principal component analysis approach. This study provides evidence that higher levels of 2nd trimester C-reactive protein is associated with increased risk of GDM in African-American women. Further research is needed to examine whether C-reactive protein may be a useful early-pregnancy screen for evaluating potential GDM risk in African-American women.

Welcoming a new Associate Editor to The Journal

— William F. Balistreri, MD I t is with regret but warm wishes that I announce that Alan H. Jobe, MD, PhD, will be stepping down from his Associate Editor role at the end of 2015. Dr Jobe played, and continues to play, a pivotal role in making The Journal the “go to” journal for high-impact neonatology research. Despite his personal “10-year rule” (“after 10 years for any academic position, new leadership should come from someone else– preferably younger–who is given the opportunity”), he has broken this rule and continued as an Associate Editor for 18 years “because I have very much enjoyed serving as a referee for some of the best research in neonatology that is being submitted to The Journal.” Dr Jobe plans to expand his involvement in international research through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Research Network. He will continue with active animal model research programs focusing on antenatal corticosteroids, fetal inflammation, and prematurity in association with colleagues at the University of California Davis National Primate Research Center and at the University of Western Australia, and will remain active both clinically and with teaching. Although Dr Jobe will be missed as an Associate Editor, we are pleased that he will continue his relationship with The Journal by serving as an Editorial Board member beginning in 2016. With the approaching departure of an Associate Editor, we started the search for a new Associate Editor to join The Journal’s leadership. After assessing outside candidates as well as the pool of current Editorial Board members, we have chosen someone who we believe will continue to attract high quality neonatology research to The Journal and who will excel as an Associate Editor. We would like to welcome and introduce Robin H. Steinhorn, MD, as The Journal’s newest Associate Editor. Dr Steinhorn began handling newmanuscripts in September. Robin H. Steinhorn, MD, joined Children’s National Medical Center in September 2015 as the Senior Vice President for Hospital Based Specialties. Prior to arriving at Children’s National, she served as Chair of the Department of Pediatrics at the University of California Davis and Pediatrician in Chief for the UC Davis Children’s Hospital. Dr Steinhorn is a member of the Council of the American Pediatric Society and serves on the American Board of Pediatrics for Neonatal Perinatal Medicine. She is an elected Fellow of the American Heart Association and a member of the Perinatal Research Society and American Thoracic Society. Dr Steinhorn’s clinical and academic interests have primarily been focused on the pulmonary vascular development of the fetus and newborn. Her translational work has spanned from in vitro studies to animal models, and she has contributed to numerous multicenter trials that have helped define the clinical treatment of pulmonary hypertension in the neonatal period. Her recent clinical research also has addressed telemedicine support of neonatal care in rural hospitals. She is married to a pediatric intensivist and has two children pursuing medical careers. She looks forward to carrying on Dr Jobe’s legacy of publishing high-impact neonatal research in The Journal, and continuing to support trainees and young investigators as they navigate presenting and publishing their research findings.

Effects of antenatal lipopolysaccharide and postnatal hyperoxia on airway reactivity and remodeling in a neonatal mouse model.

BackgroundAntenatal inflammation and preterm birth are associated with the development of airway diseases such as wheezing and asthma. Utilizing a newborn mouse model, we assessed the effects of maternal inflammation and postnatal hyperoxia on the neonatal airway.MethodsPregnant C57/Bl6 dams were injected with lipopolysaccharide (LPS) or saline on embryonic day 16. Offspring were placed in room air or hyperoxia (50% O2) for 7 days and then returned to normoxia. Airway mechanics, histology, and laser capture micro-dissection (LCM) were performed.ResultsAt postnatal day 21, maternal LPS- and 50% O2-exposed pups exhibited increased resistance and decreased compliance compared to 21% O2 pups; however their effects were not synergistic. LPS and hyperoxia each increased the thickness of airway smooth muscle (ASM), but not the airway epithelial layer. Structural changes were largely limited to the conducting airways. Up-regulation of inflammatory markers in the lung was observed at birth. LCM revealed increased collagen-3, transforming growth factor β, and connective tissue growth factor expression with LPS and hyperoxia within the ASM layer.ConclusionThese novel studies provide functional, structural and molecular evidence that antenatal inflammation is detrimental to the developing airway. Exposure to moderate hyperoxia does not exacerbate LPS effects on the airway.

The effect of prenatal maternal infection on respiratory function in mouse offspring: evidence for enhanced chemosensitivity.

Systemic maternal inflammation is implicated in preterm birth and bronchopulmonary dysplasia (BPD) and may induce morbidities including reduced pulmonary function, sleep-disordered breathing, and cardiovascular disorders. Here we test the hypothesis that antenatal maternal inflammation per se causes altered alveolar development and increased chemoreflex sensitivity that persists beyond infancy. Pregnant C57BL/6 mice were administered lipopolysaccharide (LPS) (150 μg/kg ip) to induce maternal inflammation or saline (SHAM) at embryonic day 16 (randomized). Pups were weighed daily. On days 7, 28, and 60 (D07, D28, and D60), unrestrained wholebody plethysmography quantified ventilation and chemoreflex responses to hypoxia (10%), hypercapnia (7%), and asphyxia (hypoxic hypercapnia). Lungs were harvested to quantify alveolar number, size, and septal thickness. LPS pups had reduced baseline ventilation per unit bodyweight (∼40%, P < 0.001) vs. SHAM. LPS increased ventilatory responses to hypoxia (D07: 66% vs. 28% increase in ventilation; P < 0.001) hypercapnia (170% vs. 88%; P < 0.001), and asphyxia (249% vs. 154%; P < 0.001); hypersensitive hypoxic responsiveness persisted until D60 (P < 0.001). LPS also increased apnea frequency (P < 0.01). LPS caused thicker alveolar septae (D07, P < 0.001), diminished alveolar number (D28, P < 0.001) vs. SHAM, but effects were minimal by D60. Pups delivered from mothers exposed to antenatal inflammation exhibit deficits in lung structure and hypersensitive responses to respiratory stimuli that persist beyond the newborn period. Antenatal inflammation may contribute to impaired gas exchange and unstable breathing in newborn infants and adversely affect long-term health.

Prenatal Exposure to Inflammation Decreases Endothelial Cell Proliferation in the Mouse Intestinal Mucosa

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease affecting premature infants. Chorioamnionitis has been shown to increase its incidence. However, the mechanism by which prenatal infection increases susceptibility to NEC remains elusive. Our lab has shown that VEGF is decreased in human NEC. VEGF may play a role in NEC pathogenesis by compromising vascular network integrity. Here we hypothesized that antenatal inflammation decreases the expression of vascular endothelial growth factor (VEGF) in intestine tissues and mucosal vascular endothelial cell proliferation. To test our hypothesis, pregnant mice were injected i.p. at E16 with LPS or normal saline. VEGF protein of Day 0 pup intestines was analyzed by western blot and band density values normalized to b‐actin. To quantify endothelial cell (E.C.) proliferation, pups were injected with BrdU i.p. 4 hours prior to euthanasia, and the number of BrdU positive cells co‐staining for CD31, an endothelial cell marker, were counted in the villi (3 fields/ sample at 10x magnification). We found that intestinal VEGF expression was significantly lower in pups from LPS‐treated dams compared to controls (mean±SEM: 1.40 ± 0.14 v.s 2.80 ± 0.15; p&lt;0.0005). Also, the number of proliferating endothelial cells was significantly decreased in newborn pups from LPS‐treated dams compared to controls (8.0 ± 0.88 v.s 26.0 ± 1.60; p&lt;0.0001). In conclusion, prenatal exposure to inflammation decreases intestinal VEGF protein and intestinal mucosal endothelial cell proliferation. This suggests that antenatal inflammation may predispose to intestinal injury and NEC by affecting mucosal microvasculature (supported by NIH grant RO1HD060876).

Gastric fluid cytokines are associated with chorioamnionitis and white blood cell counts in preterm infants.

AimThe aim of this study was to determine whether the concentration of cytokines in the gastric fluid at birth was associated with chorioamnionitis or funisitis and with the white blood cell counts of very premature newborns.MethodsWe retrieved gastric fluid from 27 preterm infants with a gestational age of <29 weeks within 1 h of birth and used enzyme‐linked immunosorbent assay to measure the concentrations of interleukin (IL)‐1beta, epithelial cell‐derived neutrophil‐activating peptide (ENA)‐78, IL‐8 and growth‐related oncogene (Gro)‐alpha. The presence of histologic chorioamnionitis or funisitis in the placentas and the highest white blood cell count of the infants during the first week of life were compared to the cytokine concentrations.ResultsGastric fluid concentrations of IL‐1beta, ENA‐78, IL‐8 and Gro‐alpha were strongly associated with chorioamnionitis and funisitis. In addition, chorioamnionitis and funisitis and gastric aspirate cytokine levels were associated with the highest white blood cell counts of the infants during the first week of life.ConclusionThis study suggests that levels of inflammatory cytokines in the gastric fluid of premature infants at birth can be used to assess the exposure of the infants to antenatal inflammation.

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.

Early pregnancy vitamin D and patterns of antenatal inflammation in African–American women

Vitamin D is essential for the health of both mother and fetus during pregnancy. In the nonpregnant state, vitamin D demonstrates anti-inflammatory effects, but little is known about this relationship during pregnancy. African–American women are at a higher risk of vitamin D deficiency and for altered inflammatory responses during pregnancy. Therefore, we investigated the association of early pregnancy vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D (25-OHD), with second-trimester inflammatory biomarkers (high-sensitivity C-reactive protein, IL-6, IL-10, IL-1β and TNF-α) in 178 pregnant African–American women. Mean serum 25-OHD was 13.4±8.4ng/ml, and most women (n=147, 82.6%) had inadequate or deficient levels of 25-OHD (<20ng/ml). Both serum 25-OHD and some inflammatory cytokines (IL-1β and TNF-α) demonstrated significant seasonal variation. In univariate models, log transformed 25-OHD was significantly and inversely associated with log transformed IL-1β (p=0.002) and log transformed IL-6 (p=0.032). After adjusting for covariates, including seasonality, only the inverse association with IL-1β remained statistically significant (p=0.027). Early pregnancy vitamin D nutrition is associated with some inflammatory biomarkers in mid-pregnancy. Additional studies are needed to determine if low vitamin D nutrition is associated with birth outcomes via an inflammatory-mediated pathway.

Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasia

Vitamin D (vit D) has anti-inflammatory properties and modulates lung growth, but whether vit D can prevent lung injury after exposure to antenatal inflammation is unknown. We hypothesized that early and sustained vit D treatment could improve survival and preserve lung growth in an experimental model of bronchopulmonary dysplasia induced by antenatal exposure to endotoxin (ETX). Fetal rats (E20) were exposed to ETX (10 μg), ETX + Vit D (1 ng/ml), or saline (control) via intra-amniotic (IA) injections and delivered 2 days later. Newborn pups exposed to IA ETX received daily intraperitoneal injections of vit D (1 ng/g) or saline for 14 days. Vit D treatment improved oxygen saturations (78 vs. 87%; P < 0.001) and postnatal survival (84% vs. 57%; P < 0.001) after exposure to IA ETX compared with IA ETX alone. Postnatal vit D treatment improved alveolar and vascular growth at 14 days by 45% and 25%, respectively (P < 0.05). Vit D increased fetal sheep pulmonary artery endothelial cell (PAEC) growth and tube formation by 64% and 44%, respectively (P < 0.001), and prevented ETX-induced reductions of PAEC growth and tube formation. Vit D directly increased fetal alveolar type II cell (ATIIC) growth by 26% (P < 0.001) and enhanced ATIIC growth in the presence of ETX-induced growth suppression by 73% (P < 0.001). We conclude that antenatal vit D therapy improved oxygenation and survival in newborn rat pups and enhanced late lung structure after exposure to IA ETX in vivo, which may partly be due to direct effects on vascular and alveolar growth.

46: Lipopolysaccharide (LPS)-induced perinatal inflammation increases postnatal airway reactivity

Antenatal inflammation can impair pulmonary maturation and potentially promote development of postnatal chronic lung disease. The purpose of our investigation is to evaluate how in utero exposure to maternal inflammation influences neonatal pulmonary function in a murine model. Our hypothesis was that inflammation leads to structural and functional airway changes that contribute to chronic diseases such as asthma.

691: Vitamin D reduces TNF-α induced MMP-9 activity in human fetal airway smooth muscle cells

Premature infants are at risk of developing lung diseases including asthma. There is a link between antenatal inflammation and airway remodeling that predisposes infants and children to development of asthma and/or wheezing. Clinically, these airway diseases appear to be modified by maternal nutritional status, with studies demonstrating inverse relationships between Vitamin D levels and prematurity, chronic lung disease, and childhood asthma. Using human fetal airway smooth muscle cells (fASMC) as an in vitro model of the developing airway, we explored the hypothesis that Vitamin D blunts the effects of inflammation in regard to extracellular matrix remodeling, thus alleviating structural airway changes that would contribute to asthma.

Altered canonical Wingless-Int signaling in the ovine fetal lung after exposure to intra-amniotic lipopolysaccharide and antenatal betamethasone

Antenatal inflammation and maternal corticosteroids induce fetal lung maturation but interfere with late lung development. Canonical Wingless-Int (Wnt) signaling directs lung development and repair. We showed that intra-amniotic (IA) lipopolysaccharide (LPS) exposure disrupted developmental signaling pathways in the preterm lamb lungs. Therefore, we hypothesized that pulmonary Wnt signaling was altered by exposure to IA LPS and/or antenatal corticosteroids. Ovine fetuses were exposed to IA LPS, maternal intramuscular betamethasone, a control saline injection, or a combination thereof at 107 and/or 114 d gestational age (term = 150 d gestational age) before delivery at 121 d gestational age. IA LPS exposure decreased the lung expression of lymphoid enhancer-binding factor 1 (LEF1), a major Wnt pathway effector. WNT1, WNT4, and downstream messenger β-catenin decreased after LPS exposure. WNT7b mRNA increased fourfold 14 d post-LPS exposure. Betamethasone treatment 7 d before LPS exposure prevented the reduction in LEF1 expression, whereas betamethasone administration after LPS normalized the LPS-induced increase in Wnt7b mRNA. IA LPS exposure decreased canonical Wnt signaling in the developing lung. Antenatal corticosteroids before or after IA inflammation had different effects on pulmonary Wnt signaling. This study provides new insights into possible mechanisms by which prenatal inflammation affects lung development and how corticosteroid can be beneficial in this setting.

Functio laesa: the consequences of the fifth cardinal sign of inflammation in preterm infants

<i>Functio laesa</i>: the consequences of the fifth cardinal sign of inflammation in preterm infants

406 The Combined Effects of Antenatal Inflammation and Betamethasone on Lung Morphometry in a Rat

AimTo investigate the effects of antenatal maternal glucocorticoids on fetal lung inflammation by determining lung morphology and inflammatory cell influx in bronchoalveolar lavage fluid.MethodsRat pups were divided into four experimental...

Chorioamnionitis as a Risk Factor for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis

To accumulate available evidence regarding the association between antenatal inflammation and necrotizing enterocolitis (NEC). A systematic literature search was performed using Medline, Embase, Cochrane Library, ISI Web of Knowledge, and reference hand searches. Human studies published in English that reported associations between chorioamnionitis or other indicators of antenatal inflammation and NEC were eligible. Relevant associations were extracted and reported. Studies reporting associations between histological chorioamnionitis (HC) and NEC, HC with fetal involvement and NEC, and clinical chorioamnionitis and NEC were pooled in separate meta-analyses. A total of 33 relevant studies were identified. Clinical chorioamnionitis was significantly associated with NEC (12 studies; n = 22 601; OR, 1.24; 95% CI, 1.01-1.52; P = .04; I(2) = 12%), but the association between HC and NEC was not statistically significant (13 studies; n = 5889; OR, 1.39; 95% CI, 0.95-2.04; P = .09; I(2) = 49%). However, HC with fetal involvement was highly associated with NEC (3 studies; n = 1640; OR, 3.29; 95% CI, 1.87-5.78; P ≤ .0001; I(2) = 10%). Selection based on study quality did not affect the results. No indications of publication bias were apparent. Multivariate analyses in single studies generally attenuated the reported associations. Several associations between other markers of antenatal inflammation and NEC are reported. Currently available evidence supports a role for antenatal inflammation in NEC pathophysiology. This finding emphasizes the need to further study the underlying mechanisms and evaluate potential interventions to improve postnatal intestinal outcomes.

Inflammation in utero exacerbates ventilation-induced brain injury in preterm lambs

Cerebral blood flow disturbance is a major contributor to brain injury in the preterm infant. The initiation of ventilation may be a critical time for cerebral hemodynamic disturbance leading to brain injury in preterm infants, particularly if they are exposed to inflammation in utero. We aimed to determine whether exposure to inflammation in utero alters cardiopulmonary hemodynamics, resulting in cerebral hemodynamic disturbance and related brain injury during the initiation of ventilation. Furthermore, we aimed to determine whether inflammation in utero alters the cerebral hemodynamic response to challenge induced by high mean airway pressures. Pregnant ewes received intra-amniotic lipopolysaccharide (LPS) or saline either 2 or 4-days before preterm delivery (at 128 ± 1 days of gestation). Lambs were surgically instrumented for assessment of pulmonary and cerebral hemodynamics before delivery and positive pressure ventilation. After 30 min, lambs were challenged hemodynamically by incrementing and decrementing positive end-expiratory pressure. Blood gases, arterial pressures, and blood flows were recorded. The brain was collected for biochemical and histological assessment of inflammation, brain damage, vascular extravasation, hemorrhage, and oxidative injury. Carotid arterial pressure was higher and carotid blood flow was more variable in 2-day LPS lambs than in controls during the initial 15 min of ventilation. All lambs responded similarly to the hemodynamic challenge. Both 2- and 4-day LPS lambs had increased brain interleukin (IL)-1β, IL-6, and IL-8 mRNA expression; increased number of inflammatory cells in the white matter; increased incidence and severity of brain damage; and vascular extravasation relative to controls. Microvascular hemorrhage was increased in 2-day LPS lambs compared with controls. Cerebral oxidative injury was not different between groups. Antenatal inflammation causes adverse cerebral hemodynamics and increases the incidence and severity of brain injury in ventilated preterm lambs.