Effects Of Intrauterine Inflammation Research Articles

Exposure to intrauterine inflammation and late-onset sepsis in very preterm infants.

Late-onset sepsis is an important cause of mortality and morbidity in preterm infants. As these infants rely mostly on their innate immune system to fight off infection, enhancing this immune system by appropriate stimuli may prevent late-onset sepsis. However, it remains unclear which stimuli can enhance the neonatal immune system. This study aims to investigate the influence of intrauterine inflammation on late-onset sepsis. This is a retrospective cohort study in a Neonatal Intensive Care Unit in the Netherlands. Between 2005 and 2016, 1014 infants with ≤32 weeks gestational age and/or with a birth weight ≤1500 g were included. Intrauterine inflammation was subdivided into histological chorioamnionitis, fetal inflammatory response, and funisitis. Logistic and Cox regression analyses were performed to investigate the influence of intrauterine inflammation on late-onset sepsis. Thirty-six percent of the included infants developed late-onset sepsis; 24% of placentas showed intrauterine inflammation. Late-onset sepsis incidence did not differ between infants with or without exposure to intrauterine inflammation after adjustment for gestational age (histological chorioamnionitis aHR 0.928 [CI: 0.727-1.185], p = 0.551; fetal inflammatory response aHR 1.011 [CI: 0.793-1.288], p = 0.930); funisitis aHR 0.965 [CI: 0.738-1.263], p = 0.797). Late-onset sepsis in very preterm infants seems not to be associated with intrauterine inflammation. Intrauterine inflammation is not protective of developing late-onset sepsis in premature infants. A large cohort study on the effect of intrauterine inflammation on neonatal outcome. This study adds to existing knowledge on finding appropriate stimuli to enhance the immune system of premature infants to improve neonatal outcome.

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain.

Fetuses exposed to an inflammatory environment are predisposed to long-term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well-established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba-1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67-positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2hr after LPS treatment, declined at 6hr and showed overall inhibition at 24hr. In summary, our study revealed that LPS-induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.

Postnatal inflammation following intrauterine inflammation exacerbates the development of atherosclerosis in ApoE-/- mice.

Atherosclerosis is a chronic inflammatory disease that has its origins in early life. Postnatal inflammation exacerbates atherosclerosis, but the possible effect of intrauterine inflammation is largely unexplored. Exposure to inflammation in utero is common, especially in infants born preterm, who have increased cardiovascular risk in adulthood. We hypothesised that exposure to inflammation before birth would accelerate the development of atherosclerosis, with the most severe atherosclerosis following exposure to both pre- and postnatal inflammation. Here we studied the effect of prenatal and postnatal inflammation on the development of atherosclerosis by combining established techniques for modelling histological chorioamnionitis and atherosclerosis using apolipoprotein E (ApoE) knockout mice. A single intra-amniotic (IA) injection of lipopolysaccharide (LPS) caused intrauterine inflammation, and increased atherosclerosis at 13 weeks of postnatal age. In mice exposed to postnatal LPS, chorioamnionitis modulated subsequent responses; atherosclerotic lesion size, number and severity were greatest for mice exposed to both intrauterine and postnatal inflammation, with a concomitant decrease in collagen content and increased inflammation of the atherosclerotic plaque. In conclusion, pre- and postnatal inflammation have additive and deleterious effects on the development of atherosclerosis in ApoE knockout mice. The findings are particularly relevant to preterm human infants, whose gestations are frequently complicated by chorioamnionitis and who are particularly susceptible to repeated postnatal infections. Human and mechanistic studies are warranted to guide preventative strategies.

Inhibitory Effect of LPS on the Proliferation of Oligodendrocyte Precursor Cells through the Notch Signaling Pathway in Intrauterine Infection-induced Rats

Periventricular white matter injury (PWMI) is very common in survivors of premature birth, and the final outcomes are a reduction in myelinated neurons leading to white matter hypomyelination. How and (or) why the oligodendrocyte lineage develops abnormally and myelination is reduced is a hot topic in the field. This study focuses on the effect of intrauterine inflammation on the proliferation of oligodendrocyte lineage cells and the underlying mechanisms. Lipopolysaccharide (LPS) (300 μg/kg) was intraperitoneally injected into pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish a rat model of intrauterine infection-induced white matter injury. Corpus callosum tissues were collected at postnatal day 14 (P14) to quantify the number of oligodendrocytes, the number and proliferation of oligodendrocyte precursor cells (OPCs), and the expression of myelin proteins (MBP and PLP). Furthermore, the expression of Wnt and Notch signaling-related proteins was analyzed. The results showed that the number of oligodendrocytes in the corpus callosum tissues of LPS-treated rats was reduced, and the expression levels of myelinating proteins were down-regulated. Further analysis showed that the Notch signaling pathway was down-regulated in the LPStreated group. These results indicate that intrauterine LPS may inhibit the proliferation of OPCs by down-regulating the Notch rather than the Wnt signaling pathway, leading to hypomyelination of white matter.

Effects of Intrauterine Inflammation on Cortical Gray Matter of Near-Term Lambs.

Introduction: Ventilation causes cerebral white matter inflammation and injury, which is exacerbated by intrauterine inflammation. However, the effects on cortical gray matter are not well-known. Our aim was to examine the effect of ventilation on the cerebral cortex of near-term lambs exposed to intrauterine inflammation.Method:Pregnant ewes at 119 ± 1 days gestation received an intra-amniotic injection of saline or lipopolysaccharide (LPS; 10 mg). Seven days later, lambs were randomized to either a high tidal volume injurious ventilation strategy (INJSAL N = 6, INJLPS N = 5) or a protective ventilation strategy (PROTSAL N = 5, PROTLPS N = 6). Respiratory parameters, heart rate and blood gases were monitored during the neonatal period. At post-mortem, the brain was collected and processed for immunohistochemical assessment. Neuronal density (NeuN), apoptotic cell death (caspase 8 and TUNEL), microglial density (Iba-1), astrocytic density (GFAP), and vascular protein extravasation (sheep serum) were assessed within the frontal, parietal, temporal and occipital lobes of the cerebral cortex.Results:A significant reduction in the number of neurons in all cortical layers except 4 was observed in LPS-exposed lambs compared to controls (layer #1: p = 0.041; layers #2 + 3: p = 0.023; layers #5 + 6: p = 0.016). LPS treatment caused a significant increase in gray matter area, indicative of edema. LPS+ventilation did not cause apoptotic cell death in the gray matter. Astrogliosis was not observed following PROT or INJ ventilation, with or without LPS exposure. LPS exposure was associated with vascular protein extravasation.Conclusion:Ventilation had little effect on gray matter inflammation and injury. Intrauterine inflammation reduced neuronal cell density, caused edema of the cortical gray matter, and blood vessel extravasation in the brain of near-term lambs.

Abstract 463: The Effect of Intrauterine Inflammation on the Early Development of Atherosclerosis

Atherosclerosis is a chronic condition that may begin prior to birth, particularly in the presence of factors that act through inflammatory pathways. Inflammation may alter epigenetic marks, and changes in methylation are observed in atherosclerotic lesions. We hypothesised that intrauterine inflammation (chorioamnionitis, which complicates 1-4% of all births in the US) would alter development of early atherosclerosis. We report preliminary findings from a novel mouse model of chorioamnionitis and atherosclerosis. We aim to investigate: 1. the effect of intrauterine inflammation on the development of early atherosclerosis in mice 2. molecular and epigenetic mechanisms Methods: Apolipoprotein E deficient pregnant mice (n=15-19 per group) received LPS (0.1 ng in 5 μl saline) or saline (5 μl) into each amniotic sac on gestational day 15. Offspring were weaned onto a high fat (21% v/v) diet at 4 weeks. Aortae, heart and plasma were collected from 6- and 12-week-old offspring. Aortae were analysed following Haematoxylin and Eosin (H&E) and Oil Red O staining. Heart and aortae cholesterol concentrations were quantified using colorimetric assay. Gene expression (Real-Time PCR) of candidate genes was measured. Results: Intra-amniotic LPS injection induced histological chorioamnionitis. In 6-week-old mice, intrauterine inflammation increased cholesterol concentrations in aorta and cardiac tissue (p<0.05), and increased aortic Dnmt1 mRNA levels (p=0.02; a key regulator of DNA methylation). No differences between LPS- and saline-treated animals were found in H&E stained aortic sinus. In 12-week-old mice, reduced mean intimal area (p=0.02) and mean intimal thickness index (p=0.02) were found in H&E stained brachiocephalic artery sections from LPS-treated offspring. No differences were found between groups in H&E stained aortic sinus or in an en face analysis of Oil Red O-stained aorta. Conclusions: Exposure to intrauterine inflammation has complex effects in this model. Contrary to our hypothesis, 12-week-old LPS-treated mice showed decreased intimal area with no other apparent histological differences, however early cholesterol and molecular biology changes exist. Differential epigenetic regulation may be an early underlying mechanism.

Effects of intrauterine infection or inflammation on fetal lung development

1. Intrauterine infection or inflammation is common in cases of preterm birth. Preterm infants are at risk of acute respiratory distress as a result of lung immaturity; evidence of exposure to infection and/or inflammation before birth is associated with a reduced risk of neonatal respiratory distress syndrome (RDS). Experimentally induced intrauterine inflammation or infection in sheep causes a precocious increase in pulmonary surfactant in the preterm lungs that improves preterm lung function, consistent with the reduced risk of RDS in human infants exposed to infection and/or inflammation before birth. 2. The effects of intrauterine inflammation on fetal lung development appear to result from direct action of proinflammatory stimuli within the lungs rather than by systemic signals, such as the classical glucocorticoid-mediated lung maturation pathway. However, paracrine and/or autocrine production and/or metabolism of glucocorticoids in fetal lung tissue may occur as a result of inflammation-induced changes in the expression of 11β-hydroxysteroid dehydrogenase (types 1 and 2). 3. Likely candidates that mediate inflammation-induced surfactant production by the preterm lung include prostaglandin E₂ and/or other arachidonic acid metabolites. Intrauterine inflammation induces the expression of enzymes responsible for prostaglandin production in fetal lung tissue. Inhibition of prostaglandin production prevents, at least in part, the effects of inflammation on fetal lungs. 4. Our experiments are identifying mechanisms of surfactant production by the preterm lungs that may be exploited as novel therapies for preventing respiratory distress in preterm infants. Elucidation of the effects of inflammation on the fetal lungs and other organs will allow more refined approaches to the care of preterm infants exposed to inflammation in utero.

Changes in Fetal Thymic Immune Cell Populations in a Sheep Model of Intrauterine Inflammation

Intrauterine inflammation is a common antecedent of preterm birth and can alter the development of the fetal thymus, the site of development, and maturation of T lymphocytes. The effects of intrauterine inflammation on specific thymic T lymphocyte populations are largely unknown. We hypothesized that intrauterine inflammation would alter fetal thymic T cell populations. Immunohistochemistry was used to quantitate the relative proportions of thymic cortical and medullary cell populations in fetal sheep 7 days after intra-amniotic lipopolysaccharide (LPS) injection. The proportions of CD8⁺and MHC II⁺ cells in the fetal thymus were reduced in response to LPS. The ratio of CD4:CD8 cells was increased by LPS exposure. No changes were observed in the percentage of CD4⁺, γδ(WC1)⁺, CD45R⁺B cells, or CD44⁺ cells. These studies indicate that intrauterine inflammation impacts thymic composition of CD8 T cells and the development and/or activation of CD4 T cells in the fetal thymus.

Effects of intrauterine inflammation on the developing mouse brain

Clinical and experimental evidence indicate that the presence of intrauterine inflammation in pregnancy is not only a cause of preterm birth but is also associated with perinatal brain damage and long-term neurological handicap. In the present study, the neuropathological outcome was investigated in surviving pups in a model of inflammation-induced preterm delivery. C57BL/6 mice were subjected to intrauterine injection of lipopolysaccharide (LPS) or saline, at a time corresponding to 79% of average gestation (gestational day 15). Fetuses that survived after LPS administration were sacrificed on postnatal day 14 (PND 14). At PND 14, the brain weight of LPS-exposed pups was significantly lower than that of saline-exposed. A high proportion of LPS-exposed brains were found affected and exhibited hypomyelination, enlarged ventricles, and in some cortical gray matter lesions were evident. None of these pathologies were detected in sham-treated animals. Conclusions: Intrauterine inflammation impaired brain development and various brain lesions were produced in both the white and gray matter after intrauterine LPS administration in mice.

Effects of intrauterine inflammation on developing mouse brain

Effects of intrauterine inflammation on developing mouse brain