Prenatal Inflammation Research Articles

Neurodevelopment: The Impact of Nutrition and Inflammation During Preconception and Pregnancy in Low-Resource Settings.

The rapid pace of fetal development by far exceeds any other stage of the life span, and thus, environmental influences can profoundly alter the developmental course. Stress during the prenatal period, including malnutrition and inflammation, impact maternal and fetal neurodevelopment with long-term consequences for physical and mental health of both the mother and her child. One primary consequence of maternal malnutrition, inflammation, and other sources of prenatal stress is a poor birth outcome, such as prematurity or growth restriction. These phenotypes are often used as indications of prenatal adversity. In fact, the original evidence supporting the fetal programming hypothesis came from studies documenting an association between birth phenotype and the development of subsequent physical and mental health problems. Fetal growth restriction in both term and preterm infants is associated with neonatal morbidities and a wide variety of behavioral and psychological diagnoses in childhood and adolescence, including attention-deficit/hyperactivity disorder, anxiety, depression, internalizing and thought problems, poor social skills, and autism spectrum disorder. Improving maternal-child health requires interventions that begin before pregnancy and continue throughout gestation and into the postpartum period. Such interventions might include supporting pregnancy intention, maternal nutrition, health/medical care, mental health, and providing social support. This article discusses the impact of maternal nutrition and inflammation during preconception and pregnancy among women living in low-resource settings, with an emphasis on key knowledge gaps that need to be addressed to guide program and policy decisions at local, regional and global levels.

Asthma and Prenatal Inflammation.

Asthma and Prenatal Inflammation.

Potential Role of Prenatal Inflammation in the Impairment of Lung Development Following Mechanical Ventilation of Preterm Lambs.

Our objective was to determine the effects of severe fetal inflammation, associated with an increase in the number and activation state of fetal polymorphonuclear leukocytes (PMNLs), on postnatal lung development in mechanically ventilated preterm lambs. Four groups of preterm fetal sheep (0.85 term) were surgically prepared: (1) a granulocyte-colony stimulating factor (GCSF) group received intravenous GCSF to increase fetal PMNL count, (2) a lipopolysaccharide (LPS) group received intra-amniotic LPS to activate the fetal PMNLs, (3) a GCSF + LPS group received both GCSF and LPS, and (4) a control group received saline. After 10-day mechanical ventilation following preterm delivery, the lungs were examined histologically and analyzed morphometrically. Compared to the control group, the GCSF + LPS group exhibited necrotizing funisitis, lower surface density of alveolar walls, lower numerical density of alveoli, greater alveolar radius, and lower volume density of secondary septal crests (all P < .05). There was no evidence of tissue destruction, or elastin fragmentation or thick deposits of elastin, in the alveolar walls in any of the 4 groups. The mechanical ventilation following severe prenatal inflammation did not lead to overt lung injury or degradation of elastin but resulted in arrested alveolarization in the lungs of preterm lambs.

15: Unraveling mechanisms of adverse neurobehavioral outcomes in preterm birth: specific metabolomics profile in the amniotic fluid, fetal and neonatal brain after exposure to prenatal inflammation

15: Unraveling mechanisms of adverse neurobehavioral outcomes in preterm birth: specific metabolomics profile in the amniotic fluid, fetal and neonatal brain after exposure to prenatal inflammation

Ascorbic Acid Protects against Hypertension through Downregulation of ACE1 Gene Expression Mediated by Histone Deacetylation in Prenatal Inflammation-Induced Offspring.

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Prenatal exposure to lipopolysaccharide (LPS) leads to hypertension in a rat offspring. However, the mechanism is still unclear. This study unraveled epigenetic mechanism for this and explored the protective effects of ascorbic acid against hypertension on prenatal inflammation-induced offspring. Prenatal LPS exposure resulted in an increase of intrarenal oxidative stress and enhanced angiotensin-converting enzyme 1 (ACE1) gene expression at the mRNA and protein levels in 6- and 12-week-old offspring, correlating with the augmentation of histone H3 acetylation (H3AC) on the ACE1 promoter. However, the prenatal ascorbic acid treatment decreased the LPS-induced expression of ACE1, protected against intrarenal oxidative stress, and reversed the altered histone modification on the ACE1 promoter, showing the protective effect in offspring of prenatal LPS stimulation. Our study demonstrates that ascorbic acid is able to prevent hypertension in offspring from prenatal inflammation exposure. Thus, ascorbic acid can be a new approach towards the prevention of fetal programming hypertension.

Paths of Causal Influence from Prenatal Inflammation and Preterm Gestation to Childhood Asthma Symptoms

Introduction: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim of the present study was to investigate paths of assumed causality leading from fetal inflammatory response syndrome (FIRS) to asthma symptoms in formerly preterm infants.

Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation.

Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood.

Prenatal Findings Leading to Early Diagnosis of X-Linked Inhibitor of Apoptosis Protein (XIAP) Deficiency

X-linked inhibitor of apoptosis protein (XIAP) deficiency is a primary hyperinflammatory immunodeficiency typically diagnosed following an episode of hemophagocytic lymphohistiocytosis (HLH) or in the setting of early onset severe inflammatory bowel disease (IBD). Hematopoietic cell transplant (HCT) is the definitive treatment. We present an infant with prenatal hepatosplenomegaly and hepatic calcifications who was subsequently diagnosed with XIAP deficiency in infancy. Whole exome sequencing (WES) for patient and parents was performed. Clinical course and immunophenotyping were reviewed. Hepatosplenomegaly, hepatic calcifications and large placenta were noted on prenatal ultrasound at 35 weeks performed for maternal pre-eclampsia. Postnatal evaluation revealed thrombocytopenia and direct hyperbilirubinemia, raising concerns for congenital infection, chromosomal abnormality, or a metabolic disorder. However, the abnormalities normalized over 7 days and he had a negative congenital infection work up, and karyotype, microarray, and metabolic evaluation were normal. WES showed a single likely pathogenic variant, a de novo c.1021_1022delAA; p.Asn341Tyr-fs*8 hemizygous deletion in XIAP, predicted to be null. Flow cytometry revealed <1.5% XIAP expression in all peripheral blood mononuclear lineages. After hospitalization at 10 mo for fever and hives, IgG and prophylactic medications were started. At 14 mo he was again hospitalized for fever, neutropenia, and elevated ferritin that spontaneously resolved. Otherwise, his development is progressing normally and HCT is planned. XIAP deficiency presented with prenatal hepatic inflammation and newborn findings mimicking congenital infection. Fever, hives and incomplete HLH occurred before 15 mo. The early diagnosis of XIAP deficiency has allowed for definitive HCT to be undertaken electively.

Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia

Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury.

Understanding the Impact of Infection, Inflammation, and Their Persistence in the Pathogenesis of Bronchopulmonary Dysplasia.

The concerted interaction of genetic and environmental factors acts on the preterm human immature lung with inflammation being the common denominator leading to the multifactorial origin of the most common chronic lung disease in infants – ­bronchopulmonary dysplasia (BPD). Adverse perinatal exposure to infection/inflammation with added insults like invasive mecha nical ventilation, exposure to hyperoxia, and sepsis causes persistent immune dysregulation. In this review article, we have attempted to analyze and consolidate current knowledge about the role played by persistent prenatal and postnatal inflammation in the pathogenesis of BPD. While some parameters of the early inflammatory response (neutrophils, cytokines, etc.) may not be detectable after days to weeks of exposure to noxious stimuli, they have already initiated the signaling pathways of the inflammatory process/immune cascade and have affected permanent defects structurally and functionally in the BPD lungs. Hence, translational research aimed at prevention/amelioration of BPD needs to focus on dampening the inflammatory response at an early stage to prevent the cascade of events leading to lung injury with impaired healing resulting in the pathologic pulmonary phenotype of alveolar simplification and dysregulated vascularization characteristic of BPD.

Protective effect of chorioamnionitis on the development of bronchopulmonary dysplasia triggered by postnatal systemic inflammation in neonatal rats.

Background:Prenatal or postnatal systemic inflammation can contribute to the development of bronchopulmonary dysplasia (BPD). We investigated whether prenatal intra-amniotic (i.a.) inflammation or early postnatal systemic inflammation can induce BPD in a rat model.Methods:One microgram of lipopolysaccharide (LPS) or vehicle was injected into the amniotic sacs 2 d before delivery (E20). After birth, 0.25 mg/kg of LPS or vehicle was injected into the peritoneum of pups on postnatal day (P)1, P3, and P5. On P7 and P14, peripheral blood (PB), bronchoalveolar lavage fluid (BALF), and lung tissue were obtained and analyzed.Results:Postnatal i.p. injections of LPS significantly increased neutrophil counts in PB and BALF on P7 and P14. Similarly, proinflammatory cytokine and angiogenic factor transcript levels were increased in the lung by i.p. LPS on P7. Alveolar and pulmonary vascular development was markedly disrupted by i.p. LPS on P14. However, pretreatment with i.a. LPS significantly negated the detrimental effects of postnatal i.p. LPS on PB and BALF neutrophil counts and on lung proinflammatory cytokine expression and histopathological changes.Conclusion:Exposure to early postnatal systemic LPS induces BPD, an arrest in alveolarization, in neonatal rats. Preceding exposure to i.a. LPS protects the lungs against BPD triggered by postnatal systemic inflammation.

Infections and Brain Development.

Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner.

A clinically relevant model of prenatal inflammation (intrauterine lipopolysaccharide) results in offspring hyperactivity

Maternal infection during pregnancy is common and can cause adverse neurodevelopmental outcomes. While systemic administration of bacterial or viral mimetics are widely used models of prenatal inflammation, an alternative approach is local inflammation of the uterus, which models chorioamnionitis (inflammation of the fetal membranes). Importantly, this mimics the most common human clinical scenario by which a fetus is exposed to prenatal inflammation. Using CD-1 mice, local inflammation was induced via intrauterine lipopolysaccharide (LPS) infusion at E15 (term = E19). Behavioral, molecular and immune endpoints were evaluated in adult offspring. Males and females demonstrated hyperactivity, as well as an overall decrease in anxiety-like behavior (open field, elevated zero, light-dark box). Operant testing was initiated to examine executive function, however all mice (regardless of prenatal condition) failed to reach criterion performance, which may be due to reduced visual acuity in the albino CD1 strain. Prenatal LPS exposure increased the number of microglia, quantified by flow cytometric analysis of the whole brain. Expression of 30 genes related to immune, epigenetic and neurotransmitter function was measured, both at baseline and in response to an acute immune challenge, and these analyses are ongoing. These data indicate that local inflammation of the uterus, in the absence of a maternal plasma cytokine response, affects offspring brain development, and support additional work in this translationally relevant model of prenatal inflammation.

Prenatal exposure to inflammatory conditions increases Cx43 and Panx1 unopposed channel opening and activation of astrocytes in the offspring effect on neuronal survival.

Several epidemiological studies indicate that children born from mothers exposed to infections during gestation, have an increased risk to develop neurological disorders, including schizophrenia, autism and cerebral palsy. Given that it is unknown if astrocytes and their crosstalk with neurons participate in the above mentioned brain pathologies, the aim of this work was to address if astroglial paracrine signaling mediated by Cx43 and Panx1 unopposed channels could be affected in the offspring of LPS-exposed dams during pregnancy. Ethidium uptake experiments showed that prenatal LPS-exposure increases the activity of astroglial Cx43 and Panx1 unopposed channels in the offspring. Induction of unopposed channel opening by prenatal LPS exposure depended on intracellular Ca2+ levels, cytokine production and activation of p38 MAP kinase/iNOS pathway. Biochemical assays and Fura-2AM/DAF-FM time-lapse fluorescence images revealed that astrocytes from the offspring of LPS-exposed dams displayed increased spontaneous Ca2+ dynamics and NO production, whereas iNOS levels and release of IL-1β/TNF-α were also increased. Interestingly, we found that prenatal LPS exposure enhanced the release of ATP through astroglial Cx43 and Panx1 unopposed channels in the offspring, resulting in an increased neuronal death mediated by the activation of neuronal P2X7 receptors and Panx1 channels. Altogether, this evidence suggests that astroglial Cx43 and Panx1 unopposed channel opening induced by prenatal LPS exposure depended on the inflammatory activation profile and the activation pattern of astrocytes. The understanding of the mechanism underlying astrocyte-neuron crosstalk could contribute to the development of new strategies to ameliorate the brain abnormalities induced in the offspring by prenatal inflammation. GLIA 2015;63:2058-2072.

Effect of maternal immune activation on pre‐ and postnatal murine brain development

Prenatal inflammation is considered a risk factor for neurodevelopmental disorders such as autism and schizophrenia. Models of maternal inflammation have been developed to study the cellular alterations in the fetal brain following challenge with agents such as lipopolysaccharide (LPS). Studies suggest that some gestation periods have higher risk for developmental abnormalities after such immune activation and different brain regions are populated by neurones and glia at different times. This study investigated the effect of early immune activation on development of the fetal and postnatal brain. Time mated c57BL/6 mice were used. On embryonic day 12 (E12), mice received either a single injection of LPS ( 50 μg/kg) or saline. Tissue was collected at prenatal and postnatal ages and used to investigate effects on the developing hippocampal and amygdalar brain structures. qPCR was carried out on placental and brain samples for relevant pro‐inflammatory cytokines. Immunohistochemistry was performed for astrocyte (GFAP), microglia (IBA‐1) and neuronal (DCX, Nestin) markers. Cresyl violet staining was used to investigate structural integrity. qPCR results showed altered pro‐inflammatory placental cytokine profile and altered cytokine profile in the pre‐and postnatal brain. The glial and neuronal environment was also altered in offspring of LPS treated mice. This preliminary data has shown that a single injection of a bacterial mimetic can have diverse effects on the neurodevelopmental process. This study found that a single low dose of LPS administered at E12 induces pro‐inflammatory cytokines which may lead to structural changes in the prenatal brain which, potentially, may persist in the adult brain.

Maternal Immune Activation Induces Changes in Myelin and Metabolic Proteins, Some of Which Can Be Prevented with Risperidone in Adolescence

Background: Maternal infection is a risk factor for schizophrenia but the molecular and cellular mechanisms are not fully known. Myelin abnormalities are amongst the most robust neuropathological changes observed in schizophrenia, and preliminary evidence suggests that prenatal inflammation may play a role. Methods: Label-free liquid chromatography-mass spectrometry was performed on the prefrontal cortex (PFC) of adult rat offspring born to dams that were exposed on gestational day 15 to the viral mimic polyinosinic:polycytidylic acid [poly(I:C), 4 mg/kg] or saline and treated with the atypical antipsychotic drug risperidone (0.045 mg/kg) or saline in adolescence. Western blotting was employed to validate protein changes. Results: Over 1,000 proteins were quantified in the PFC with pathway analyses implicating changes in core metabolic pathways, following prenatal poly(I:C) exposure. Some of these protein changes were absent in the PFC of poly(I:C)-treated offspring that subsequently received risperidone treatment in adolescence. Particularly interesting reductions in the expression of the myelin-related proteins myelin basic protein isoform 3 (MBP1) and rhombex 29 were observed, which were reversed by risperidone treatment. Validation by Western blotting confirmed changes in MBP1 and mitogen-activated kinase 1 (MAPK1). Western blotting was extended to assess the MAPK signalling proteins due to their roles in inflammation, namely phosphorylated MAPK1 and phosphorylated MAPK-activated protein kinase 2. Both were upregulated by poly(I:C) treatment and reversed by risperidone treatment. Conclusions: Overall, our data suggest that maternal inflammation may contribute to an increased risk for schizophrenia through mechanisms involving metabolic function and myelin formation and that risperidone in adolescence may prevent or reverse such changes.

Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury.

Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation.

Séroprévalence du Parvovirus B19 dans un groupe de patients schizophrènes

Schizophrenia is a highly disabling chronic mental illness. It is considerded as a neurodeveloppemental illness resulting from the interaction of genetic and environmental factors. Growing evidence supports the major role of prenatal infections and inflammation in the genesis of schizophrenia. The hypothesis including viral infections has been the subject of several studies and the role of parvovirus B19 (PB19) in the onset of the disease has been suggested. However, there is, up till now, no seroepidemiological evidence of his involvement. To determine the prevalence of parvovirus B19 (PB19) in schizophrenic patients and in control subjects and to examine clinical associations between viral prevalence, risk factors of infectious disease and clinical features. We carried out a case-control seroepidemiological study in the Psychiatry department of Farhat-Hached general hospital of Sousse (Tunisia). We recruited108 schizophrenic patients and 108 healthy controls free from any psychotic disorder and matched for age and sex. We collected sociodemographic data, medical history, axis I comorbid disorders and infectious risk factors. We assessed patients for psychopathology and severity of illness using respectively the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions (CGI). For each study participant, blood sample was collected and levels of IgG and IgM anti-PB19 were measured using the ELISA technique. The prevalence of IgG antibodies to PB19 was significantly higher in schizophrenic patients than in controls (73.1% vs 60.2%; P=0.04). There were no statistical differences between the two groups regarding the prevalence of IgM antibodies to PB19. No association was found between viral prevalence and sociodemographic data, risk factors for infection or clinical characteristics. The presence of PB19 antibodies was associated with a lower score on the PANSS negative subscale (P=0.04). No other signficative association were found. In our study, prevalence of IgG antibodies to PB19 was significantly higher in schizophrenic patients than in controls. This finding supports the hypothesis of the involvement of PB19 in schizophrenia. Further studies including both virological and immunological aspects are needed to better clarify the etiopathogenic mechanisms of schizophrenia which would challenge the management of this disease.

Effect of prenatal exposure to LPS combined with pre- and post-natal high-fat diet on hippocampus in rat offspring

ObjectivePrenatal exposure to lipopolysaccharide (LPS) or high-fat diet (HFD) results in hippocampal impairment and cognitive deficits in offspring rats. What is not clear is how prenatal exposure to LPS combined with pre- and post-natal HFD would affect the hippocampus in offspring rats. Methods32 pregnant rats were randomly divided into four groups, including control group; LPS group (pregnant rats were injected with LPS 0.4mg/kg intraperitoneally on the 8th, 10th and 12th day of pregnancy); HFD group (maternal rats had HFD during pregnancy and the lactation period, and their pups also had HFD up to the third month of life); LPS+HFD group (rats were exposed to the identical experimental scheme with LPS group and HFD group). The serum IL-6 and TNF-alpha concentration was measured in three-month-old offspring rats in all groups. Hippocampal morphology and expressions of glial fibrillary acidic protein (GFAP), Tau and synaptophysin (SYP) in offspring rats were measured. ResultsSerum IL-6 and TNF-alpha concentration in the HFD group increased significantly compared with the control group, LPS group and LPS+HFD group. Compared with the control group and the LPS+HFD group, cells in the LPS and HFD groups were smaller and arranged in disorder, and cell membrane was not complete, nucleoli and nuclear heterochromatin stained darkly with hematoxylin. GFAP and Tau expression in the hippocampus of the LPS and HFD groups increased significantly compared with the control group and LPS+HFD group. SYP expression in the LPS and HFD groups decreased significantly compared with the control group and HFD group, increased in the LPS+HFD group. ConclusionPrenatal exposure to LPS combined with pre- and post-natal HFD result in a protective effect on the hippocampus in offspring rats, and it might be a benefit from the predictive adaptive response to prenatal inflammation.

Perinatal oxygen in the developing lung.

Lung diseases, such as bronchopulmonary dysplasia (BPD), wheezing, and asthma, remain significant causes of morbidity and mortality in the pediatric population, particularly in the setting of premature birth. Pulmonary outcomes in these infants are highly influenced by perinatal exposures including prenatal inflammation, postnatal intensive care unit interventions, and environmental agents. Here, there is strong evidence that perinatal supplemental oxygen administration has significant effects on pulmonary development and health. This is of particular importance in the preterm lung, where premature exposure to room air represents a hyperoxic insult that may cause harm to a lung primed to develop in a hypoxic environment. Preterm infants are also subject to increased episodes of hypoxia, which may also result in pulmonary damage and disease. Here, we summarize the current understanding of the effects of oxygen on the developing lung and how low vs. high oxygen may predispose to pulmonary disease that may extend even into adulthood. Better understanding of the underlying mechanisms will help lead to improved care and outcomes in this vulnerable population.