Alan H Jobe

..These results have implications for lung inflammation and bronchopulmonary dysplasia in preterm infants exposed to chorioamnionitis and maternal glucocorticoids...

..Ventilation strategies that minimize injury need to be developed...

..In this article, the hypothesis developed is that bronchopulmonary dysplasia occurs because of repetitive adverse lung exposures, or hits, and that the initial hits may be antenatal glucocorticoid exposure and/or antenatal inflammation...

..We asked whether maternal or fetal cortisol treatments induced fetal lung maturation and growth restriction compared with betamethasone and whether medroxyprogesterone (MPA) influenced lung maturation...

..Different infants probably have quite variable sensitivities to oxygen injury, but there are no biomarkers available to predict the risk of oxygen injury...

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..05). In this model in preterm lambs CPAP results in lower indicators of acute lung injury than does mechanical ventilation during the first 2 h of life...

..The hypothalamic-pituitary-adrenal (HPA) axis was unresponsive to standard dose stimulation tests until 11 days of age in preterm baboons, indicating HPA immaturity...

..However, chorioamnionitis is also associated with a paradoxical reduction in the incidence of surfactant deficiency-related respiratory distress syndrome in preterm infants...

..Therefore, the presence of a mediator such as TNF-alpha in a developing animal does not necessarily mean that it is causing the responses anticipated from previous results in adult animals...

..Surfactant protein A and B mRNAs were highest at 2 d, suggesting that oxidative stress did not contribute to the lung maturation response. A modest lung oxidative stress in chorioamnionitis could contribute to bronchopulmonary dysplasia...

..Inhibition of CXCR2 did not change IA LPS-induced lung maturation. IL-8 signaling does not mediate LPS-induced lung inflammation and lung maturation...

..We conclude that IL-1 and LPS both can cause chorioamnionitis, but IL-1 is not an important mediator of LPS-induced chorioamnionitis in fetal sheep...

..Recent literature suggests hypothermia may protect against lung injury. We evaluated body temperature as a variable in lung inflammation due to oxygenation and mechanical ventilation following delivery of near-term lambs...

..The findings have implications for preterm infants exposed to chorioamnionitis for both responses to lung injury and postnatal nosocomial infections...

..LPS or IL-1 can induce robust expression of MCP-1 or MCP-2 in the fetal lung. LPS induction of MCP-1 is not IL-1 dependent in fetal sheep. MCP-1 and MCP-2 may be significant contributors to fetal inflammation...

..Intra-amniotic LPS recruits leukocytes to the fetal air space that have a persistent activation. These results have implications for the pathogenesis of lung inflammatory disorders in the preterm...

..Contrary to our hypothesis, a prolonged fetal exposure to intra-amniotic endotoxin caused mild persistent inflammation but did not lead to progressive structural abnormalities in lungs of near-term gestation lambs...

..Premature infants are exposed to potentially injurious ventilation in the delivery room. Assessments of lung injury are confounded by effects of subsequent ventilatory support...

..In preterm lambs, intraamniotic endotoxin and interleukin 1 (IL-1) induce lung inflammation followed by lung maturation...

..HSP70 protein decreased in the lung tissue and increased in BALF with ventilation. Initiation of ventilation induced a stress response and inflammatory cytokines in small and medium-sized airways...

..We evaluated lung maturation responses to the mixture of betamethasone phosphate (Beta-PO4) + betamethasone acetate (Beta-Ac) in comparison to Beta-PO4 or Beta-Ac in fetal sheep...

..IL-1α is a potent mediator of the fetal inflammatory response syndrome...

..We conclude that TLR2 and TLR4 mRNAs increase through gestation and expression of TLR2 and TLR4 are induced by LPS in the fetal sheep lung...

..IP-10 and MIG are potent angiostatic chemokines that may contribute to lung injury and altered pulmonary vascular development in the preterm exposed to chorioamnionitis...

..The use of PEEP during initiation of ventilation at birth decreased early mediators of lung injury. Surfactant administration changed the distribution of injury and had a moderate additive protective effect...

..After lung inflammation was induced by intra-amniotic endotoxin injection, ventilation did not increase lung injury...

..A small amount of endogenous Sat PC is required for preterm lambs to breathe successfully with CPAP. CPAP 8 improves early newborn respiratory transition relative to CPAP 5...

..Preterm lambs tolerated a very high PCO(2) without physiologic compromise for 6 h. The high PCO(2) may attenuate ventilator-induced lung injury in the preterm...

..Increased pro-inflammatory cytokines in tracheal aspirates correlate with the development of BPD in preterm infants. Ventilation of preterm lambs increases pro-inflammatory cytokines and causes lung inflammation...

..The i.v. IL-1alpha caused no lung inflammation or injury but did result in severe neutropenia and hypotension leading to early death. IT IL-1alpha can cause intense lung inflammation and systemic shock in ventilated preterm lungs...

..We hypothesized that maternal treatments with betamethasone acetate induce fetal lung maturation comparably to the betamethasone phosphate+betamethasone acetate used clinically...

..parvum. The findings increase our understanding of how chorioamnionitis-exposed preterm infants may respond to lung injury and postnatal nosocomial infections...

..We conclude that a brief period of high V(T) ventilation causes a proinflammatory cascade, a maturation of lung monocytic cells, and an induction of surfactant protein mRNA...

..Our experiments show rapid induction of an APR gene in lung in response to proinflammatory stimuli...

..An antenatal exposure of the fetal lung to endotoxin enhanced the subsequent inflammatory response of the ventilated preterm lung...

..Intra-amniotic endotoxin caused surfactant secretion, inflammation, cell death, and remodeling as indications of lung injury. The recovery phase was accompanied by maturational changes in the fetal lung...

..Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation...

..Exposure to antenatal inflammation may cause vascular remodeling and contribute to the development of BPD...

..Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia...

..The reduced phagocytosis of apoptotic cells by monocytes from the preterm may contribute to prolonged inflammation in diseases such as bronchopulmonary dysplasia...

..The adaptations that permit survival after very preterm birth may have adverse effects in later life. The biology of multiple organ system plasticities resulting from very preterm birth remains to be extensively explored...

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..However, a change from current practice will require further randomized controlled trials...

..We conclude that the order of exposures of intra-amniotic LPS or maternal betamethasone had large effects on fetal lung inflammation and maturation...

..In experimental models, chorioamnionitis can both injure and mature the fetal lung and cause immune nodulation. Postnatal care strategies also change how chorioamnionitis relates to clinical outcomes such as bronchopulmonary dysplasia...

..These experimental observations contribute to explanations of why preterm infants have variable degrees of lung maturation at birth and unpredictably develop bronchopulmonary dysplasia BPD...

..Prenatal corticosteroids complement surfactant to further enhance lung function. The magic of surfactant therapy results from the multiple interactions between surfactant and the preterm lung...

..CONCLUSIONS: Early bubble CPAP reduced delivery room intubations, days on mechanical ventilation, postnatal steroid use and was associated with increased postnatal weight gain with no increased complications...

..Transporting premature infants from a neonatal intensive care unit (NICU) to a radiology department for MRI has medical risks and logistical challenges...

..Exposure to large tidal volumes (V(T)s) at birth causes lung inflammation, and oxygen may amplify the injury. We hypothesized that normal V(T) ventilation at birth causes lung injury that is exacerbated by 95% oxygen...

..Here, we review the evolution of 'the developmental origins of health and disease' as a concept and discuss recent advances in the association of specific stimuli to obesity, an epidemic cause of human morbidity and mortality...

..Antenatal glucocorticoid therapy is very effective, and no adverse effects of a single treatment course have been identified...

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..An approach to minimizing risk is to use low-dose, short-duration treatments in the highest risk ventilator-dependent patients. Questions remain about which corticosteroid is the safest and how to dose that corticosteroid...

..Bronchopulmonary dysplasia (BPD) remains the most common severe complication of preterm birth. A number of recent animal models and clinical studies provide new information about pathophysiology and treatment...

..Abnormalities in adaptation are frequently found following preterm birth or cesarean delivery at term, and many of these infants need delivery room resuscitation to assist in this transition...

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..Our purpose was to determine whether improved preterm lung function caused by intraamniotic endotoxin treatment requires endotoxin entry into the respiratory tract...

..The effectors of this antenatally-induced lung maturation are not understood. Matrix metalloproteinases (MMPs) 2 and 9 are type-IV collagenases that can degrade alveolar basement membranes...

..Modulation of fetal innate immune responses by exposure to inflammation may alter subsequent immune adaptation after birth...

..Despite the complex cascade of events initiated by antenatal endotoxin exposure, variability in lung tissue mechanics is associated primarily with changes in alveolar Sat PC pool and lung morphology...

..The time-dependent changes in maternal betamethasone modulation of the responses of fetal monocytes may influence immune function of the preterm lamb after delivery...

..This study was undertaken to determine whether subchorionic endotoxin infusion causes chorioamnionitis and preterm lung maturation, as occurs after intra-amniotic endotoxin...

..We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses...

..The purpose of this study was to compare efficacy on fetal lung maturation of intra-amniotic betamethasone or budesonide with the efficacy of maternal intramuscular betamethasone...

..Lung compliance, lung volume, and alveolar Sat PC were positively correlated with residual alveolar wash leukocyte numbers 7 days after IL-1 treatment, suggesting a link between lung inflammation and maturation...

..Thus, mechanisms involving proinflammatory stimulation, unrelated to glucocorticoid hormones, can induce maturation of the AOE system of the fetal lung...

..Renal and cardiovascular function improves in preterm newborn lambs after a single prenatal betamethasone treatment. We hypothesized that multiple betamethasone exposures would further improve renal and cardiovascular adaptation...

..Measurements with stable isotopes are comparable to measurements with radioactive tracers and measurements at autopsy...

..Chorioamnionitis may alter lung function and possibly lead to chronic injury without clinical features of systemic inflammation or compromise...

..Study design Pregnant baboons received saline or BETA (6 mg) 48 and 24 hours before preterm delivery at 125 days' gestation. The newborn baboons were ventilated for 6 days, and assessed for renal, cardiovascular, and endocrine function...

..We hypothesized that intra-amniotic ureaplasmas would cause lung inflammation and alter fetal lung development...

..The objective of the study was to determine the effects in late gestation of Ureaplasma parvum serovar 3 colonization and the effects, preterm, of U. parvum serovar 6...

..Similar structural changes induced by intra-amniotic corticosteroids and maternal intramuscular betamethasone were associated with improvements in lung function at 2 and 7 d...

..Intra-amniotic endotoxin induced lung monocytes to develop into functionally mature cells consistent with macrophages. These findings have implications for lung immune responses after exposure to chorioamnionitis...

..The technique used to provide continuous positive airway pressure (CPAP) to the newborn may influence lung function and breathing efficiency...

..These effects may contribute to the impaired alveolar and pulmonary vascular development that is the hallmark of the new form of BPD...

..IL-1alpha induced large increases in alveolar surfactant saturated phosphatidylcholine and increased lung gas volumes. Lung inflammation and maturation result from direct exposure of the fetal lung to a single cytokine - IL-1alpha...

..The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD...

..Both exposures can either increase or decrease fetal inflammatory responses depending on the timing of the exposures. The immunomodulatory ability of the fetus to fetal exposures remains an unexplored research field...

..The outcomes that were studied included the rates of fetal death and the features of inflammation and lung maturation in survivors...

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