IL-6 is constitutively expressed during lung morphogenesis and enhances fetal lung explant branching

Previous studies have shown that chorioamnionitis, with increased IL-6, promotes fetal lung maturation and decreases the incidence of respiratory distress syndrome in premature neonates. However, the expression pattern and the effects of IL-6 on fetal lung growth mechanisms remain unknown. IL-6 expression was assessed by in situ hybridization and by real-time PCR between 14.5 and 21.5 d postconception. Normal and nitrofen-induced hypoplastic lung explants were cultured with increasing IL-6 doses or IL-6 neutralizing antibodies. Branching, cellular proliferation (Ki-67) and MAPK phosphorylation in fetal lung explants were analyzed. Pulmonary primitive epithelium expressed IL-6 constitutively throughout all gestational ages, displaying highest levels during earliest stages. In normal and hypoplastic lung explants, IL-6 neutralizing antibodies significantly reduced, whereas IL-6 supplementation induced a biphasic effect (lower doses increased, while the highest dose did not accomplish additional effect) on branching and cellular proliferation. IL-6 enhanced p38-MAPK phosphorylation without changing MEK1/2 and JNK pathways. The present study suggests a physiological role for IL-6 on pulmonary branching mechanisms most likely involving p38-MAPK intracellular signalling pathway

Smoking onset and the time-varying effects of self-efficacy, environmental smoking, and smoking-specific parenting by using discrete-time survival analysis

This study examined the timing of smoking onset during mid- or late adolescence and the time-varying effects of refusal self-efficacy, parental and sibling smoking behavior, smoking behavior of friends and best friend, and parental smoking-specific communication. We used data from five annual waves of the ‘Family and Health’ project. In total, 428 adolescents and their parents participated at baseline. Only never smokers were included at baseline (n = 272). A life table and Kaplan–Meier survival curve showed that 51% of all adolescents who did not smoke at baseline did not start smoking within 4 years. The risk for smoking onset during mid- or late adolescence is rather stable (hazard ratio between 16 and 19). Discrete-time survival analyses revealed that low refusal self-efficacy, high frequency of communication, and sibling smoking were associated with smoking onset one year later. No interaction effects were found. Conclusively, the findings revealed that refusal self-efficacy is an important predictor of smoking onset during mid- or late adolescence and is independent of smoking-specific communication and smoking behavior of parents, siblings, and (best) friend(s). Findings emphasize the importance of family prevention programs focusing on self-efficacy skills

Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child

Background: Countries worldwide recommend women planning pregnancy to use daily 400 mg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). Conclusions: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use

Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep

<p>Abstract</p> <p>Background</p> <p>Initiation of ventilation using high tidal volumes in preterm lambs causes lung injury and inflammation. Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia.</p> <p>Objective</p> <p>To test if antenatal or postnatal corticosteroids would decrease resuscitation induced lung injury.</p> <p>Methods</p> <p>129 d gestational age lambs (n = 5-8/gp; term = 150 d) were operatively delivered and ventilated after exposure to either 1) no medication, 2) antenatal maternal IM Betamethasone 0.5 mg/kg 24 h prior to delivery, 3) 0.5 mg/kg Dexamethasone IV at delivery or 4) Cortisol 2 mg/kg IV at delivery. Lambs then were ventilated with no PEEP and escalating tidal volumes (<it>V</it>_T) to 15 mL/kg for 15 min and then given surfactant. The lambs were ventilated with <it>V</it>_T8 mL/kg and PEEP 5 cmH₂0 for 2 h 45 min.</p> <p>Results</p> <p>High V_Tventilation caused a deterioration of lung physiology, lung inflammation and injury. Antenatal betamethasone improved ventilation, decreased inflammatory cytokine mRNA expression and alveolar protein leak, but did not prevent neutrophil influx. Postnatal dexamethasone decreased pro-inflammatory cytokine expression, but had no beneficial effect on ventilation, and postnatal cortisol had no effect. Ventilation increased liver serum amyloid mRNA expression, which was unaffected by corticosteroids.</p> <p>Conclusions</p> <p>Antenatal betamethasone decreased lung injury without decreasing lung inflammatory cells or systemic acute phase responses. Postnatal dexamethasone or cortisol, at the doses tested, did not have important effects on lung function or injury, suggesting that corticosteroids given at birth will not decrease resuscitation mediated injury.</p

Non-neutralizing antibodies elicited by recombinant Lassa-Rabies vaccine are critical for protection against Lassa fever

Lassa fever (LF), caused by Lassa virus (LASV), is a viral hemorrhagic fever for which no approved vaccine or potent antiviral treatment is available. LF is a WHO priority disease and, together with rabies, a major health burden in West Africa. Here we present the development and characterization of an inactivated recombinant LASV and rabies vaccine candidate (LASSARAB) that expresses a codon-optimized LASV glycoprotein (coGPC) and is adjuvanted by a TLR-4 agonist (GLA-SE). LASSARAB elicits lasting humoral response against LASV and RABV in both mouse and guinea pig models, and it protects both guinea pigs and mice against LF. We also demonstrate a previously unexplored role for non-neutralizing LASV GPC-specific antibodies as a major mechanism of protection by LASSARAB against LF through antibody-dependent cellular functions. Overall, these findings demonstrate an effective inactivated LF vaccine and elucidate a novel humoral correlate of protection for LF.NIH grants R01 AI105204 to M.J.S., by the Jefferson Vaccine Center, and by the Fundação para a Ciência e Tecnologia (FCT) scholarship PD/BD/105847/2014 (to T.A.-M.). This work was also funded in part through the NIAID Division of Intramural Research and the NIAID Division of Clinical Research, Battelle Memorial Institute’s prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016Iinfo:eu-repo/semantics/publishedVersio

Lung morphometry after repetitive antenatal glucocorticoid treatment in preterm sheep

Antenatal glucocorticoids are thought to be less effective when delivery occurs more than 7 d after initiation of treatment; therefore, repeat courses are often administered. We examined lung structure after single or repetitive antenatal glucocorticoid injections in fetal sheep. Pregnant ewes received single or repetitive doses of 0.5 mg/kg betamethasone at 7-d intervals by maternal or fetal injection, beginning at D104 or D114 with delivery at D125, D135, or D146 gestation (term = 150 d). Changes in lung structure were more pronounced after repetitive versus single injections. Repetitive fetal or maternal injections beginning at D104 (delivery at D125) resulted in comparable structural changes: alveolar volume increased by 50 to 80%, alveolar numerical density decreased by 30 to 40%, and pleural and interlobular septal volumes decreased by as much as 70%. Similar changes were seen in animals delivered at D135 after repetitive maternal injections beginning at D114. There were no structural differences between control and repetitive betamethasone animals when delivery was delayed until D146, indicating that betamethasone induced structural changes were reversible

Lung morphometry and collagen and elastin content: Changes during normal development and after prenatal hormone exposure in sheep

This study examined whether the improvement in lung function after prenatal hormone exposure coincided with changes in lung morphometry or in collagen and elastin content. Fetal lambs received a single intramuscular injection of betamethasone (0.5 mg/kg) plus L-thyroxine (T-4) (15 mu g/kg) or vehicle control 48 h before delivery at 121, 128, or 135 d gestational age (d 121, d 128, d 135, term = 150 d). T-4 was administered in conjunction with betamethasone in an attempt to enhance the maturational response. The right-upper lobes were instillation fixed at 30 cm H2O by Karnovsky's fixative after a 40-min period of mechanical ventilation. A number of significant changes occurred between d 121 and d 135 in control animals: alveolar airspace volume increased by 270%; despite a 40% reduction in alveolar septal thickness, alveolar septal volume did not change appreciably, suggesting a "redistribution" of septal tissue into the formation of secondary alveolar septa, which doubled in number; and both parenchymal collagen and elastin volume increased significantly, whereas pleural collagen and elastin volume did not change. In contrast to the changes seen in control animals, exposure to betamethasone plus T-4 led to alveolar septal thinning at each gestational age without an associated increase in secondary septal number, a 40% decrease in alveolar septal volume, and a proportionate reduction in parenchymal elastin at d 121. Although attenuation of alveolar septa coincides with redistribution of septal tissue into the formation of secondary septa during normal maturation, exposure to betamethasone plus T-4 promotes thinning of alveolar septa in the absence of secondary septal formation, which results in a loss of alveolar septal tissue