Immature Lung Research Articles

Value of the spiral computed tomography in detecting severity of bronchopulmonary dysplasia in infants and newborns

For today the bronchopulmonary dysplasia is polyetiological chronic disease of morphologically immature lungs that develops in newborns especially extremely premature ones as a result of intensive care of respiratory distress-syndrome and\or pneumonia. The aim of research : improvement of BPD diagnostics by the study of SCT image of chest organs and elaboration of criteria of injury severity. Materials and methods . There were analyzed the data of SCT of chest organs CO) of 42 patients with BPD (28 boys, 14 girls) 25 days – 3 years old. 34 (81,0 %) were premature (19,0 %) – mature. Results . The radiographic criteria of BPD severity are: an intensity of pulmonary vasculature changes (from the local moderate one to diffuse pneumofibrosis), pulmonary hyperpneumatosis, emphysematous bullas (isolated or multiple), the pulmonary hypertension and pleuro-diaphragm, pleuro-pericardial commissures. Conclusions . SCT allows reveal the early signs of pulmonary changes at BPD and detect its severity that influences on the choice of treating tactics. With the help of SCT it is possible to establish the combination of BPD with anomalies and development disorders of lungs that detect its further prognosis and life quality

Advances in arrested late lung development and bronchopulmonary dysplasia

The process of late lung development is disturbed in bronchopulmonary dysplasia (BPD). One of the keys in late lung development is secondary septation, in which secondary septa arise from primary septa, producing plenty of small alveoli, which significantly increase the surface area of gas exchange.Secondary septation, together with architectural changes to the vascular structure of the lung which minimize the distance between the blood and the inspired air, are the targets of late lung development.BPD is a disease of premature infants in which development of the alveoli is stunted caused by many factors including volutrauma, inflammation, and oxygen toxicity.Compared with early lung development, the later development of the immature lung remains unclear.This paper is to emphasize remarkable latest research of arrested late lung development and BPD. Key words: Bronchopulmonary dysplasia; Alveolarization; Lung development; Preterm infant

Cardiorespiratory events in preterm infants: etiology and monitoring technologies.

Every year, an estimated 15 million infants are born prematurely (<37 weeks gestation) with premature birth rates ranging from 5 to 18% across 184 countries. Although there are a multitude of reasons for this high rate of preterm birth, once birth occurs, a major challenge of infant care includes the stabilization of respiration and oxygenation. Clinical care of this vulnerable infant population continues to improve, yet there are major areas that have yet to be resolved including the identification of optimal respiratory support modalities and oxygen saturation targets, and reduction of associated short- and long-term morbidities. As intermittent hypoxemia is a consequence of immature respiratory control and resultant apnea superimposed upon an immature lung, improvements in clinical care must include a thorough knowledge of premature lung development and pathophysiology that is unique to premature birth. In Part 1 of a two-part review, we summarize early lung development and diagnostic methods for cardiorespiratory monitoring.

Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus.

Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis.

Cerebral oxygenation following preterm delivery

The Neonatal Resuscitation Program (NRP) has progressed over 25 years from assumptions and professional opinion about resuscitation of the term infant to evidence-based recommendations for the initial support of both term and preterm infants. This evidence base has been developed by interested investigators using traditional and newer monitoring techniques to measure the transitions in oxygenation, cardiopulmonary function, and metabolism following birth. Supplemental oxygen can cause oxidant exposures that may cause long-term organ injury. As the monitoring has improved, the challenges are to learn if monitoring can change outcomes rather than simply improve physiologic variables that may not impact long-term outcomes. The report by Kenosi et al illustrates this point. They evaluated cerebral oxygenation immediately following delivery of preterm infants with the hypothesis that those infants that received >30% oxygen would have more brain regional oxygen saturations >85% and, thus, the possibility of oxidant injury relative to infants receiving <30%. They found no difference in >85% saturation values between the groups, but more of the infants receiving >30% oxygen had saturations <55%, indicating brain hypoxia. The infants requiring more oxygen had more lung immaturity and presumably a less mature cardiovascular adaptation to birth. This report demonstrates interesting but transient differences in cerebral oxygen saturations. But, the bigger challenge will be to evaluate if the differences are clinically relevant and if measurements of cerebral oxygen saturation are of value during delivery, beyond experimental studies. The physiology is fascinating, and more studies are required to identify which measurements can improve outcomes.Article page 1007▶ The Neonatal Resuscitation Program (NRP) has progressed over 25 years from assumptions and professional opinion about resuscitation of the term infant to evidence-based recommendations for the initial support of both term and preterm infants. This evidence base has been developed by interested investigators using traditional and newer monitoring techniques to measure the transitions in oxygenation, cardiopulmonary function, and metabolism following birth. Supplemental oxygen can cause oxidant exposures that may cause long-term organ injury. As the monitoring has improved, the challenges are to learn if monitoring can change outcomes rather than simply improve physiologic variables that may not impact long-term outcomes. The report by Kenosi et al illustrates this point. They evaluated cerebral oxygenation immediately following delivery of preterm infants with the hypothesis that those infants that received >30% oxygen would have more brain regional oxygen saturations >85% and, thus, the possibility of oxidant injury relative to infants receiving <30%. They found no difference in >85% saturation values between the groups, but more of the infants receiving >30% oxygen had saturations <55%, indicating brain hypoxia. The infants requiring more oxygen had more lung immaturity and presumably a less mature cardiovascular adaptation to birth. This report demonstrates interesting but transient differences in cerebral oxygen saturations. But, the bigger challenge will be to evaluate if the differences are clinically relevant and if measurements of cerebral oxygen saturation are of value during delivery, beyond experimental studies. The physiology is fascinating, and more studies are required to identify which measurements can improve outcomes. Article page 1007▶ Effects of Fractional Inspired Oxygen on Cerebral Oxygenation in Preterm Infants following DeliveryThe Journal of PediatricsVol. 167Issue 5PreviewTo explore regional cerebral oxygen saturations (rcSO2) in preterm neonates initially stabilized with 0.3 fractionated inspired oxygen (FiO2) concentrations. We hypothesized that those infants who received >0.3 FiO2 during stabilization following delivery would have relatively higher rcSO2 postdelivery compared with those stabilized with a lower FiO2. Full-Text PDF

Longitudinal assessment of the lung mechanics of very low birth weight preterm infants with and without bronchopulmonary dysplasia.

Prematurity has been correlated with altered lung mechanics. Some infants develop lung injury as a consequence of lung immaturity, invasive mechanical ventilation and exposure to oxygen, thus resulting in bronchopulmonary dysplasia. The aim here was to compare the lung mechanics of preterm infants with and without bronchopulmonary dysplasia during the first year of life. Prospective cohort study in a tertiary-level hospital. This study included premature infants at a public hospital who underwent two pulmonary function tests: one at discharge and the other at the corrected age of 4 to 8 months. Tidal volume, lung compliance and lung resistance were measured. Statistical tests were used for comparisons between infants with and without bronchopulmonary dysplasia. 102 children with mean gestational age of 29 ± 2.0 weeks were studied; 17 with bronchopulmonary dysplasia. Lung compliance (0.84 ± 0.29 versus 1.28 ± 0.46; P < 0.001) and tidal volume (6.1 ± 0.94 versus 7.2 ± 1.43; P < 0.01) at discharge were significant lower in children with bronchopulmonary dysplasia than in those without the disease, but no differences were observed at the second test (compliance: 1.53 ± 0.77 versus 1.94 ± 1.01; P = 0.12; and tidal volume: 6.9 ± 1.4 versus 7.3 ± 1.6; P = 0.42). Differences in lung mechanics were observed between infants with and without bronchopulmonary dysplasia at hospital discharge but these differences were no longer detected at the final follow-up. The lung mechanics of all the infants improved over this period of time.

Lung volume recruitment in a preterm pig model of lung immaturity

A translational preterm pig model analogous to infants born at 28 wk of gestation revealed that continuous positive airway pressure results in limited lung recruitment but does not prevent respiratory distress syndrome, whereas assist-control + volume guarantee (AC+VG) ventilation improves recruitment but can cause injury, highlighting the need for improved ventilation strategies. We determined whether airway pressure release ventilation (APRV) can be used to recruit the immature lungs of preterm pigs without injury. Spontaneously breathing pigs delivered at 89% of term (model for 28-wk infants) were randomized to 24 h of APRV (n = 9) vs. AC+VG with a tidal volume of 5 ml/kg (n = 10). Control pigs (n = 36) were provided with supplemental oxygen by an open mask. Nutrition and fluid support was provided throughout the 24-h period. All pigs supported with APRV and AC+VG survived 24 h, compared with 62% of control pigs. APRV resulted in improved lung volume recruitment compared with AC+VG based on radiographs, lower Pco2 levels (44 ± 2.9 vs. 53 ± 2.7 mmHg, P = 0.009) and lower inspired oxygen fraction requirements (36 ± 6 vs. 44 ± 11%, P < 0.001), and higher oxygenation index (5.1 ± 1.5 vs. 2.9 ± 1.1, P = 0.001). There were no differences between APRV and AC+VG pigs for heart rate, ratio of wet to dry lung mass, proinflammatory cytokines, or histopathological markers of lung injury. Lung protective ventilation with APRV improved recruitment of alveoli of preterm lungs, enhanced development and maintenance of functional residual capacity without injury, and improved clinical outcomes relative to AC+VG. Long-term consequences of lung volume recruitment by using APRV should be evaluated.

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation.

Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. In fully treated animals (LPS + MV + 60% O(2)) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.Bronchopulmonary dysplasia (BPD) is a chronic lung disease occurring in ~30% of preterm infants born less than 30 wk of gestation (1). Its main risk factors include lung immaturity due to preterm delivery, mechanical ventilation (MV), oxygen toxicity, chorioamnionitis, and sepsis. The main feature is an arrest of alveolar and capillary formation (2). Models trying to decipher genes involved in the pathophysiology of BPD are mainly based on MV and oxygen application to young mammals with immature lungs of different species (3). In newborn rodent models, analyses of lung structure and gene and protein expression are performed for practical reasons directly at the end of MV (4,5,6). However, later appearing changes of gene expression might also have an impact on lung development and the evolution towards BPD and cannot be discovered by such models. Recently, we developed a newborn rat model of MV using an atraumatic (orotracheal) intubation technique that allows the weaning of the newborn animal off anesthesia and MV, the extubation to spontaneous breathing, and therefore allows the evaluation of effects of MV after a ventilation-free period of recovery (7). Indeed, applying this concept of atraumatic intubation by direct laryngoscopy, we recently were able to show significant differences between gene expression changes appearing directly after MV compared to those measured after a ventilation-free interval of 48 h. Immediately after MV, inflammation-related genes showed a transitory modified expression, while another set of more structurally related genes changed their expression only after a delay of 2 d (7). Lung structure, analyzed by conventional 2D histology and also by 3D reconstruction using synchrotron x-ray tomographic microscopy revealed, 48 h after end of MV, a reduced complexity of lung architecture compared to the nonventilated rat lungs, similar to the typical findings in BPD. To extend these observations about late gene expression modifications, we performed with a similar model a full gene expression profile of lung tissue 48 h after the end of MV with either room air or 60% oxygen. Essentially, we measured changes in the expression of genes related to the MMPs and complement system which played a role in many of the six identified mostly affected pathways.

Tissue Characterization with Gray-level Histogram Width in Obstetrics and Gynecology

ABSTRACT Aim Clinical ultrasound tissue characterization, using usual B-mode devices. Materials and methods Malignant neoplasia in ovary, uterine cervix, and endometrium; placental intervillous space fibrin deposit; fetal growth restriction; fetal brain, fetal lung immaturity; meconium-stained amniotic fluid and healthy adult liver; Tissue was characterized by gray-level histogram width (GLHW) divided by full gray scale length. Results Malignant GLHW was higher than in benign one (it was malignant if the GLHW was 50% or more in ovary, uterine cervix, and endometrium). The GLHW of placental fibrin deposit was higher than normal placenta. It was reduced by heparin and normal neonate was obtained. Fetal brain echo density, immature fetal lung, and meconium-stained amniotic fluid were diagnosed by GLHW, and normal adult liver GLHW was studied. Helsinki declaration was followed. Conclusion The GLHW tissue characterization objectively diagnosed ultrasound B-mode image in obstetrics and gynecology; thus, it would also be applied in common adult human cases. How to cite this article Maeda K, Kihaile PE, Ito T, Utsu M, Yamamoto N, Serizawa M. Tissue Characterization with Gray-level Histogram Width in Obstetrics and Gynecology. Donald School J Ultrasound Obstet Gynecol 2017;11(1):7-10.

Prenatal exposure to bisphenol A disrupts mouse fetal lung development.

Developmental exposure to bisphenol A (BPA) is associated with lung dysfunction and diseases. However, it is unknown if this association has a fetal origin. The present study addressed this important question by examining the effects of BPA on fetal lung development. BPA was administered to pregnant mice via diet from embryonic day (E) 7.5 to E18.5. Fetal lungs were analyzed at E18.5 for changes in structure and expression of key molecular markers of lung maturation. Our main findings were as follows: BPA severely retards fetal lung maturation, as evidenced by diminished alveolar airspace (15% of control) and thickened septa, hallmarks of lung immaturity; this immaturity is characterized by aberrant alveolar epithelial type I cell differentiation because expression of the type I cell marker, aquaporin 5, but not type II cell markers, is dramatically reduced (16% of control); and the effects of BPA are likely mediated through the glucocorticoid signaling pathway because the expression of epithelial sodium channel γ and glutathione peroxidase, 2 well-known glucocorticoid target genes, is down-regulated in BPA-exposed fetal lungs, and, importantly, maternal dexamethasone administration rescues the lung immaturity phenotype. Taken together, these findings demonstrate that BPA disrupts fetal lung maturation, thus suggesting a fetal origin for BPA-induced lung diseases.

Pathogenesis of iridal coloboma in mice

Our research is exploiting the marsupial as a model to understand the signals required for lung development. Marsupials have a unique reproductive strategy, the mother gives birth to altricial neonate with an immature lung and the changes in milk composition during lactation in marsupials appears to provide bioactives that can regulate diverse aspects of lung development, including branching morphogenesis, cell proliferation and cell differentiation. These effects are seen with milk collected between 25 and 100 days postpartum. To better understand the temporal effects of milk composition on postnatal lung development we used a cross-fostering technique to restrict the tammar pouch young to milk composition not extending beyond day 25 for 45 days of its early postnatal life. These particular time points were selected as our previous study showed that milk protein collected prior to ~ day 25 had no developmental effect on mouse embryonic lungs in culture. The comparative analysis of the foster group and control young at day 45 postpartum demonstrated that foster pouch young had significantly reduced lung size. The lungs in fostered young were comprised of large intermediate tissue, had a reduced size of airway lumen and a higher percentage of parenchymal tissue. In addition, expression of marker genes for lung development (BMP4, WNT11, AQP-4, HOPX and SPB) were significantly reduced in lungs from fostered young. Further, to identify the potential bioactive expressed by mammary gland that may have developmental effect on pouch young lungs, we performed proteomics analysis on tammar milk through mass-spectrometry and listed the potential bioactives (PDGF, IGFBP5, IGFBPL1 and EGFL6) secreted in milk that may be involved in regulating pouch young lung development. The data suggest that postnatal lung development in the tammar young is most likely regulated by maternal signalling factors supplied through milk.

Index of Suspicion in the Nursery

A male infant is born at 324/7 weeks of gestation with a birth weight of 2,870 g. He is born to a 27-year-old gravida 2, para 1001 mother who received appropriate prenatal care. The infant is noted to have severe isolated abdominal ascites on a 21-week ultrasonogram, which is confirmed with subsequent ultrasonography. No pleural or pericardial effusion, skin edema, or structural abnormalities in the heart are noted. Doppler ultrasonography reveals normal middle cerebral artery velocity. The mother’s blood group is O+, antibody test result is negative, and serologic test results for hepatitis B, human immunodeficiency virus, and syphilis are negative. The mother is rubella immune and tests group B Streptococcus negative. The results of Neisseria gonorrhea and Chlamydia tests are negative. IgM test results are negative for toxoplasma, parvovirus, varicella zoster virus, and cytomegalovirus. The mother presents with premature rupture of the membranes, which occurs 16 hours before delivery, and receives 2 doses of betamethasone. Before an elective low transverse caesarean delivery, 1.5 L of clear fluid is removed through amniocentesis and 180 mL through paracentesis secondary to concerns of fetal lung immaturity and abdominal distension. The infant is electively intubated at delivery in anticipation of respiratory distress from extensive ascites, administered one dose of surfactant, and given mechanical ventilatory assistance. Apgar scores are 6 and 8 at 1 and 5 minutes, respectively. The infant passes urine and meconium soon after birth. On physical examination, the infant is noted to have a distended abdomen and bilateral scrotal edema. Cord arterial and venous blood gas …

Activation of the nuclear factor-κB pathway during postnatal lung inflammation preserves alveolarization by suppressing macrophage inflammatory protein-2

A significant portion of lung development is completed postnatally during alveolarization, rendering the immature lung vulnerable to inflammatory stimuli that can disrupt lung structure and function. Although the NF-κB pathway has well-recognized pro-inflammatory functions, novel anti-inflammatory and developmental roles for NF-κB have recently been described. Thus, to determine how NF-κB modulates alveolarization during inflammation, we exposed postnatal day 6 mice to vehicle (PBS), systemic lipopolysaccharide (LPS), or the combination of LPS and the global NF-κB pathway inhibitor BAY 11-7082 (LPS + BAY). LPS impaired alveolarization, decreased lung cell proliferation, and reduced epithelial growth factor expression. BAY exaggerated these detrimental effects of LPS, further suppressing proliferation and disrupting pulmonary angiogenesis, an essential component of alveolarization. The more severe pathology induced by LPS + BAY was associated with marked increases in lung and plasma levels of macrophage inflammatory protein-2 (MIP-2). Experiments using primary neonatal pulmonary endothelial cells (PEC) demonstrated that MIP-2 directly impaired neonatal PEC migration in vitro; and neutralization of MIP-2 in vivo preserved lung cell proliferation and pulmonary angiogenesis and prevented the more severe alveolar disruption induced by the combined treatment of LPS + BAY. Taken together, these studies demonstrate a key anti-inflammatory function of the NF-κB pathway in the early alveolar lung that functions to mitigate the detrimental effects of inflammation on pulmonary angiogenesis and alveolarization. Furthermore, these data suggest that neutralization of MIP-2 may represent a novel therapeutic target that could be beneficial in preserving lung growth in premature infants exposed to inflammatory stress.

Neonatal exposure to mild hyperoxia causes persistent increases in oxidative stress and immune cells in the lungs of mice without altering lung structure

Preterm infants often require supplemental oxygen due to lung immaturity, but hyperoxia can contribute to an increased risk of respiratory illness later in life. Our aim was to compare the effects of mild and moderate levels of neonatal hyperoxia on markers of pulmonary oxidative stress and inflammation and on lung architecture; both immediate and persistent effects were assessed. Neonatal mice (C57BL6/J) were raised in either room air (21% O2), mild (40% O2), or moderate (65% O2) hyperoxia from birth until postnatal day 7 (P7d). The mice were killed at either P7d (immediate effects) or lived in air until adulthood (P56d, persistent effects). We enumerated macrophages in lung tissue at P7d and immune cells in bronchoalveolar lavage fluid (BALF) at P56d. At P7d and P56d, we assessed pulmonary oxidative stress [heme oxygenase-1 (HO-1) and nitrotyrosine staining] and lung architecture. The data were interrogated for sex differences. At P7d, HO-1 gene expression was greater in the 65% O2 group than in the 21% O2 group. At P56d, the area of nitrotyrosine staining and number of immune cells were greater in the 40% O2 and 65% O2 groups relative to the 21% O2 group. Exposure to 65% O2, but not 40% O2, led to larger alveoli and lower tissue fraction in the short term and to persistently fewer bronchiolar-alveolar attachments. Exposure to 40% O2 or 65% O2 causes persistent increases in pulmonary oxidative stress and immune cells, suggesting chronic inflammation within the adult lung. Unlike 65% O2, 40% O2 does not affect lung architecture.

Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells.

BackgroundMechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury.MethodsExpression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively.ResultsTRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4.ConclusionThese studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.

Bombesin staining in neuroendocrine cell hyperplasia of infancy (NEHI) and other childhood interstitial lung diseases (chILD).

We have analysed levels of bombesin-positive neuroendocrine cells (NECs) in neuroendocrine cell hyperplasia of infancy (NEHI) and other childhood interstitial lung diseases (chILDs) in order to validate proposed histological criteria for NEHI and investigate its aetiology. The extent of bombesin-positive cells within airway epithelium was analysed in lung biopsies from seven patients diagnosed with NEHI, including two classified previously as non-diagnostic, and other chILDs (n = 64) with age ranges of 1 month-18 years. NECs were counted and calculated as a percentage of airways containing NECs, average percentage of NECs per airway, percentage of airways with >10% NECs and number of neuroendocrine bodies (NEBs). Correlation with age and gender was also undertaken. Patients with NEHI had the highest average percentage of bombesin-positive NECs per airway compared to other chILDs. However, NEH was also seen in many other chILDs, and appears to be most prominent in disorders associated with lung immaturity such as histological patterns associated with surfactant protein-related disorders and pulmonary interstitial glycogenosis. NEH may, to a degree, be a marker of airway immaturity rather than the direct cause of NEHI. This possibility is supported by the fact that the number of bombesin-positive NECs decreased with age in this cohort, independent of disease type. The average percentage of bombesin-positive NECs per airway appears to be the best histological criterion for assessing the extent of NECs in the context of NEHI.

Maternal Tobacco Smoke Exposure Alters Elastin Splicing at Exon 7 and 34 in the Lung of Rat Pups

Maternal tobacco smoke (MTS) exposure reduces offspring lung function in humans and animal models. We showed that MTS increases static lung compliance in female, but not male, rat pups. Lung function depends on expression of alternatively spliced elastin transcripts. Using RNA‐seq, we identified alternative splicing at exons 7 and 34 of elastin transcripts in the immature rat lung. We hypothesized that levels of exon 7‐ and 34‐containing elastin transcripts would vary with lung development in male and female rat lung, and with MTS exposure, in female rat lung.Pregnant rats were exposed to tobacco smoke (MTS) or room air (Control) and pups killed at term birth (d0‐immature lung), or cross‐fostered to a control dam and killed at day of life 21 (d21‐mature lung). We measured elastin mRNA transcripts that contained exon 7 (E+7) and exon 34 (E+34). (n=5/group).Results: Between d0 and d21, lung E+7 decreased in control female (46±15%*) and male (61±14%*) rats, while E+34 increased in female (140±28%*) and was unchanged in male rats. Compared to age‐and sex‐matched controls, in females, MTS decreased E+7 at d0 (16±2%*), and increased E+7 at d21 (589±176%*). Similarly, in female pups, MTS decreased E+34 at d0 (25±16%*), and increased E+34 at d21 (200±51%*). In male lung, MTS did not affect levels of E+7 at d0, but increased E+7 at d21 (462±85%*). MTS did not affect E+34 in males. *p&lt;0.05ConclusionsExon 7‐ and 34‐containing elastin transcripts in rat lung are developmentally regulated and sex‐specifically altered by MTS. We speculate that MTS‐induced differences in elastin alternative splicing during development may alter lung function and structure through disruption of the timing and integrity of elastic fiber assembly in the rat.*Funding: APS and NHLBI; 1 R25 HL115473‐01

Neonatal lung physiology and respiratory support of newborns

Article elucidates the neonatal lung physiology in newborns, methods of respiratory support, particularly positive pressure ventilation, and pulmonary changes caused by anesthesia and surgery. Optimal methods of respiratory support in preterm and full-term newborns are considered. It was noted that newborn infants have a high risk of respiratory complications during anesthesia which can be attributed to their respiratory physiology. The balance between volume of closing and functional residual capacity can be easily disrupted during anesthesia and surgery, which immediately leads to respiratory disorders. Therefore the strategy should include «open lung» ventilation conception and avoid high tidal volume and excessive oxygen inspiratory fraction. High-frequency oscillatory ventilation (HFOV) often used in babies with severe respiratory failure does not have the advantages in reducing of the BPD development, other pulmonary fatalities, as well as severe neurological complications in preterm infants comparing with conventional ventilation. Regarding full-term newborns, the timely start of HFOV may be more effective than conventional mechanical ventilation. This review also applies to such issues as use of inhaled nitric oxide, using of cuffed endotracheal tubes, the influence of anesthetics on immature lungs and breathing problems that may occur during anesthesia and surgery.

RESPIRATORY SUPPORT OF PRETERM INFANTS AFTER EXTUBATION: COMPARISON OF CLINICAL EFFICACY OF STANDART AND HIGH FREQUENCY NON-INVASIVE VENTILATION

In animal models nasal high frequency oscillatory ventilation appears to provide better development of immature lung causing less injury. This open randomized study compared the clinical efficacy of the standard (SV) and high frequency (HFV) non-invasive (nasal) ventilation after primary extubation of very preterm infants. The study included 24 very premature infants with birth weight ≤1500 gand respiratory distress syndrome. Before the first extubation infants were randomized into the main (n = 12) or control (n = 12) group. A certain mode of respiratory support was used according to the protocol for at least 72 hrs. The primary study outcome was the need for re-intubation within 72 hrs after the initial extubation. Mortality, incidences of bronchopulmonary dysplasia (BPD) and other important complications of prematurity were also compared in these groups. The frequency of re-intubation within the first 72 hrs. of non-invasive respiratory support was similar in both groups (41.67%). No differences were observed between the groups for the total duration of respiratory support as well. The incidence of BPD was twice higher in the group of infants who were treated using nasal HFV (main group) according to physiological definition, but this difference was not significant (2 cases (16.67%) compared to 1 case (8.33%) accordingly; p = 0.78). BPD incidences according to the clinical definition were similar in the both groups (5 cases - 41.67%). The use of high-frequency non-invasive ventilation after primary extubation of very preterm infants has no obvious clinical advantages over the extubation followed by standard non-invasive ventilation.

Bronchopulmonary dysplasia - an overview about pathophysiologic concepts.

Neonatal chronic lung disease in the preterm infant, i.e. bronchopulmonary dysplasia (BPD) is characterized by impaired pulmonary development with its effects persisting into adulthood. Triggered in the immature lung by infectious complications, oxygen toxicity and the impact of mechanical ventilation, a sustained inflammatory response, extensive remodeling of the extracellular matrix, increased apoptosis as well as altered growth factor signaling characterize the disease. The current review focuses on selected pathophysiologic processes and their interplay in disease development. Furthermore, the potential of both, acute and long-term changes to the pulmonary scaffold and the cellular interface in concert with dysregulated growth factor signaling to affect aging and repair processes in the adult lung is discussed.