Lung Surfactant Production Research Articles

Betamethasone improved near-term neonatal lamb lung maturation in experimental maternal asthma.

Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant-producing cells and lower surfactant-protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term=150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45min before tissue collection. Lung function and structure were similar in control lambs (n=16, 11 ewes) and lambs from asthma ewes (n=14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n=12, 8 ewes) compared to those from controls (P=0.003) or asthma ewes (P=0.008). Lung expression of surfactant protein genes SFTPA (P=0.048) and SFTPB (P<0.001), but not SFTPC (P=0.177) or SFTPD (P=0.285), was higher in lambs from asthma+beta than those from asthma ewes. Female lambs had higher tidal volume (P=0.007), dynamic lung compliance (P<0.001), and SFTPA (P=0.037) and SFTPB gene expression (P=0.030) than males. These data suggest that betamethasone stimulates lung maturation and function of near-term neonates, even in the absence of impairment by maternal asthma.

The Potential of Ambroxol as a Panacea for Neonatal Diseases: A Scoping Review.

Ambroxol, a commonly used mucolytic agent, has been extensively studied for its clinical effectiveness in managing respiratory conditions in pediatric and adult patients. The existing body of research on ambroxol demonstrates its safety and efficacy. However, its potential role in preventing and treating neonatal diseases still needs to be explored. This scoping review aims to shed light on the unexplored potential of ambroxol, particularly its applications in perinatal and neonatal care. We aim to offer valuable insights for healthcare professionals, researchers, and academics, thus presenting a positive perspective. Key scientific databases such as Google Scholar, PubMed, Cochrane Library, and Europe PMC were meticulously searched for relevant literature on ambroxol in perinatal and neonatal medicine. Gray literature was also surveyed, and the search encompassed all study designs and languages up to June 2024. Furthermore, citations and reference lists of relevant articles were scrutinized to identify additional pertinent literature. Ambroxol has demonstrated promising effects in preventing and managing respiratory distress syndrome (RDS). It can enter the placental circulation and rapidly build up in human lung tissue to a much greater extent than in plasma. It promotes fetal lung maturation, surfactant production, and alveolar expansion. Numerous studies have demonstrated the efficacy of antenatal and postnatal ambroxol in the prevention and treatment of RDS. Ambroxol has the potential to be administered intravenously or through nebulization, offering the hopeful possibility of reducing the high failure rate typically associated with non-invasive ventilation in extremely preterm infants, instilling a sense of hope and optimism about the potential of ambroxol. It also shows potential in treating bronchopulmonary dysplasia, meconium aspiration syndrome, and neonatal infections. Ambroxol has been observed to assist in the closure of patent ductus arteriosus in preterm infants by inhibiting vasodilator agents such as nitric oxide and exerting vasoconstrictive properties. However, these biological actions may raise concerns regarding the potential induction of pulmonary hypertension and an increased risk of necrotizing enterocolitis. The present scoping review also examines the clinical evidence and the potential of ambroxol in reducing the incidence of intraventricular hemorrhage in preterm infants. Ambroxol may have potential analgesic properties in managing neonatal pain, and as it can penetrate the blood-brain barrier, it suggests potential neuroprotective properties. These properties may encompass the modulation of microglial activation and the antagonistic impact on glutamate receptors. Ambroxol's attributes could contribute to a decreased susceptibility to neurological complications and have demonstrated anticonvulsant effects in preclinical studies. While low-to-moderate-quality evidence indicates potential applications of ambroxol in neonatal care, further research is needed to determine the drug's optimal dosing, timing, and safety profiles in this patient population. We need to investigate ambroxol's potential synergistic effects with antenatal steroids. Exploration is required to assess ambroxol's potential in reducing the high failure rate associated with non-invasive respiratory support for RDS. Lastly, comprehensive studies on the long-term neurodevelopmental outcomes of neonates exposed to ambroxol are essential.

A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

Lysophosphatidylcholine acyltransferase 1 protein is present in maternal blood in the third trimester and is upregulated by antenatal corticosteroids.

Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is involved in the production of fetal lung surfactant. We have shown that LPCAT1 mRNA is present in amniotic fluid and maternal plasma and that its quantity correlates with the amniotic fluid lamellar body count. The purpose of the present study was to assay maternal plasma for the LPCAT1 protein in term and preterm pregnancies; and to measure the impact of antenatal corticosteroids. Maternal and newborn plasma samples were obtained from 7 women admitted to the hospital for induction of labor. Maternal plasma was also obtained before administration of corticosteroids and 24h after thesecond dose of corticosteroids from 12 women with premature labor and premature rupture of membranes. After sample preparation, LPCAT1 protein levels were determined using sandwich ELISA. We discovered LPCAT1 protein in maternal plasma in measurable quantities after 32weeks gestation. Further, there was a rise of maternal plasma LPCAT1 in response to the clinical administration of antenatal corticosteroids. Quantitation of maternal plasma LPCAT1 protein offers promise in the ongoing study of fetal lung maturation.

The COVID-19 Cell Signalling Problem: Spike, RAGE, PKC, p38, NFκB &amp; IL-6 Hyper-Expression and the Human Ezrin Peptide, VIP, PKA-CREB Solution

SARS-CoV-2 infection inhibits interferon expression, while hyper-activating innate-immune signalling and expression of pro-inflammatory cytokines. SARS-CoV-2 proteins: Spike, M and nsp6, nsp12 and nsp13 inhibit IFR3-mediated Type-1-interferon defence, but hyper-activate intracellular signalling, which leads to dysfunctional expression of pro-inflammatory cytokines, particularly IL-1β IL-6, IL-8, and TNFα. Ezrin, a sub-membrane adaptor-protein, organises multi-protein-complexes such as ezrin+NHERF1+NHE+CFTR, which control the density and location of ACE2 receptor expression on the luminal surface of airway-epithelial-cells, as well as determining susceptibility to SARS-CoV-2 infection. This protein complex is vital for lung-surfactant production for efficient gas-exchange. Ezrin also forms multi-protein-complexes that regulate signalling kinases; Ras, PKC, PI3K, and PKA. m-RAGE is a pattern-recognition-receptor of the innate immune system that is triggered by AGEs, which are chemically modified proteins common in the elderly and obese. m-RAGE forms multi-protein complexes with ezrin and TIRAP, a toll-like-receptor adaptor-protein. The main cause of COVID-19 is not viral infection but pro-inflammatory p38MAPK signalling mediated by TLRs and RAGE. In contrast, it appears that activated ezrin+PKA signalling results in the activation of transcription-factor CREB, which suppresses NFκB mediated pro-inflammatory cytokine expression. In addition, competition between ezrin and TIRAP to form multi-protein-complexes on membrane PIP2-lipid-rafts is a macromolecular-switch that changes the priority from innate immune activation programs to adaptive immune activation programs. Human Vasoactive Intestinal Peptide (VIP), and Human Ezrin Peptides (HEP-1 and RepG3) probably inhibit COVID-19 by activating the ezrin+PKA and ras&gt;Raf&gt;MEK&gt;ERK&gt;RSK&gt;CREB&gt;IL-10 signalling, which favours activation of adaptive immunity programs and inhibition of the dysfunctional innate-inflammation, the cause of COVID-19. HEP-1, RepG3, and VIP in individual human volunteers and in small clinical studies have been shown to be effective COVID-19 therapies, and seem to have a closely related mechanism of action.

Clinical implications of dexamethasone administration on Doppler indices of umbilical and middle cerebral arteries in preterm fetuses

BackgroundMaternal administration of dexamethasone is essential to improve fetal lung surfactant production and hasten the fetal lung maturity in women at risk for preterm birth. Umbilical and fetal middle cerebral arteries' (MCAs) Doppler indices are important to evaluate the effects of dexamethason on fetal and uteroplacental circulation in pregnancies at risk for preterm birth.ObjectiveThe aim was to evaluate the effects of maternal dexamethasone administration on umbilical and fetal MCAs Doppler indices (Resistance index (RI), Pulsalitility index (PI), and S/D ratio) in singleton pregnancies considered at risk for preterm delivery.Patients and methodsA total of 100 women were included in this study. They were at risk of preterm labor and were divided in two groups: 50 participants who took dexamethasone as a study group and 50 participants did not take dexamethasone as a control group. Doppler examination of umbilical and MCAs was performed, and comparisons between values of study group and control group were done after 0, 1, 4, and 7 weeks of dexamethasone administration.ResultsThe authors found a significant change in the mean values of the pulsatility and resistive indices and systolic-diastolic ratios of study group in umbilical artery and fetal MCA after 1 week after dexamethasone administration.ConclusionAdministration of dexamethasone improves Doppler indices and biophysical profile and decreases NICU admission. In healthy fetuses, a transient, significant, and unexplained decrease in fetal MCA impedance occurs on the fourth day following maternal dexamethasone administration.

3434 The Study of Fetal Tracheal Occlusion to Treat Congenital Diaphragmatic Hernia in the EXTEND Model

OBJECTIVES/SPECIFIC AIMS: The goal of this project is to study fetal pulmonary vasculature in a CDH animal model, to understand how FETO affects developing vasculature, and to develop a modifiable fetal tracheal occlusive therapeutic device that avoids previously seen sequelae of FETO, like alveolar distension, decreased surfactant production, and decreased Type II Pneumocytes. The primary outcome is lung volume/kilogram. The secondary outcomes are contrast-enhanced ultrasound perfusion metrics (Time to Peak, Mean Transit Time, Wash-in Rate, Wash-in Perfusion Index), pulmonary vascular density, Lung Injury Histology Scores, and Lung Compliance upon ventilation. METHODS/STUDY POPULATION: Congenital diaphragmatic hernias will be modeled by surgical hernia creation via maternal laparotomy and hysterotomy at gestational age 72 - 74 days. The ewe will undergo a second laparotomy at 105 - 115 days gestational age. After a second hysterotomy is made, the fetus will be removed from the amniotic sac, though placental circulation will be maintained (EXIT Procedure). The animal is cannulated via the umbilical vein and arteries onto the pumpless ECMO circuit. The balloon and pressure sensor complex is placed into the trachea via direct laryngoscopy, and the fetus aseptically sealed into the Biobag. The wires of the tracheal occlusive device (balloon catheter and pressure sensor) will egress via the port of the Biobag. The fetus remains in the Biobag for fourteen days, with the tracheal occlusive device in place for ten days, followed by a four day recovery period. Daily contrast-enhanced ultrasounds and pulmonary artery dopplers are performed. Upon study completion, the fetus is intubated and placed on a conventional ventilator. A full necropsy is then performed, with perfusion fixation of the lungs via the pulmonary artery. RESULTS/ANTICIPATED RESULTS: Hypothesis 1: Modifiable Tracheal Occlusion will have statistically different effects on developing lung parenchyma, surfactant production, and abundance of Type II Pneumocytes Hypothesis 2: Modifiable Tracheal Occlusion will have lower levels of pulmonary hypertension than negative control animals, as measured by contrast-enhanced ultrasound (pulmonary artery velocity and washout time). DISCUSSION/SIGNIFICANCE OF IMPACT: This project will provide insight into the development of pulmonary hypertension in the CDH fetus. It will provide insight into the physiology of FETO, a novel therapy for congenital diaphragmatic hernias, and will demonstrate the utility of the EXTEND System for fetal treatments that are not possible in the maternal uterus.

Antenatal dexamethasone effect on Doppler blood flow velocity in women at risk for preterm birth: prospective case series.

Maternal administration of corticosteroids is essential to improve fetal lung surfactant production and hasten the fetal lung maturity in women at risk for preterm birth. The current study aims to evaluate the effects of dexamethasone on fetal and uteroplacental circulation in pregnancies at risk for preterm birth after 24 hours of its administration. A prospective cross-sectional study was carried out in a tertiary University Hospital and included 52 pregnant women with singleton pregnancies. Doppler studies were performed on maternal uterine arteries, umbilical artery, fetal middle cerebral artery (MCA) and fetal descending aorta and just before dexamethasone administration and repeated 24 hours after completion of the course. There was a statistically significant difference between all Doppler indices in the umbilical artery (PI= 1.09±0.4 and 1.05±0.39, RI= 0.66±0.14 and 0.63±0.14; p=0.001), fetal MCA (RI= 0.86±0.12 and 0.83±0.13, PI= 2.19±0.72 and 2.15±0.72; p=0.001) and aorta (RI= 0.9±0.55 and 0.87±0.55; p=0.001, PI= 1.91±0.44 and 1.89±0.44; p=0.040) in comparison before and 24 hours after maternal dexamethasone administration respectively. Also uterine artery PI was significantly different (0.9±0.27 and 0.87±0.26; p=0.001). Antenatal dexamethasone for women at risk of preterm birth improves the fetal and uteroplacental blood flow at 24 hours after its administration.

Effects of tracheal occlusion with retinoic acid administration on normal lung development.

Tracheal occlusion (TO) is an investigational therapy for severe congenital diaphragmatic hernia that decreases pulmonary hypoplasia, but sustained TO also induces deficient surfactant synthesis. Intramuscular maternal administration of retinoic acid (RA) in a surgical rabbit model of congenital diaphragmatic hernia showed a beneficial effect on lung maturation. We evaluated the potential of RA delivery into the trachea and studied the combined effects of TO and RA on normal lung development. Experiments were performed on normal rabbit fetuses. Liposomes and capric triglyceride (Miglyol® ), alone and with RA, were administered in the trachea just before TO (d26). Lung morphology and surfactant production were studied at term (d30). Tracheal occlusion increased lung weight and enhanced alveolar development but increased apoptotic activity and decreased surfactant expression. Tracheal injection of RA improved surfactant production to levels of normal controls. We established the potential of liposome and Miglyol as RA vehicle for delivering this bioactive molecule in the fetal airways. Tracheal RA injection seems to oppose the effects of TO in fetuses with normal lungs. © 2017 John Wiley & Sons, Ltd.

Effects of antenatal dexamethasone administration on fetal and uteroplacental Doppler waveforms in women at risk for spontaneous preterm birth

Abstract Objective Maternal administration of synthetic corticosteroids is essential to improve fetal lung surfactant production and hasten the fetal lung maturity in women at risk for preterm birth. The current study aimed to investigate the effects of dexamethasone exerted on fetal and uteroplacental circulation as measured by Doppler in pregnancies at risk for preterm birth after 24 h of its administration. Materials and methods A prospectively registered study at www.ClinicalTrials.gov (NCT02662790) was conducted in Women Health Hospital, Assiut, Egypt, included 50 pregnant women with singleton pregnancies. Doppler studies were performed on the umbilical artery, fetal middle cerebral artery (MCA), fetal descending aorta and maternal uterine arteries just before dexamethasone administration and repeated 24 h after completion of the dexamethasone course. Results The mean age of the study group was 27.7 ± 4.5 years. There was a statistically significant difference between all Doppler indices in umbilical artery, fetal MCA and aorta in comparison before and 24 h after maternal dexamethasone administration. Also uterine artery Pulsatility index was significantly different ( p = 0.001). Conclusion Maternal dexamethasone administration to pregnant women at risk of preterm labor improves the blood flow of the maternal uterine artery, fetal MCA, descending aorta and umbilical artery 24 h after its administration.

Effect of high fat diet on pulmonary expression of parathyroid hormone-related protein and its downstream targets

AimsParathyroid hormone-related protein (PTHrP) is involved in lung development and surfactant production. The latter one requires a paracrine interaction between type II alveolar cells and lipofibroblasts in which leptin triggers PTHrP-induced effects. Whether increased plasma leptin levels, as they occur in high fat diet, modify the expression of PTHrP remains unclear. Furthermore, the effect of high fat diet under conditions of forced pulmonary remodelling such as response to post myocardial infarction remains to be defined.Materials and methodsC57 bl/6 mice were randomized to either normal diet or high fat diet at an age of 6 weeks. Seven months later, the mice were euthanized and the lung was removed and frozen in fluid nitrogen until use. Samples were analyzed by real-time RT-PCR and western blot. Leptin deficient mice were used to investigate the effect of leptin on pulmonary expression of PTHrP more directly. A subgroup of mice with and without high fat diet underwent in vivo ischemia (45 min) and reperfusion (4 weeks). Finally, experiments were repeated with prolonged high-fat diet.Key findingsHigh fat diet increased plasma leptin levels by 30.4% and the pulmonary mRNA expression of PTHrP (1,447-fold), PTH-1 receptor (4.21-fold), and PTHrP-downstream targets ADRP (7.54-fold) and PPARγ (5.27-fold). Pulmonary PTHrP expression was reduced in leptin deficient mice by 88% indicating leptin dependent regulation. High fat diet further improved changes in pulmonary adaptation caused by ischemia/reperfusion (1.48-fold increased PTH-1 receptor protein expression). These effects were lost during prolonged high fat diet.SignificanceThis study established that physiological regulation of leptin plasma levels by high fat diet affects the pulmonary PTHrP expression and of PTHrP downstream targets. Modification of pulmonary expression of PTH-1 receptors by high fat diet after myocardial infarction suggests that the identified interaction may participate in the obesity paradox.

Role of Sphingolipids in the Pathobiology of Lung Inflammation.

Sphingolipid bioactivities in the respiratory airways and the roles of the proteins that handle them have been extensively investigated. Gas or inhaled particles or microorganisms come into contact with mucus components, epithelial cells, blood barrier, and immune surveillance within the airways. Lung structure and functionality rely on a complex interplay of polar and hydrophobic structures forming the surfactant layer and governing external-internal exchanges, such as glycerol-phospholipids sphingolipids and proteins. Sphingolipids act as important signaling mediators involved in the control of cell survival and stress response, as well as secreted molecules endowed with inflammation-regulatory activities. Most successful respiratory infection and injuries evolve in the alveolar compartment, the critical lung functional unit involved in gas exchange. Sphingolipid altered metabolism in this compartment is closely related to inflammatory reaction and ceramide increase, in particular, favors the switch to pathological hyperinflammation. This short review explores a few mechanisms underlying sphingolipid involvement in the healthy lung (surfactant production and endothelial barrier maintenance) and in a selection of lung pathologies in which the impact of sphingolipid synthesis and metabolism is most apparent, such as acute lung injury, or chronic pathologies such as cystic fibrosis and chronic obstructive pulmonary disease.

What We Talk About When We Talk About Evolution

Currently, the biologic sciences are a Tower of Babel, having become so highly specialized that one discipline cannot effectively communicate with another. A mechanism for evolution that integrates development and physiologic homeostasis phylogenetically has been identified—cell-cell interactions. By reducing this process to ligand-receptor interactions and their intermediate down-stream signaling partners, it is possible, for example, to envision the functional homologies between such seemingly disparate structures and functions as the lung alveolus and kidney glomerulus, the skin and brain, or the skin and lung. For example, by showing the continuum of the lung phenotype for gas exchange at the cell-molecular level, being selected for increased surface area by augmenting lung surfactant production and function in lowering surface tension, we have determined an unprecedented structural-functional continuum from proximate to ultimate causation in evolution. It is maintained that tracing the changes in structure and function that have occurred over both the short-term history of the organism (as ontogeny), and the long-term history of the organism (as phylogeny), and how the mechanisms shared in common can account for both biologic stability and novelty, will provide the key to understanding the mechanisms of evolution. We need to better understand evolution from its unicellular origins as the Big Bang of biology.

Extreme caution is needed before scale-up of antenatal corticosteroids to reduce preterm deaths in low-income settings.

Extreme caution is needed before scale-up of antenatal corticosteroids to reduce preterm deaths in low-income settings.

Structure, function and deficiency diseases of lung surfactant protein-c

Pulmonary surfactant is a mixture of lipids and hydrophobic surfactant proteins B (SP-B) and SP-C and hydrophilic proteins SP-A and SP-D. Pulmonary surfactant reduces the surface tension at the air-water interface of the lung alveoli by forming a surface active film. In this way, it prevents alveoli from collapsing and facilitates the process of breathing. SP-C cooperates with SP-B to enhance the surface active properties of surfactant phospholipids. Reports on the association of lung disease with SP-C deficiency have led to new insights into the importance of SP-C for proper surfactant homeostasis. In most animal species the major form of SP-C is a 35-residue peptide chain which contains two thioester-linked palmitoyl groups, giving a total molecular mass of 4.2 kDa. Though t he function of SP-C in vivo remains unclear, but effects of SP-C on the adsorption, spreading, and stability of lipid films at an air ⁄ water interface have been documented in a number of in vitro studies. Genetic disorders disrupting normal surfactant metabolism (surfactant dysfunction disorders) have been recognized in the neonatal and pediatric populations. Although rare, these disorders cause significant mortality and morbidity, including acute respiratory distress and failure in full-term neonates, and interstitial lung disease (ILD) in older infants, children, and adults. The genes involved in these disorders are critical for surfactant production and function in the lung and include SP-C gene ( SFTPC ) besides others . More than 40 mutations in the SFTPC gene have been identified in people with dysfunction of lung surfactant. Mutations in the SFTPC gene result in the reduction or absence of mature SP-C and accumulation of abnormal forms of SP-C, resulting into breathing problems in newborns and onset of breathing difficulties in children and adults. SFTPC gene mutations associated with surfactant dysfunction affect the processing of the SP-C protein. Many of these mutations occur in a region of gene called the BRICHOS domain, which appears to be involved in the processing of SP-C protein. It is not known which of these outcomes causes the symptoms of SP-C dysfunction. Recent reports suggest that abnormally processed SP-C proteins form altered three-dimensional shape and accumulate inside lung cells. These misfolded proteins may trigger a cellular response that results in cell damage and death. Mutations in BRICHOS domain of SP-C have been associated to ER stress, proteasome dysfunction, and apoptosis. This article reviews information on structure and function of SP-C and the associated mutations in SFTPC gene in relation to SP-C deficiency diseases.

Delineating residential macrophage heterogeneity in lung disease (P3282)

Abstract In healthy lungs, alveolar macrophages comprise &amp;gt;95% of the immune cells in the alveolar airspaces where they regulate local lung surfactant production and act as the primary sentinels of respiratory pathogens. Interestingly, increased AMΦ numbers are observed in many animal models of chronic lung diseases and also clinically in patients with COPD. Combining flow cytometry and chimeric mice studies, we observed that residential AMΦs form two distinct subpopulations (by either remaining Mac-1neg/low or turning Mac-1pos) during acute inflammation and in chronic inflammatory lung disease subsequent to SHIP-1 deletion. SHIP-1-/- mice which spontaneously develop COPD-like lung disease maintain both Mac-1neg/low and Mac-1pos AMΦ subpopulations. This additional Mac-1pos subpopulation highly expresses MMP-12 and tracks with the induction of lung disease using SHIP-1-/- chimeric mice. Altogether, our results suggest that residential AMΦ heterogeneity is a component of acute lung inflammation and chronic inflammatory lung disease. Consequently, whether residential AMΦ heterogeneity may be a novel hallmark of inflammation-driven human lung diseases has been our final area of study. Overall, our studies of both animal models and patient samples may allow us to better understand the role of AMΦ heterogeneity in lung homeostasis and disease.

Assisting instrumental delivery for breech babies at the limits of viability

As caesarean sections became safer, it was assumed that surgery would improve survival for babies at the limits of viability, however, evidence indicates that this is not the case for otherwise uncomplicated pregnancies. Therefore, taking into account risks for mother and baby associated with surgery and extreme prematurity, there is a general consensus that even if the baby is breech, a vaginal delivery is preferable. I attended such a delivery of a breech preterm at 24 ? 4 weeks gestation. The head could not be delivered for 10 min despite attempts to engage Neville Barnes forceps. Such forceps were never designed for the dimensions of the preterm at the limits of viability, and so I discuss new forceps for specifically this situation. Neonatal survival is inversely proportional to gestational age, and in the range of \5, 30, 50, and 70 % for 22, 23, 24, and 25 weeks, respectively [1]. Failure to sufficiently clear lung fluid in caesarean section exacerbates lung immaturity and surfactant production insufficiency, which already results in respiratory distress syndrome in 86–100 % of 23–25 week neonates [2]. Prolonged exposure to mechanical ventilation increases risk of chronic lung disease, which affects 16–89 % of 23–25 week neonates [3]. Necrotising enterocolitis occurs in *9 % of these neonates and can result in the need for surgery, with 10–40 % mortality [4]. The most feared complication is neurological morbidity, and very low birthweight infants have a 15 % incidence of grade III–IV intraventricular haemorrhage and 6 % incidence for periventricular leukomalacia [5]. Under 25 weeks gestation, 25 % are diagnosed with cerebral palsy [6]. 62, 38, and 31 % of 23, 24, and 25 week neonates, respectively, will develop some form of neurological impairment [7]. For the mother, risk of placenta praevia increases from 0.26 % with an unscarred uterus to 10 % after four or more sections [8]. Risk of placenta accrete (mortality of 7 %) rises from 5 % in cases of placenta praevia with an unscarred uterus to 24 %, if there is placenta praevia with one previous section, and to 67 % with two to three previous sections. Furthermore, the diameter of the uterine lower segment is 0.5, 1.0, and 4.0 cm at 20, 28, and 34 weeks, respectively [9], so in the majority of cases, to safely deliver the extremely premature baby requires a classical caesarean section (vertical incision) associated with 12 % rate of uterine rupture even in the absence of subsequent labour [10]. Therefore, to deliver by caesarean section at these gestations puts the mother’s life at risk and impacts future pregnancies for the theoretical benefit of increasing neonatal survival, but is there any evidence supporting this? Grant et al. [11] performed a meta-analysis of six RCTs comparing mode of delivery for babies from 24 to 36 weeks gestation, and found a significant increase in maternal morbidity, but no significant decrease in neonatal morbidity following surgery; a conclusion supported by observational studies [12, 13]. The general consensus is that caesarean section is not indicated for uncomplicated pregnancies at the limits of viability. For breech vaginal deliveries at this gestation, there is risk of cord prolapse and cervical entrapment of the foetal head [14, 15]. Some studies have reported better mortality figures with caesarean section [16, 17], although others have not [18]. But even if surgery increases immediate survival, this does not change the general maternal and A. Q. T. Ismail (&) Walsall Manor Hospital, Moat Road, Walsall, West Midlands WS2 9PS, UK e-mail: aqt.ismail@bnc.oxon.org

Neonatology Specialty Grand Challenge

Neonatology Specialty Grand Challenge

Prostaglandins mediate the fetal pulmonary response to intrauterine inflammation

Intra-amniotic (IA) lipopolysaccharide (LPS) induces intrauterine and fetal lung inflammation and increases lung surfactant and compliance in preterm sheep; however, the mechanisms are unknown. Prostaglandins (PGs) are inflammatory mediators, and PGE(2) has established roles in fetal lung surfactant production. The aim of our first study was to determine PGE(2) concentrations in response to IA LPS and pulmonary gene expression for PG synthetic [prostaglandin H synthase-2 (PGHS-2) and PGE synthase (PGES)] and PG-metabolizing [prostaglandin dehydrogenase (PGDH)] enzymes and PGE(2) receptors. Our second study aimed to block LPS-induced increases in PGE(2) with a PGHS-2 inhibitor (nimesulide) and determine lung inflammation and surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid PGE(2) concentrations increased (P < 0.05) 12 h and 3-6 days after LPS. Fetal lung PGHS-2 mRNA and PGES mRNA increased 2 (P = 0.0084) and 7 (P = 0.014) days after LPS, respectively. In study 2, maternal intravenous nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later. Nimesulide inhibited LPS-induced increases in PGE(2) and decreased fetal lung IL-1β and IL-8 mRNA (P ≤ 0.002) without altering lung inflammatory cell infiltration. Nimesulide decreased surfactant protein (SP)-A (P = 0.05), -B (P = 0.05), and -D (P = 0.0015) but increased SP-C mRNA (P = 0.023). Thus PGHS-2 mediates, at least in part, fetal pulmonary responses to inflammation.

Human Lysophosphatidylcholine Acyltransferases 1 and 2 Are Located in Lipid Droplets Where They Catalyze the Formation of Phosphatidylcholine

Phosphatidylcholine (PC) is synthesized by two different pathways, the Lands cycle and the Kennedy pathway. The recently identified key enzymes of the Lands cycle, lysophosphatidylcholine acyltransferase 1 and 2 (LPCAT1 and -2), were reported to localize to the endoplasmic reticulum and to function in lung surfactant production and in inflammation response. Here, we show in various mammalian cell lines that both enzymes additionally localize to lipid droplets (LDs), which consist of a core of neutral lipids surrounded by a monolayer of phospholipid, mainly PC. This dual localization is enabled by the monotopic topology of these enzymes demonstrated in this study. Furthermore, we show that LDs have the ability to locally synthesize PC and that this activity correlates with the LPCAT1 and -2 expression level. This suggests that LPCAT1 and -2 have, in addition to their known function in specialized cells, a ubiquitous role in LD-associated lipid metabolism.