Surfactant Pool Size Research Articles

Maternal protein restriction during perinatal life affects lung mechanics and the surfactant system during early postnatal life in female rats.

Limited information is available on how fetal growth retardation (FGR) affects the lung in the neonatal period in males and females. This led us to test the hypothesis that FGR alters lung mechanics and the surfactant system during the neonatal period. To test this hypothesis a model of FGR was utilized in which pregnant rat dams were fed a low protein diet during both the gestation and lactation period. We subsequently analyzed lung mechanics using a FlexiVent ventilator in male and female pups at postnatal day 7 and 21. Lung lavage material was obtained at postnatal day 1, 7 and 21, and was used for analysis of the surfactant system which included measurement of the pool size of surfactant and its subfraction as well as the surface tension reducing ability of the surfactant. The main result of the study was a significantly lower lung compliance and higher tissue elastance which was observed in FGR female offspring at day 21 compared to control offspring. In addition, female LP offspring exhibited lower surfactant pool sizes at postnatal day 1compared to controls. These changes were not observed in the male offspring. It is concluded that FGR has a different impact on pulmonary function and on surfactant in female, as compared to male, offspring.

The effects of aging and exercise on lung mechanics, surfactant and alveolar macrophages

IntroductionIt has been well established that advancing age leads to changes to the respiratory system and an associated susceptibility to lung diseases. Furthermore, exercise may counteract this pulmonary disease susceptibility. To start to investigate the underlying processes of these effects we explored the baseline characteristics due to aging and exercise on lung mechanics and on two important components of a healthy pulmonary environment, alveolar macrophage function and the pulmonary surfactant system. It was hypothesized that aging would impact lung mechanics, macrophage polarization and the status of the surfactant system, and that these changes would be mitigated by exercise.Experimental approach: Male C57BL/6 mice were housed from 2–3 to 22 months, for the aged group, or until 4 months of age for young control mice. Mice in both the young and aged groups were randomized to either voluntarily running exercise or non‐exercise for a 2 month period. Mice were euthanized and lung mechanics were analyzed using a Flexivent ventilator. Subsequently, the lungs were lavaged to obtain pulmonary surfactant and alveolar macrophages. Pulmonary surfactant was analyzed for surfactant pool sizes and activity whereas alveolar macrophages were examined for a response to pro‐and anti‐inflammatory stimuli.ResultsChanges in lung mechanics, such as increased compliance and decreased airway resistance, were observed in the aged cohorts. These changes were not affected by exercise.The quantity as well as the biophysical activity of the pulmonary surfactant system was unaffected by either aging or exercise. More alveolar macrophages were recovered from exercising aged mice as compared to both the young and non‐exercising groups.Support or Funding InformationWestern Strategic Support, Lawson Internal Research FundsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Surfactants in Acute Respiratory Distress Syndrome in Infants and Children: Past, Present and Future.

There is a lack of definitive data on the effective management of acute respiratory distress syndrome (ARDS) in infants and children. The development and validation of the Berlin definition (BD) for ARDS and the Pediatric Acute Lung Injury Consensus Conference (PALICC) recommendations in children represented a major advance in optimizing research and treatment, mainly due to the introduction of a severe ARDS category. Proposed reasons for the lack of consistent results with surfactants in children and infants compared with neonates include different causes, type of lung damage (direct or indirect), timing and mode of administration as well as the type of surfactant used. Secretory phospholipase A2 plays an important role in inflammation and possible dysfunction of surfactants in ARDS. Bronchoalveolar lavage (BAL) with normal saline and surfactant allows the removal of inhaled material, the recruitment of non-ventilating areas and the maintenance of the surfactant pool size. BAL with diluted surfactant allows rapid absorption of the surfactant at the air/liquid interface, which blocks the progression of pathological lung disease and in turn disrupts the inflammatory cycle. Importantly, it is now recognized that the type of surfactant, the time of administration and the method of administration could all play an important role in the management of ARDS, and there is evidence that surfactant is effective and well tolerated in children and infants with ARDS.

Neonatal Respiratory Diseases in the Newborn Infant: Novel Insights from Stable Isotope Tracer Studies

Respiratory distress syndrome is a common problem in preterm infants and the etiology is multifactorial. Lung underdevelopment, lung hypoplasia, abnormal lung water metabolism, inflammation, and pulmonary surfactant deficiency or disfunction play a variable role in the pathogenesis of respiratory distress syndrome. High-quality exogenous surfactant replacement studies and studies on surfactant metabolism are available; however, the contribution of surfactant deficiency, alteration or dysfunction in selected neonatal lung conditions is not fully understood. In this article, we describe a series of studies made by applying stable isotope tracers to the study of surfactant metabolism and lung water. In a first set of studies, which we call ‘endogenous studies', using stable isotope-labelled intravenous surfactant precursors, we showed the feasibility of measuring surfactant synthesis and kinetics in infants using several metabolic precursors including plasma glucose, plasma fatty acids and body water. In a second set of studies, named ‘exogenous studies', using stable isotope-labelled phosphatidylcholine tracer given endotracheally, we could estimate surfactant disaturated phosphatidylcholine pool size and half-life. Very recent studies are focusing on lung water and on the endogenous biosynthesis of the surfactant-specific proteins. Information obtained from these studies in infants will help to better tailor exogenous surfactant treatment in neonatal lung diseases.

Nebulization of Poractant alfa via a vibrating membrane nebulizer in spontaneously breathing preterm lambs with binasal continuous positive pressure ventilation.

Surfactant replacement therapy is the gold standard treatment of neonatal respiratory distress (RDS). Nebulization is a noninvasive mode of surfactant administration. We administered Poractant alfa (Curosurf) via a vibrating perforated membrane nebulizer (eFlow Neonatal Nebulizer) to spontaneously breathing preterm lambs during binasal continuous positive pressure ventilation (CPAP). Sixteen preterm lambs were operatively delivered at a gestational age of 133 ± 1 d (term ~150 d), and connected to CPAP applied via customized nasal prongs. Nebulization was performed (i) with saline or (ii) with surfactant for 3 h in humidified or (iii) nonhumidified air, and with surfactant (iv) for 60 min or (v) for 30 min. We measured arterial oxygenation, lung gas volumes and surfactant pool size and deposition. Nebulization of surfactant in humidified air for 3 h improved oxygenation and lung function, and surfactant was preferentially distributed to the lower lung lobes. Shorter nebulization times and 3 h nebulization in dry air did not show these effects. Nebulized surfactant reached all lung lobes, however the increase of surfactant pool size missed statistical significance. Positive effects of surfactant nebulization to spontaneously breathing preterm lambs depend on treatment duration, surfactant dose, air humidity, and surfactant distribution within the lung.

Orphan G Protein–Coupled Receptor GPR116 Regulates Pulmonary Surfactant Pool Size

Pulmonary surfactant levels within the alveoli are tightly regulated to maintain lung volumes and promote efficient gas exchange across the air/blood barrier. Quantitative and qualitative abnormalities in surfactant are associated with severe lung diseases in children and adults. Although the cellular and molecular mechanisms that control surfactant metabolism have been studied intensively, the critical molecular pathways that sense and regulate endogenous surfactant levels within the alveolus have not been identified and constitute a fundamental knowledge gap in the field. In this study, we demonstrate that expression of an orphan G protein-coupled receptor, GPR116, in the murine lung is developmentally regulated, reaching maximal levels 1 day after birth, and is highly expressed on the apical surface of alveolar type I and type II epithelial cells. To define the physiological role of GPR116 in vivo, mice with a targeted mutation of the Gpr116 locus, Gpr116(Δexon17), were generated. Gpr116(Δexon17) mice developed a profound accumulation of alveolar surfactant phospholipids at 4 weeks of age (12-fold) that was further increased at 20 weeks of age (30-fold). Surfactant accumulation in Gpr116(Δexon17) mice was associated with increased saturated phosphatidylcholine synthesis at 4 weeks and the presence of enlarged, lipid-laden macrophages, neutrophilia, and alveolar destruction at 20 weeks. mRNA microarray analyses indicated that P2RY2, a purinergic receptor known to mediate surfactant secretion, was induced in Gpr116(Δexon17) type II cells. Collectively, these data support the concept that GPR116 functions as a molecular sensor of alveolar surfactant lipid pool sizes by regulating surfactant secretion.

Leptin does not influence surfactant synthesis in fetal sheep and mice lungs

In the fetus, leptin in the circulation increases at late gestation and likely influences fetal organ development. Increased surfactant by leptin was previously demonstrated in vitro using fetal lung explant. We hypothesized that leptin treatment given to fetal sheep and pregnant mice might increase surfactant synthesis in the fetal lung in vivo. At 122-124 days gestational age (term: 150 days), fetal sheep were injected with 5 mg of leptin or vehicle using ultrasound guidance. Three and a half days after injection, preterm lambs were delivered, and lung function was studied during 30-min ventilation, followed by pulmonary surfactant components analyses. Pregnant A/J mice were given 30 or 300 mg of leptin or vehicle by intraperitoneal injection according to five study protocols with different doses, number of treatments, and gestational ages to treat. Surfactant components were analyzed in fetal lung 24 h after the last maternal treatment. Leptin injection given to fetal sheep increased fetal body weight. Control and leptin-treated groups were similar in lung function (preterm newborn lamb), surfactant components pool sizes (lamb and fetal mice), and expression of genes related to surfactant synthesis in the lung (fetal mice). Likewise, saturated phosphatidylcholine and phospholipid were normal in mice lungs with absence of circulating leptin (ob/ob mice) at all ages. These studies coincided in findings that neither exogenously given leptin nor deficiency of leptin influenced fetal lung maturation or surfactant pool sizes in vivo. Furthermore, the key genes critically required for surfactant synthesis were not affected by leptin treatment.

Pharmacokinetics and clinical predictors of surfactant redosing in respiratory distress syndrome

Limited data are available on predictors for surfactant retreatment in preterm infants with respiratory distress syndrome (RDS). To study the pharmacokinetics of exogenous surfactant and the clinical parameters associated with surfactant redosing. Exogenous surfactant pharmacokinetics was studied in 125 preterm infants (birth weight 997 ± 432 g; gestational age 28.0 ± 2.6 weeks) with moderate to severe RDS requiring mechanical ventilation. Clinical and respiratory parameters were recorded hourly, and surfactant disaturated-phosphatidylcholine (DSPC) half-life, pool size, and endogenous synthesis were calculated by stable isotope tracing of surfactant DSPC isolated from serial tracheal aspirates. Univariate and multiple logistic regression were used to study the effects of clinical and surfactant kinetic variables on the need for redosing. Fifty-three infants (42.4%) received one dose, 51 (40.8%) two doses, and 21 (16.8%) three doses. Median (interquartile range, IQR) DSPC half-life was 21 (13-39), 11 (7-17), and 10 (7-16) h after the first, second, and third dose, respectively (p = 0.07). Univariate analysis showed a significantly shorter DSPC half-life in infants requiring more surfactant doses. On logistic analysis, risk of redosing was higher with lower birth weight, worse radiological score, shorter DSPC half-life, and surfactant dose of 100 mg/kg, whilst it was lower with elective high-frequency ventilation at time of intubation, instead of conventional ventilation. When optimizing surfactant replacement therapy and its cost-benefit ratio, pharmacokinetics and clinical variables associated with need of redosing should be taken into account.

Inhibitors of inflammation and endogenous surfactant pool size as modulators of lung injury with initiation of ventilation in preterm sheep

BackgroundIncreased 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.ObjectiveWe tested the hypothesis that selective inhibitors of pro-inflammatory signaling would decrease lung inflammation induced by ventilation in preterm newborn lambs. We also examined if the variability in injury response was explained by variations in the endogenous surfactant pool size.MethodsDate-mated preterm lambs (n = 28) were operatively delivered and mechanically ventilated to cause lung injury (tidal volume escalation to 15 mL/kg by 15 min at age). The lambs then were ventilated with 8 mL/kg tidal volume for 1 h 45 min. Groups of animals randomly received specific inhibitors for IL-8, IL-1, or NF-κB. Unventilated lambs (n = 7) were the controls. Bronchoalveolar lavage fluid (BALF) and lung samples were used to quantify inflammation. Saturated phosphatidylcholine (Sat PC) was measured in BALF fluid and the data were stratified based on a level of 5 μmol/kg (~8 mg/kg surfactant).ResultsThe inhibitors did not decrease the cytokine levels or inflammatory response. The inflammation increased as Sat PC pool size in BALF decreased. Ventilated lambs with a Sat PC level > 5 μmol/kg had significantly decreased markers of injury and lung inflammation compared with those lambs with < 5 μmol/kg.ConclusionLung injury caused by high tidal volumes at birth were decreased when endogenous surfactant pool sizes were larger. Attempts to decrease inflammation by blocking IL-8, IL-1 or NF-κB were unsuccessful.

Allometry of the mammalian intracellular pulmonary surfactant system

Alveolar epithelial (AE) surface area is closely correlated with body mass (BM) in mammals. The AE is covered by a surfactant layer produced by alveolar epithelial type II (AE2) cells. We hypothesized that the total number of AE2 cells and the volume of intracellular surfactant-storing lamellar bodies (Lb) are correlated with BM with a similar slope as AE surface area. We used light and electron microscopic stereology to estimate the number and mean volume of AE2 cells and the total volume of Lb in 12 mammalian species ranging from 2 to 3 g (Etruscan shrew) to 400-500 kg (horse) BM. The mean size of Lb was evaluated using the volume-weighted mean volume and the volume-to-surface ratio of Lb. The mean volume of AE2 cells was 500-600 μm(3) in most species, but was higher in Etruscan shrew, guinea pig, and human lung. The mean volume of Lb per AE2 cell was 80-100 μm(3) in most species, with the same exceptions as above. However, the total number of AE2 cells and the total volume of Lb were closely correlated with BM and exhibited an allometric relationship similar to the slope of AE surface area. The mean size of Lb was similar in all investigated species. In conclusion, the mean volume of AE2 cells and their Lb are independent of BM but show some interspecific variations. The adaptation of the intracellular surfactant pool size to BM is obtained by the variation of the number of AE2 cells in the lung.

Surfactant protein-D regulates the postnatal maturation of pulmonary surfactant lipid pool sizes

Surfactant protein (SP)-D plays an important role in host defense and pulmonary surfactant homeostasis. In SP-D-deficient (Sftpd(-/-)) mice, the abnormal large surfactant forms seen at the ultrastructural level are taken up inefficiently by type II cells, resulting in an over threefold increase in the surfactant pool size. The mechanisms by which SP-D influences surfactant ultrastructure are unknown. We hypothesized that SP-D binds to surfactant immediately after being secreted and influences surfactant ultrastructure conversion. In newborn and adult sheep lungs, immunogold-labeled SP-D was associated with both lamellated membranous lipid structures of newly secreted surfactant and with small aggregate surfactant but not with tubular myelin. Since SP-D preferentially binds to phosphatidylinositol (PI) in vitro, the postnatal changes in PI were assessed. PI content in the bronchoalveolar lavage fluid increased after birth and peaked at 2-5 days of age, a time of rapid conversion of surfactant forms that is associated with the peak of surfactant lipid pool size. SP-D selectively interacted with PI-rich liposomes in vitro, causing their lysis. Similarly, the abnormal surfactant ultrastructure in Sftpd(-/-) mice was corrected by the addition of SP-D or melittin, and both peptides caused lysis of lipid vesicles. The normal conversion of surfactant ultrastructure requires SP-D that preferentially interacts with PI-rich, newly secreted surfactant, causing lysis of surfactant lipid membranes, converting the lipid forms into smaller surfactant lamellated structures that are critical for surfactant uptake by type II cells and normal surfactant homeostasis. SP-D regulates the dramatic decreases in the surfactant pool size that occurs in the newborn period.

Long-term exposure to LPS enhances the rate of stimulated exocytosis and surfactant secretion in alveolar type II cells and upregulates P2Y2receptor expression

Bacterial LPS is a potent proinflammatory molecule. In the lungs, LPS induces alterations in surfactant pool sizes and phospholipid (PL) contents, although direct actions of LPS on the alveolar type II cells (AT II) are not yet clear. For this reason, we studied short- and long-term effects of LPS on basal and agonist-stimulated secretory responses of rat AT II by using Ca(2+) microfluorimetry, a microtiter plate-based exocytosis assay, by quantitating PL and (3)H-labeled choline released into cell supernatants and by using quantitative PCR and Western blot analysis. Long term, but not short term, exposures to LPS led to prolonged ATP-induced Ca(2+) signals and an increased rate in vesicle fusions with an augmented release of surfactant PL. Most notably, the stimulatory effect of LPS was ATP-dependent and may be mediated by the upregulation of the purinergic receptor subtype P2Y(2). Western blot analysis confirmed higher levels of P2Y(2), and suramin, a P2Y receptor antagonist, was more effective in LPS-treated cells. From these observations, we conclude that LPS, probably via Toll-like receptor-4, induces a time-dependent increase in P2Y(2) receptors, which, by yet unknown mechanisms, leads to prolonged agonist-induced Ca(2+) responses that trigger a higher activity in vesicle fusion and secretion. We further conclude that chronic exposure to endotoxin sensitizes AT II to increase the extracellular surfactant pool, which aids in the pulmonary host defense mechanisms.

Surfactant Status in Preterm Neonates Recovering From Respiratory Distress Syndrome

The goal was to establish whether reduced amounts of pulmonary surfactant contribute to postextubation respiratory failure in preterm infants recovering from respiratory distress syndrome. We prospectively recruited preterm infants who needed mechanical ventilation and exogenous surfactant for treatment of moderate/severe respiratory distress syndrome and could not be extubated before day 3 of life. (13)C-labeled dipalmitoyl-phosphatidylcholine was administered endotracheally as tracer before extubation, for estimation of surfactant disaturated phosphatidylcholine pool size and half-life. Patients were retrospectively divided into 3 groups, that is, extubation failure if, after extubation, they needed reintubation or continuous positive airway pressure treatment of >or=6 cmH(2)O and fraction of inspired oxygen of >0.4, extubation success if they did not meet the failure criteria, and not extubated if they needed ongoing ventilation. Clinical and respiratory parameters were recorded hourly. Reliable kinetic data could be obtained for 63 of the 88 enrolled neonates. Sixteen, 23, and 24 neonates were categorized in the extubation failure, extubation success, and not extubated groups, respectively. Clinical and demographic characteristics did not differ between the extubation failure and extubation success groups. Disaturated phosphatidylcholine pool size was smaller in the extubation failure group than in the extubation success group (25 +/- 12 vs 43 +/- 24 mg/kg) and was 37 +/- 32 mg/kg in the not extubated group. Disaturated phosphatidylcholine half-life was 19 +/- 7, 24 +/- 12, and 28 +/- 18 hours in the extubation failure, extubation success, and not extubated groups, respectively. In a selected population of preterm infants with moderate/severe respiratory distress syndrome who could not be extubated in the first 3 days of life, infants who were reintubated or needed high continuous positive airway pressure settings after extubation had a smaller disaturated phosphatidylcholine pool size than did those who were successfully extubated or needed low continuous positive airway pressure settings.

Alterations to surfactant precede physiological deterioration during high tidal volume ventilation

Lung injury due to mechanical ventilation is associated with an impairment of endogenous surfactant. It is unknown whether this impairment is a consequence of or an active contributor to the development and progression of lung injury. To investigate this issue, the present study addressed three questions: Do alterations to surfactant precede physiological lung dysfunction during mechanical ventilation? Which components are responsible for surfactant's biophysical dysfunction? Does exogenous surfactant supplementation offer a physiological benefit in ventilation-induced lung injury? Adult rats were exposed to either a low-stretch [tidal volume (Vt) = 8 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O, respiratory rate (RR) = 54-56 breaths/min (bpm), fractional inspired oxygen (Fi(O2)) = 1.0] or high-stretch (Vt = 30 ml/kg, PEEP = 0 cmH2O, RR = 14-16 bpm, Fi(O2) = 1.0) ventilation strategy and monitored for either 1 or 2 h. Subsequently, animals were lavaged and the composition and function of surfactant was analyzed. Separate groups of animals received exogenous surfactant after 1 h of high-stretch ventilation and were monitored for an additional 2 h. High stretch induced a significant decrease in blood oxygenation after 2 h of ventilation. Alterations in surfactant pool sizes and activity were observed at 1 h of high-stretch ventilation and progressed over time. The functional impairment of surfactant appeared to be caused by alterations to the hydrophobic components of surfactant. Exogenous surfactant treatment after a period of high-stretch ventilation mitigated subsequent physiological lung dysfunction. Together, these results suggest that alterations of surfactant are a consequence of the ventilation strategy that impair the biophysical activity of this material and thereby contribute directly to lung dysfunction over time.

Maternal Betamethasone and Chorioamnionitis Induce Different Collagenases during Lung Maturation in Fetal Sheep

Background: Fetal lung maturation occurs after both maternal corticosteroid administration and chorioamnionitis. 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. Objectives: We hypothesized that the structural changes of lung maturation by both antenatal corticosteroid treatment and chorioamnionitis would be associated with increases in these MMPs. Methods: 64 pregnant ewes were randomly assigned to one of four treatment groups: intra-amniotic injection of 10 mg endotoxin, maternal intramuscular injection of 0.5 mg/kg betamethasone, both treatments combined or saline-treated controls. We quantified MMP-2 which is derived from connective tissue and MMP-9 which is predominantly derived from neutrophils in fetal lung fluid of lambs after maternal corticosteroid therapy and induction of chorioamnionitis and the combination of both therapies given at 109–111 days’ gestational age with delivery 1, 5 or 15 days later. Results: Betamethasone, endotoxin and the combined treatments increased both surfactant pool size, lung gas volume and reduced alveolar wall thickness at 15 days. MMP-2 concentration was increased after betamethasone. MMP-9 concentration increased after endotoxin-induced chorioamnionitis but decreased by the combined treatments. Conclusion: Lung maturation via different pathways may use different forms of collagenases for remodelling lung structure.

Alveolar macrophage depletion is associated with increased surfactant pool sizes in adult rats

Pulmonary surfactant is a lipid-protein material that is essential for normal lung function. Maintaining normal and consistent alveolar amounts of surfactant is in part dependent on clearance of surfactant by alveolar macrophages (AM). The present study utilized a rat model of AM depletion to determine the impact on surfactant pool sizes and function over time. Male Sprague-Dawley rats were anesthetized and intratracheally instilled with PBS-liposomes (PBS-L) or dichloromethylene diphosphonic acid (DMDP) containing liposomes (DMDP-L) and were killed at various time points up to 21 days for compliance measurements, AM cell counts, and surfactant analysis. AM numbers were significantly decreased 1, 2, and 3 days after instillation in DMDP-L vs. PBS-L, with 72% depletion at 3 days. AM numbers returned to normal levels by 5 days. In DMDP-L rats, there was a rapid increase in surfactant-phospholipid pools, showing a ninefold increase in the amount of surfactant in the lavage 3 days after liposome instillation. Surfactant accumulation progressed up to 7 days, with pools normalizing by 21 days. The increase in surfactant was due to increases in both subfractions of surfactant, the large aggregates (LA) and small aggregates. Surfactant protein A levels, relative to LA phospholipids, were not increased. There was a decreased extent of surfactant conversion in vitro for LA from DMDP-L rats compared with controls. It is concluded that the procedure of AM depletion significantly affects surfactant metabolism. The increased endogenous surfactant must be considered when utilizing the AM depletion model to study the role of these cells during lung insults.

High-dose vascular endothelial growth factor increases surfactant protein gene expressions in preterm rat lung

Aims To investigate the effects of intra-amniotic vascular endothelial growth factor (VEGF) treatment on surfactant pool sizes and surfactant protein (SP) gene expressions in fetal rat lung. Method On the 18th day of gestation, an abdominal midline incision was performed on timed pregnant Sprague–Dawley rats and the two uterine horns were exposed. VEGF (2.5 μg or 5.0 μg) and saline were injected into the amniotic cavity of the left and right uterine horns, respectively. On the 19th day of gestation, fetuses were delivered by caesarean section. Results We analyzed the data between the fetuses within the same dam in each group. Mean fetal body weight and lung tissue saturated phosphatidylcholine and total phospholipids were comparable between control and VEGF-treated rats at each VEGF dosage. Lung SP mRNA expressions were comparable between control and VEGF 2.5 μg-treated rats. VEGF 5.0 μg treatment increased lung SP mRNA expressions and the values were statistically significant for SP-B and SP-D mRNAs when compared with the control rats. Conclusions These results suggest that VEGF might have potential therapeutic implications in enhancing fetal lung maturation.

Genetic basis of respiratory distress syndrome

Respiratory distress syndrome (RDS) is a multifactorial developmental disease caused by lung immaturity and presenting as high-permeability lung edema ("hyaline membrane disease"). It is characterized by a transient deficiency of alveolar surfactant during the first week of life. During the first few days of life, the alveolar surfactant pool size increases up to that in the controls. The allelic variants of the genes encoding the surfactant proteins (SP) SP-A1, SP-A2, SP-B, and SP-C have been associated with RDS. The main SP-A haplotype, interactively with the SP-B Ile131Thr polymorphism and with constitutional and environmental factors, influence the risk. Case reports on mutations with partially functional SP-B have been published. The genetic susceptibility factors depend on the degree of prematurity at birth, consistent with sequential differentiation of the lung and gestation-dependent differences in clinical presentation. The preferentially type 2 cell expressed genes involved in critical functions (such as ATP-binding cassette transporter, ABCA3), those involved in susceptibility to acute lung damage, and those with known susceptibility to other severe lung diseases (such as G protein-coupled receptor for asthma susceptibility, GPR154 alias GPRA) will possibly serve as candidate genes in future studies. RDS associated with near-term and term births may have a different genetic predisposition and pathogenesis compared to RDS after very preterm birth. As we learn more about the molecular consequences of allelic variation, new therapies based on a new generation of surfactant diagnostics and individualized therapies may follow.

Surfactant Protein D Levels in Umbilical Cord Blood and Capillary Blood of Premature Infants. The Influence of Perinatal Factors

Surfactant protein D (SP-D) is a collectin that plays an important role in the innate immune system and takes part in the surfactant homeostasis by regulating the surfactant pool size. The aims of this study were to investigate the values of SP-D in umbilical cord blood and capillary blood of premature infants and to relate the levels to perinatal conditions. A total of 254 premature infants were enrolled in the present study. Umbilical cord blood was drawn at the time of birth and capillary blood at regular intervals throughout the admission. The concentration of SP-D in umbilical cord blood and capillary blood was measured using ELISA technique. The median concentration of SP-D in umbilical cord blood was twice as high as in mature infants, 769 ng/mL (range 140-2,551), with lowest values in infants with intrauterine growth retardation (IUGR) and rupture of membranes (ROM). The median concentration of SP-D in capillary blood day 1 was 1,466 ng/mL (range 410-5,051 ng/mL), with lowest values in infants born with ROM and delivered vaginally. High SP-D levels in umbilical cord blood and capillary blood on day 1 were found to be more likely in infants in need for respiratory support or surfactant treatment and susceptibility to infections. We conclude that SP-D concentrations in umbilical cord blood and capillary blood in premature infants are twice as high as in mature infants and depend on several perinatal conditions. High SP-D levels in umbilical cord blood and capillary blood on day 1 were found to be related to increased risk of RDS and infections.

Pharmacology Review

After completing this article, readers should be able to: 1. Explain the sources of immediate and delayed treatment responses to surfactant. 2. List the factors that affect surfactant distribution in the preterm lung. 3. List the mechanisms that can inhibit surfactant function. 4. Explain why antenatal corticosteroids and surfactant improve lung function and outcomes of preterm infants. Surfactant treatments have been the standard of care for infants who have respiratory distress syndrome (RDS) ever since the United States Food and Drug Administration approved its use in 1990. The development of surfactant is one of the great success stories in neonatal care because the therapy specifically treats the surfactant deficiency and changes the pathophysiology and outcome of RDS. Many clinicians now use surfactant without appreciating the research that was essential to learning how to use it and to understanding why it works so well for most infants. That research history is the basis for interpreting new approaches to the care of infants who have RDS, such as the early use of continuous positive airway pressure (CPAP). Surfactant works because of complicated biophysical and metabolic effects within the preterm lung. These effects are modified by clinical variables such as antenatal steroids, lung injury, and gestational age. The standard diagram of the pathophysiology of RDS developed in the 1980s still holds today (Fig. 1). Infants who have RDS have surfactant lipid pools of less than 10 mg/kg compared with the surfactant lipid pool sizes in term infants of perhaps 100 mg/kg. Further, lung structure is immature at less than 32 weeks’ gestation. The fetal human lung is in the saccular stage of development during the period of viability from 23 weeks’ gestation to the initiation of secondary septation (alveolarization), which begins at about 32 weeks’ gestation. The structure of the preterm lung affected by RDS limits lung …