An overview of pulmonary surfactant in the neonate: Genetics, metabolism, and the role of surfactant in health and disease (original) (raw)
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The importance of surfactant on the development of neonatal pulmonary diseases
Clinics, 2007
Pulmonary surfactant is a substance composed of a lipoprotein complex that is essential to pulmonary function. Pulmonary surfactant proteins play an important role in the structure, function, and metabolism of surfactant; 4 specific surfactant proteins have been identified: surfactant proteins-A, surfactant proteins-B, surfactant proteins-C, and surfactant proteins-D. Clinical, epidemiological, and biochemical evidence suggests that the etiology of respiratory distress syndrome is multifactorial with a significant genetic component. There are reports about polymorphisms and mutations on the surfactant protein genes, especially surfactant proteins-B, that may be associated with respiratory distress syndrome, acute respiratory distress syndrome, and congenital alveolar proteinosis. Individual differences regarding respiratory distress syndrome and acute respiratory distress syndrome as well as patient response to therapy might reflect phenotypic diversity due to genetic variation, in part. The study of the differences between the allelic variants of the surfactant protein genes can contribute to the understanding of individual susceptibility to the development of several pulmonary diseases. The identification of the polymorphisms and mutations that are indeed important for the pathogenesis of the diseases related to surfactant protein dysfunction, leading to the possibility of genotyping individuals at increased risk, constitutes a new research field. In the future, findings in these endeavors may enable more effective genetic counseling as well as the development of prophylactic and therapeutic strategies that would provide a real impact on the management of newborns with respiratory distress syndrome and other pulmonary diseases.
Pulmonary surfactant-update on function, molecular biology and clinical implications
Current Respiratory Medicine Reviews
Departments of 1 Cellular and Molecular Physiology, 2 Pediatrics, and 3 Abstract: This review is based on the contents of an international congress entitled, "Surfactant 2004", organized by Drs. B. Lachmann and L.M.G. van Golde and held in Berlin, Germany. This is the fourth meeting of its kind; the first one was held in 1989. The purpose was to bring together investigators, interested in surfactant research from different disciplines to review progress in basic and clinical sciences, evaluate findings from clinical trials, and build upon the current knowledge to design better clinical trials for the prematurely born infant and other groups of patients, who are identified with surfactant dysfunction, as well as formulate new hypotheses for surfactant investigation both at the basic science and clinical science levels. Although the importance of surfactant in normal lung function was initially appreciated in the case of the prematurely born infant the importance of surfacta...
Endogenous Surfactant Metabolism in Newborn Infants with and without Respiratory Failure
Pediatric Research, 2003
Studies using stable isotopically labeled glucose and palmitate as precursors of pulmonary surfactant synthesis have demonstrated slow surfactant turnover in premature infants with respiratory distress syndrome (RDS). However, only limited data about surfactant turnover are available for term infants. Because acetate is a direct precursor of de novo synthesized surfactant fatty acid, we measured [1-13 C 1 ]acetate incorporation into surfactant of term infants without respiratory dysfunction (control group), preterm infants with RDS, and term infants with primary respiratory failure to determine whether stable isotopically labeled acetate would yield similar results to previous studies of preterm infants with RDS and, furthermore, would distinguish normal from abnormal surfactant turnover. Despite similar amounts of phospholipids and acetate precursor enrichment, the control group had higher fractional synthetic rate and shorter half-life of clearance than preterm infants with RDS, (fractional synthetic rate, 15.4 Ϯ 2.4 versus 2.2 Ϯ 0.4%/d, p Ͻ 0.001; half-life of clearance, 27 Ϯ 3 versus 105 Ϯ 11 h, p Ͻ 0.001). Term infants with severe respiratory failure had a lower fractional synthetic rate than those with mild disease (2.9 Ϯ 0.6 versus 13.8 Ϯ 3.5%/d, p ϭ 0.014) and a reduced amount of phospholipids recovered from tracheal aspirates (54 Ϯ 17 versus 300 Ϯ 28 nmol, severe versus mild disease, respectively, p Ͻ 0.001). The amount of phospholipids in tracheal aspirates correlated inversely with disease severity, (r ϭ Ϫ0.75, p ϭ 0.01). We conclude that normal surfactant turnover in term infants is faster than in preterm infants with RDS. Surfactant turnover in term infants with severe respiratory failure is similar to that of preterm infants with RDS, suggesting either delayed maturity of the surfactant system or disruption from the underlying disease process. (Pediatr Res 54: 185-191, 2003) Abbreviations DPPC, dipalmitoylphosphatidylcholine E max , maximum enrichment FSR, fractional synthetic rate FiO 2 , fraction of inspired oxygen GC/MS, gas chromatography/mass spectrometry MIDA, mass isotopomer distribution analysis RDS, respiratory distress syndrome T1/2, half-life of clearance TA, tracheal aspirate T app , time of appearance T max , time of maximum enrichment TTR, tracer to tracee ratio
Effect of Exogenous Surfactant on the Development of Surfactant Synthesis in Premature Rabbit Lung
Pediatric Research, 2003
Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full recovery from respiratory distress syndrome requires development of endogenous surfactant synthesis and metabolism. The influence of exogenous surfactant on the development of surfactant synthesis in premature lungs is not known. We hypothesized that different exogenous surfactants have different effects on the development of endogenous surfactant production in the premature lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg body weight of natural rabbit surfactant, Survanta, and Exosurf and measured their effects on the development of surfactant synthesis. Additional experiments tested how these surfactants and Curosurf affected surfactant protein (SP) SPA , SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the incorporation of 3 H-choline and 14 C-glycerol into disaturated phosphatidylcholine recovered from lamellar bodies. Randomized-block ANOVA showed significant differences among treatments for incorporation of both labels (p Ͻ 0.01), with natural rabbit surfactant less than control, Survanta greater than control, and Exosurf unchanged. Additional experiments with natural rabbit surfactant alone showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated disaturated phosphatidylcholine synthesis (173 Ϯ 41% of control; p ϭ 0.01), increased total lamellar body disaturated phosphatidylcholine by 22% (p Ͻ 0.05), and increased 14 C-disat-PC specific activity by 35% (p Ͻ 0.05). The response to Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant release. No surfactant altered the expression of mRNA for SPA , SP-B, or SP-C. We conclude that surfactant replacement therapy can enhance the maturation of surfactant synthesis, but this potential benefit differs with different surfactant preparations. (Pediatr Res 53: 671-678, 2003) Abbreviations DPPC, dipalmitoyl phosphatidylcholine disat-PC, disaturated phosphatidylcholine LB, lamellar body NARS, natural adult rabbit surfactant PC, phosphatidylcholine PG, phosphatidylglycerol PI, phosphatidylinositol RDS, neonatal respiratory distress syndrome SPA , surfactant protein A SP-B, surfactant protein B SP-C, surfactant protein C
Distribution of intracellular and secreted surfactant during postnatal rat lung development
Pediatric Pulmonology, 2007
Pulmonary surfactant prevents alveolar collapse via reduction of surface tension. In contrast to human neonates, rats are born with saccular lungs. Therefore, rat lungs serve as a model for investigation of the surfactant system during postnatal alveolar formation. We hypothesized that this process is associated with characteristic structural and biochemical surfactant alterations. We aimed to discriminate changes related to alveolarization from those being either invariable or follow continuous patterns of postnatal changes. Secreted active (mainly tubular myelin (tm)) and inactive (unilamellar vesicles (ulv)) surfactant subtypes as well as intracellular surfactant (lamellar bodies (lb)) in type II pneumocytes (PNII) were quantified before (day (d) 1), during , at the end of alveolarization , and after completion of lung maturation (d 42) using electron microscopic methods supplemented by biochemical analyses (phospholipid quantification, immunoblotting for SP-A). Immunoelectron microscopy determined the localization of surfactant protein A (SP-A). (1) At d 1 secreted surfactant was increased relative to d 7-42 and then decreased significantly. (2) Air spaces of neonatal lungs comprised lower fractions of tm and increased ulv, which correlated with low SP-A concentrations in lung lavage fluid (LLF) and increased respiratory rates, respectively. (3) Alveolarization (d 7-14) was associated with decreasing PNII size although volume and sizes of Lb continuously increased. (4) The volume fractions of Lb correlated well with the pool sizes of phospholipids in lavaged lungs. Our study emphasizes differential patterns of developmental changes of the surfactant system relative to postnatal alveolarization.
The Journal of Lipid Research, 2009
In mammals, pulmonary surfactant reduces lung surface tension, maintains lung fl uid balance, provides lung stability, and reduces the risk of infection. Preterm infants have immature lungs and are prone to develop respiratory distress syndrome (RDS), a disease caused by lack of surfactant production and secretion into the alveoli. The alveolar type II cell is the primary site of synthesis, storage, and secretion of pulmonary surfactant that consists of a mixture of lipids and proteins that are highly enriched with dipalmitoyl-phosphatidylcholine (DPPC) and other phospholipids with saturated fatty acids in the one and two position of the glycerol moiety (1-3). While much work has focused on the pathways of pulmonary phospholipid synthesis in animals, little is known about the provision of its synthetic precursors in animals and even more so in humans. From a biochemical point of view, the FA moiety of surfactant phospholipids may be derived from the circulating FFA or from FAs denovo synthesized from glucose via acetate and lactate precursors. De novo FA synthesis or lipogenesis has been shown to occur in the lung or in the liver (4, 5). The interplay among these various sources of pulmonary FAs is poorly understood, but it may be infl uenced by the concentrations of available substrates, dietary and hormonal factors, and altered physiologic states (6-8). The relative contribution of each of the potential sources of FA (glucose, acetate, lactate, and FFA) for incorporation into the lung surfactant disaturated-phosphatidylcholine (DSPC) has been studied in animals by radioactive and, more recently, stable isotopes tracers (4, 9-13).
Genetic surfactant dysfunction in newborn infants and children with acute and chronic lung disease
2017
Mutations in genes encoding surfactant protein B (SP-B), ATP-binding cassette transporter A3 (ABCA3) and surfactant protein C (SP-C) can result in neonatal and pediatric lung disease. We retrospectively reviewed 391 molecular analyses of genes encoding SP-B ( SFTPB ), SP-C ( SFTPC ) and ABCA3 ( ABCA3 ) performed in our laboratory from 2000 to 2015 in term and preterm newborn infants with severe respiratory distress syndrome (RDS), infants and children with interstitial lung disease (ILD), chorionic villi for prenatal diagnosis, parents and siblings of affected infants. Direct sequencing of SFTPB , SFTPC and ABCA3 was performed on genomic DNA extracted from peripheral blood. Histopathologic, immunohistochemical and ultrastructural analyses were performed when lung tissue was available. Genetic variants in SFTPB , SFTPC , ABCA3 were identified in 71 of 181 (39%) term and preterm newborn infants tested for severe and unexplained RDS and in 38 of 74 (51%) infants and children with ILD. ...
Highlights of Early Pulmonary Surfactant: Research from Bench to Clinic Corespondence
Pneumon, 2014
Nowadays we know a great deal about the lung. We understand its major functions, how it achieves most of these, how it looks microscopically, and other physiological attributes such as that adequate amounts of pulmonary surfactant in the prematurely born infant are essential for lung function and consequently for life. In this review, we summarize highlights of the history, i.e. the journey of pulmonary surfactant discovery and how it moved from the lab bench to the patient's bedside. Pneumon 2013, 26(4):1-6.