Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476273 (respiratory distress)
 19,632 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Decreased production of vascular endothelial growth factor (VEGF) in ARDS may favour vascular lesions, since VEGF promotes endothelial survival by inhibiting apoptosis. This study sought to document low VEGF levels in lung tissue from ARDS patients, to determine whether the cause was injury to alveolar type II cells (the main pulmonary source of VEGF) and to evaluate the vascular consequences. Lung specimens were obtained by open biopsy or autopsy from 29 patients with severe ARDS (two survivors) and five controls. As compared with controls, homogenates of lung tissue from ARDS patients contained less VEGF (median (interquartile range) ARDS 8.2 (4.7-12.2) versus controls 28.4 (9.9-47.1) ng x g(-1) protein). Increased immunostaining with surfactant protein B was seen in ARDS lungs. Extensive cellular apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining), including endothelial and alveolar type II cells, was demonstrated, and vascular bed density (CD31 immunostaining) decreased in ARDS lungs as compared with controls. VEGF levels were negatively correlated to apoptotic endothelial cell counts. In conclusion, decreased vascular endothelial growth factor levels in lung tissue may participate in the decrease in lung perfusion in acute respiratory distress syndrome.
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PMID:Decreased VEGF concentration in lung tissue and vascular injury during ARDS. 1564 Mar 35

Lucinactant, formerly known as KL(4) surfactant, is a novel synthetic lung surfactant containing phospholipids and an engineered peptide, sinapultide, which is designed to mimic the actions of human surfactant protein B. It has been developed for use in the prevention or treatment of respiratory distress syndrome (RDS), a common problem in premature infants, which results from a deficiency or degradation of pulmonary surfactant. Lucinactant is administered intratracheally soon after birth as a replacement surfactant. In the pivotal randomized, double-blind, prophylaxis trial in premature infants, the incidence of RDS at 24 hours after birth was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate, a synthetic non-protein-containing surfactant. RDS-related mortality at 14 days was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate or beractant, a bovine-derived surfactant. In another randomized, double-blind, prophylaxis trial in premature infants, the rate of survival without bronchopulmonary dysplasia at 28 days of age in lucinactant recipients was not inferior to that in recipients of poractant alfa, a porcine-derived surfactant. Lucinactant was generally well tolerated. Adverse events were transient and related to the administration procedure. There were no differences in the incidences of complications of prematurity between lucinactant and the other surfactants.
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PMID:Lucinactant: in neonatal respiratory distress syndrome. 1581 66

The first successful trial of surfactant treatment for respiratory distress syndrome (RDS) was reported in 1980. Since then there have been numerous randomised trials demonstrating first, the efficacy of surfactant treatment in reducing pulmonary air leaks and increasing survival and second, assessing various other aspects of therapy. These studies show that multiple doses may be needed if surfactant is used to treat established RDS but early or prophylactic treatment is superior for infants with gestational ages less than 30 weeks. Natural surfactants (containing proteins) are more effective than synthetic products (protein free), the latter now being infrequently used. Natural surfactants vary and should not be considered to be equivalent in their effects. A porcine surfactant (poractant alfa) acts more rapidly than a bovine preparation (beractant) in infants with moderate to severe RDS. A meta-analysis of 5 comparative studies suggests that a dose of 200 mg/kg of poractant alfa is associated with lower mortality compared with 100 mg/kg of beractant. Chronic lung disease remains a problem but it is hoped that early treatment with surfactant combined with extubation to continuous positive airway pressure will reduce this complication of prematurity. The newer synthetic surfactants, containing analogues of surfactant protein B or C, have undergone some trials for treatment of RDS but comparative studies which have just been published do not show that they are superior to existing natural surfactants. However, as they are more resistant to inactivation they may have a role in treatment of adult or acute RDS. The last 25 years have seen a large increase in basic science research on surfactants with determination of the structure and function of the four surfactant proteins probably being the most important advances. Future studies will focus on widening the indications for surfactant treatment, developing non-invasive means of administration and assessing the role of the newer synthetic surfactants.
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PMID:History of surfactant from 1980. 1598 54

Genetic variants in intron 4 of the surfactant protein B gene SFTPB have been associated with pulmonary morbidity in newborn infants and adults. Genetic variant discovery in intron 4 requires high fidelity polymerase amplification due to a variable number of intermotif dinucleotide repeats and reliable characterization of alleles genetically distinct due to insertion, deletion, or both of 11 conserved sequence motifs. To optimize genetic variant discovery, we selected a high fidelity polymerase enzyme by replicate amplification and compared automated sequencing with agarose gel electrophoresis for all variant alleles (N=68) in a cohort of Missouri infants with (N=187) and without (N=53) respiratory distress. We identified and characterized six new alleles based on sequence motifs and two pairs of variant alleles with similar mobilities by agarose gel electrophoresis but distinct motif sequences. We confirmed uniformity of invariant alleles by sequencing (N=77). Logistic regression using race and intron 4 genotype for infants > or = 35 weeks gestation suggested that the invariant allele was independently associated with increased risk of respiratory distress (OR for the invariant allele 2.7, 95% CI 1.0-7.2). Reliable characterization of genetic variants in intron 4 requires both a high fidelity polymerase and sequencing of variant alleles.
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PMID:Genetic variant characterization in intron 4 of the surfactant protein B gene. 1621 53

Genetic variants of surfactant protein B (SP-B) have been associated with respiratory distress syndrome (RDS) in the prematurely born infant. We wished to determine linkage between RDS and SP-B single nucleotide polymorphisms (SNPs) [-18 (A/C), 1013 (A/C), 1580 (C/T), and 9306 (A/G)] or SP-B-linked microsatellite [(D2S388, D2S2232, (AAGG)n, and GATA41E01 (or D2S1331)] loci and identify susceptibility or protective alleles and haplotypes. We genotyped 132 families consisting of one or two parents and at least one child affected with RDS and performed biallelic and multiallelic family-based association test (FBAT) analysis, and extended transmission disequilibrium test (ETDT). ETDT analysis identified the microsatellite SP-B-linked loci (except D2S2232) to be linked to RDS. One allele from each of these three marker loci contributes to the risk of RDS. Multiallelic FBAT analysis detected a signal of linkage for the region of the four SNP loci. Three haplotypes within this region contribute to RDS risk. Although no other region showed significant linkage as judged by multiallelic FBAT, biallelic FBAT analysis revealed three potential susceptibility haplotypes formed by two to four loci within the SP-B and SP-B-linked microsatellite region. Each haplotype included GATA41E01, which was identified by ETDT analysis to be linked to RDS. We conclude that SP-B or SP-B-linked loci are linked to RDS and certain alleles or haplotypes are susceptibility or protective factors for the development of RDS in infants born prematurely.
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PMID:Family-based association tests suggest linkage between surfactant protein B (SP-B) (and flanking region) and respiratory distress syndrome (RDS): SP-B haplotypes and alleles from SP-B-linked loci are risk factors for RDS. 1654 40

Exposing BLES (bovine lipid extract surfactant), a clinical surfactant, to reactive oxygen species (ROS) alters surfactant protein B (SP-B), as indicated by Coomassie Blue staining, silver staining, and Western analysis. Hypochlorous acid (HOCl) treatment leads to elevated maximum surface tension (gammamax) and a deterioration in minimum gamma (gammamin) during surface area cycling. Fenton reaction resulted in immediate increases in gammamin and gammamax. Intrinsic fluorescence measurements indicated Fenton, but not HOCl, induced conversion of Trp9 of SP-B to hydroxyTrp (OHTrp), N-formylkynurenine (NFKyn), and kynurenine (Kyn). Electrospray ionization mass spectrometry (ESI-MS) revealed molecular weight alterations consistent with oxidation of Met (HOCl, Fenton) and Trp (Fenton) residues. Oxidative alterations to Met29 and Met65 (HOCl, Fenton) and to Trp9 (OHTrp with HOCL and NFKyn plus Kyn with Fenton) were confirmed by matrix-assisted laser desorption mass spectrometry (MALDI-MS) studies on SP-B tryptic fragments. Some Met oxidation was observed with control SP-B. When taken together with captive bubble tensiometer measurements, these studies suggest that Met oxidation of SP-B by HOCl or Fenton interferes with phospholipid respreading during compression-expansion of surfactant films, while Fenton oxidation, which produces more extensive Met oxidation and disruption of the indole ring of Trp9, further abrogated the ability of such films to attain low surface tensions during compression. These studies provide insight into the manner by which ROS generated during acute lung injury and the acute respiratory distress syndrome act to inhibit not only endogenous surfactant but also therapeutic surfactants administered to counteract these conditions.
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PMID:Modification of tryptophan and methionine residues is implicated in the oxidative inactivation of surfactant protein B. 1742 86

Genetic abnormalities of pulmonary surfactant were identified by DNA sequence analysis in 14 (12 full-term, 2 preterm) of 17 newborn infants with fatal respiratory distress of unknown etiology. Deficiency of adenosine triphosphate-binding cassette protein, member A3 (n = 12) was a more frequent cause of this phenotype than deficiency of surfactant protein B (n = 2).
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PMID:Unexplained neonatal respiratory distress due to congenital surfactant deficiency. 1751 55

Polymorphisms and mutations in the surfactant protein B (SP-B) gene have been associated with the pathogenesis of respiratory distress syndrome (RDS). The objective of the present study was to compare the frequencies of SP-B gene polymorphisms between preterm babies with RDS and healthy term newborns. We studied 50 preterm babies with RDS (inclusion criteria - newborns with RDS and gestational age between 28 and 33 weeks and 6 days), and 100 healthy term newborns. Four SP-B gene polymorphisms were analyzed: A/C at nucleotide -18, C/T at nucleotide 1580, A/G at nucleotide 9306, and G/C at nucleotide 8714, by PCR amplification of genomic DNA and genotyping by cRFLP. The healthy newborns comprised 42 female and 58 male neonates; 39 were white and 61 non-white. The RDS group comprised 21 female and 29 male preterm neonates; 28 were white and 22 non-white. Weight ranged from 640 to 2080 g (mean: 1273 g); mean gestational age was 31 weeks and 2 days (range: 28-33 weeks and 6 days). When white children were analyzed separately, a statistically significant difference in the G/C polymorphism at 8714 was observed between groups (P = 0.028). All other genotype frequencies were similar for both groups when sex and race were analyzed together. Analysis of the SP-B polymorphism G/C at nucleotide 8714 showed that among white neonates the GG genotype was found only in the RDS group at a frequency of 17% and the GC genotype was more frequently found in healthy term newborns. These data demonstrate an association of GG genotype with RDS.
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PMID:Comparison of surfactant protein B polymorphisms of healthy term newborns with preterm newborns having respiratory distress syndrome. 1758 75

Completely penetrant mutations in the surfactant protein B gene (SFTPB) and >75% reduction of SFTPB expression disrupt pulmonary surfactant function and cause neonatal respiratory distress syndrome. To inform studies of genetic regulation of SFTPB expression, we created a catalogue of SFTPB variants by comprehensive resequencing from an unselected, population-based cohort (n = 1,116). We found an excess of low-frequency variation [81 SNPs and five small insertion/deletions (in/dels)]. Despite its small genomic size (9.7 kb), SFTPB was characterized by weak linkage disequilibrium (LD) and high haplotype diversity. Using the HapMap Yoruban and European populations, we identified a recombination hot spot that spans SFTPB, was not detectable in our focused resequencing data, and accounts for weak LD. Using homology-based software tools, we discovered no definitively damaging exonic variants. We conclude that excess low-frequency variation, intragenic recombination and lack of common disruptive exonic variants favor complete resequencing as the optimal approach for genetic association studies to identify regulatory SFTPB variants that cause neonatal respiratory distress syndrome in genetically diverse populations.
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PMID:Comprehensive genetic variant discovery in the surfactant protein B gene. 1759 50

Bronchopulmonary dysplasia (BPD) is a common perinatal complication of very low birth weight preterm infants with a significant risk of long-term disability and morbidity. While clinical conditions such as prematurity and mechanical ventilation are its major risk factors, studies suggest that there is an individual susceptibility to BPD. This comprehensive review summarizes data collected about the implication of genetic polymorphisms in BPD and in its risk factors. Some studies have directly related the risk of BPD to genotype. Indeed, carrier states of genetic variants of cytokines (IFNgamma T+874A), adhesion molecules (L-selectin-Pro213Ser), elements of renin-angiotensin system (ACE-I/D), antioxidant enzymes (GST-P1 Val105Ile), and surfactant proteins (SPA1, SPB intron 4) has been identified as risk factors to BPD. Other studies investigated the role of genotype in BPD risk factors. Premature birth has been linked to carrier states of genetic variants with an impact on immune status (such as IL-6 G(-174)C, MBL2 54G/A, VEGF G+405C, HSP72 A+1267G genes) and matrix metalloproteases. Fetal inflammatory response syndrome, a major determinant of BPD is also affected by genotype (including LTalpha A+250G). Disturbed intrauterine lung development and vascularization may also contribute to BPD; these processes may be impaired in the presence of some rare genetic mutations. Furthermore, there is also a genetic component in the susceptibility to other perinatal adaptational disturbances such as respiratory distress syndrome that are associated with an increased need for mechanical ventilation, and, hence, with lung damage. The genetic variants presented in this article may help to identify infants at risk for BPD.
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PMID:Dysplasia: a review. 1772 3


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