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)

Surfactant administration has proven remarkably effective in the prevention and treatment of infantile respiratory distress syndrome (IRDS) and may also be beneficial in other forms of acute lung injury. Several surfactant products are available commercially along with others in various phases of development and clinical trials. While all of these products share an ability to lower surface tension in vitro, there are substantial compositional differences that appear to affect their in vivo efficacy. At present, the 'modified natural' surfactants containing the hydrophobic surfactant proteins SP-B and SP-C appear most effective. Calfactant may have a particular advantage because of its relatively high content of SP-B and its lack of contamination with non-surfactant lipids and proteins.
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PMID:Calfactant. 1158 26

Inactivation of pulmonary surfactant may be important in acute lung injury and acute respiratory distress syndrome. Treatment of surfactant dysfunction by instilling exogenous surfactants may improve gas exchange and pulmonary mechanics. Surfactants used for treatment vary in their attributes and effects, so when various surfactants are considered for therapy, resistance to inactivation is an important consideration. Animal models of acute lung injury exist in which the relative merits of surfactants can be compared. We hypothesize that the surfactants most resistant to inactivation in vitro will be the ones that are most effective in treatment of animal models of acute lung injury. Surfactants with higher concentrations of surfactant proteins specificallly A, B, and C) are more resistant to inactivation. Nonionic polymers mimic surfactant proteins in preventing surfactant inactivation under some conditions. Adding nonionic polymers to surfactant containing minimal amounts of SP-B and SP-C markedly improves lung function of animals with lung injury. Making surfactants more "inactivation-proof" may improve surfactant therapy of acute lung injuries.
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PMID:Inactivation of pulmonary surfactant and the treatment of acute lung injuries. 1169 77

Surfactant replacement preparations containing either surfactant protein (SP)-B or SP-C significantly improve lung function in surfactant-deficient infants, suggesting that these peptides may be functionally redundant. SP-B is absent and SP-C is greatly diminished in the airspaces of SP-B (-/-) mice, which die of respiratory distress syndrome (RDS) shortly after birth. The goal of this study was to determine if elevated expression of SP-C mature peptide could reverse the neonatal lethality in SP-B (-/-) mice. SP-C peptide (residues 24-57 of mouse SP-C proprotein) with a hemagglutinin epitope (SP-C(24-57)HA) was expressed in type II cells of transgenic mice, with the goal of crossing these animals into the SP-B (-/-) background. Unexpectedly, expression of the SP-C(24-57)HA transgene resulted in delayed/arrested lung development and lethal, neonatal RDS of all transgenic progeny in two independent transgenic lines. In transgenic mice, SP-C(24-57)HA was localized predominantly to the endoplasmic reticulum and Golgi; in contrast, SP-B and SP-C were very difficult to detect in the endoplasmic reticulum of wild-type mice. These results suggest that elevated expression of SP-C(24-57)HA in type II cells resulted in aggregation of SP-C in the early secretory pathway, leading to cytotoxicity and, ultimately, altered lung development.
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PMID:Overexpression of surfactant protein-C mature peptide causes neonatal lethality in transgenic mice. 1175 Dec 7

Pulmonary surfactant apoprotein C (SP-C) is a small, unique peptide that contributes to the reduction of alveolar surface tension. Due to the extreme hydrophobic nature of this peptide it was hitherto not possible to quantify SP-C in biological samples by immunological techniques. Using a newly developed polyclonal antibody raised against recombinant human SP-C in rabbits, we now describe an enzyme-linked immunosorbent assay (ELISA) to quantitate SP-C in bronchoalveolar lavage fluid (BALF). Solid phase binding of the hydrophobic SP-C was achieved by transfer of the standard or BALF samples (diluted in 80% isopropanol, pH 3.5) to polystyrene microtiter plates. Sequential treatment with trifluoroethanol and methanol (2x) was employed to improve antigen presentation and to minimize the influence of phospholipids. With this assay, SP-C from human, rabbit, porcine, and bovine surfactant was detectable. No cross-reactivity of the antibody to human SP-A and monomeric and dimeric SP-B was encountered. Total serum proteins did not affect ELISA signals, as evident from spiking experiments. The detection limit of the ELISA ranged below 3 ng/ml, and intra- and interassay coefficients of variation were 3.5% (n = 16) and 5.3% (n = 6), respectively. Serial dilutions of BALF showed good linearity, and excellent recovery rates were obtained upon spiking of human BALF. A mean value of 579.5 +/- 45.9 ng/ml (mean +/- SEM) SP-C was found in BALF samples of human healthy volunteers (n = 22), corresponding to 26.61 +/- 1.91 microg SP-C/mg total phospholipids (PL). SP-C levels were significantly lower in BALF of patients with acute respiratory distress syndrome (ARDS) (286.9 +/- 19.8 ng/ml [p < 0.001]; 13.92 +/- 1.93 microg SP-C/mg PL [p < 0.001], n = 48). We conclude that SP-C may be quantified with high specificity, reproducibility, and sensitivity in bronchoalveolar lavage samples by the presently described ELISA technique and that SP-C levels are significantly decreased in ARDS.
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PMID:An ELISA technique for quantification of surfactant apoprotein (SP)-C in bronchoalveolar lavage fluid. 1185 Mar 38

Intra-amniotic lipopolysaccharide (LPS) and cytokines may decrease respiratory distress syndrome (RDS) and increase chronic lung disease in the newborn. The aim was to identify the primary inflammatory mediators regulating the expression of surfactant proteins (SP) in explants from immature (22-day-old fetus) and mature (30-day term fetus and 2-day-old newborn) rabbits. In immature lung, interleukin (IL)-1alpha and IL-1beta upregulated the expression of SP-A and SP-B. These effects of IL-1 were diminished, and SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-alpha and either LPS or interferon (IFN)-gamma. LPS, TNF-alpha, or IFN-gamma had no effect alone. In explants from the term fetus and the newborn, LPS, IL-1alpha, and TNF-alpha additively suppressed the SPs. LPS acutely induced IL-1alpha in alveolar macrophages in mature lung but not in the immature lung. IFN-gamma that generally has low expression in intrauterine infection decreased the age dependence of the other agonists' effects on SPs. The present study serves to explain the variation of the pulmonary outcome after an inflammatory insult. We propose that IL-1 from extrapulmonary sources induces the SPs in premature lung and is responsible for the decreased risk of RDS in intra-amniotic infection.
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PMID:Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. 1188 Mar 7

The purpose of the present study was to investigate the impact of bronchoscopic surfactant administration, on the biochemical and biophysical surfactant properties, in patients with severe and early acute respiratory distress syndrome (ARDS) and septic shock. A total number of 27 ARDS patients received 300-500 mg x kg x body x weight(-1) of a natural bovine surfactant extract (Alveofact) via a flexible bronchoscope. Bronchoalveolar lavages were performed 3 h prior to, and 15-18 h and 72 h after surfactant administration. A comparison to healthy volunteers, undergoing an identical lavage procedure, was made (control, n=12). Severe biophysical and biochemical surfactant abnormalities were encountered throughout in the ARDS patients. These included a massive alveolar protein load, a reduced percentage of large surfactant aggregates (LA), a loss of palmitoylated phosphatidylcholine species and a significant reduction of surfactant apoprotein (SP)-A, SP-B and SP-C in the LA fraction. Both minimum (gammamin) and adsorption (gammaads) surface tension values (pulsating bubble surfactometer) were dramatically increased. Surfactant treatment resulted in a marked increase in the lavagable phospholipid (PL) pool, but predominance of the alveolar surfactant-inhibitory protein load was still encountered. Far-reaching or even complete normalization of the PL profile, the LA fraction and its SP-B and SP-C (but not SP-A) content as well as the fatty acid composition of the phosphatidylcholine class was noted. Surface tension lowering properties (gammamin and gammaads) significantly improved, but were still not fully normalized. Bronchoscopic administration of large quantities of natural bovine surfactant in severe acute respiratory distress syndrome causes far-reaching restoration of biochemical surfactant properties and significant improvement, however not full normalization, of biophysical surfactant function.
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PMID:Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant properties. 1203 Jul 13

Pulmonary surfactant, a thin lipid/protein film lining mammalian lungs, functions in vivo to reduce the work of breathing and to prevent alveolar collapse. Analogues of two hydrophobic surfactant proteins, SP-B and SP-C, have been incorporated into therapeutic agents for respiratory distress syndrome, a pathological condition resulting from deficiency in surfactant. To facilitate rational design of therapeutic agents, a molecular level understanding of lipid interaction with surfactant proteins or their analogues in aqueous monolayer films is necessary. The current work uses infrared reflection-absorption spectroscopy (IRRAS) to determine peptide conformation and the effects of S-palmitoylation on the lipid interactions of a synthetic 13 residue N-terminal peptide [SP-C13(palm)(2)] of SP-C, in mixtures with 1,2-dipalmitoylphosphatidylcholine (DPPC) or 1,2-dipalmitoylphosphatidylglycerol (DPPG). Two Amide I' features, at approximately 1655 and approximately 1639 cm(-1) in the peptide IRRAS spectra, are assigned to alpha-helical peptide bonds in hydrophobic and aqueous environments, respectively. In binary DPPC/SP-C13(palm)(2) films, the proportion of hydrated/hydrophobic helix increases reversibly with surface pressure (pi), suggestive of the peptide being squeezed out from hydrophobic regions of the monolayer. No such effect was observed for DPPG/peptide monolayers, indicative of stronger, probably electrostatic, interactions. Depalmitoylation produced a weakened interaction with either phospholipid as deduced from IRRAS spectra and from pi-area isotherms. S-Palmitoylation may modulate peptide hydration and conformation in the N-terminal region of SP-C and may thus permit the peptide to remain in the film at the high surface pressures present during lung compression. The unique capability of IRRAS to detect the surface pressure dependence of protein or peptide structure/interactions in a physiologically relevant model for surfactant is clearly demonstrated.
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PMID:Secondary structure and lipid interactions of the N-terminal segment of pulmonary surfactant SP-C in Langmuir films: IR reflection-absorption spectroscopy and surface pressure studies. 1208 87

The use of mammalian lung surfactant extracts has sharply reduced mortality and morbidity from respiratory distress syndrome in premature infants. Synthesis of surfactant protein B and C (SP-B and SP-C) analogues may lead the way to a synthetic surfactant preparation. Dimeric SP-B(1-25) (dSP-B(1-25)) is based on the N-terminal domain of human SP-B and SP-Cfc is a modified human SP-C in which a single phenylalanine is substituted for a palmitoylated cysteine residue in the N-terminal segment (Phe-4 > Cys-4 variant). We tested the effects of synthetic surfactants with 1 or 2% dSP-B(1-25) and 1% SP-Cfc on lung function in surfactant-deficient rats. Four experimental surfactant preparations were prepared by mixing 1% dSP-B(1-25), 2% dSP-B(1-25), 1% dSP-B(1-25) +1% SP-Cfc, and 2% dSP-B(1-25) +1% SP-Cfc with phospholipids (PL). PL and Survanta, a bovine lung extract, were controls. Groups of 8 rats were ventilated, lavaged until surfactant deficiency, and treated with 100 mg/kg surfactant. Arterial blood gas values and dynamic compliance were measured every 15 min and after 2 h of ventilation, the rats were killed and pressure-volume curves performed. Oxygenation improved quickly after instillation of surfactant with synthetic peptides and Survanta. Oxygenation and lung volumes were consistently higher in the 2% than in the 1% dSP-B(1-25) groups. Addition of 1% SP-Cfc to the synthetic surfactants further improved oxygenation and lung volume, but to a lesser extent than increasing the dSP-B(1-25) content from 1 to 2%. These data indicate that improvements in oxygenation and lung volume in lavaged rats are dependent on the concentration of dSP-B(1-25) in the surfactant preparation and that the presence of SP-Cfc has a relative minor effect on these parameters.
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PMID:Surfactant with SP-B and SP-C analogues improves lung function in surfactant-deficient rats. 1237 69

Surfactant proteins, SP-A, SP-B, SP-C and SP-D, play important roles in pulmonary surfactant function and metabolism. SP-A and SP-D, being members of the collectin family of proteins, also interact with pathogens and are involved in pulmonary host defense. Respiratory diseases are among the most common causes of death worldwide. Several life-threatening lung diseases, such as neonatal respiratory distress syndrome (RDS) and acute ROS (ARDS), are associated with impaired surfactant function. Allelic variations of the SP-A and SP-B genes have been shown to be important genetic determinants in individual susceptibility to RDS, which is a good general model for a multifactorial pulmonary disease resulting from complex interactions between several environmental and genetic factors. Because SP-A and SP-D act directly in the clearance of common lung pathogens, the genes encoding these proteins have been implicated as candidates in a few infectious diseases, including respiratory syncytial virus (RSV) infections and tuberculosis.
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PMID:Surfactant proteins as genetic determinants of multifactorial pulmonary diseases. 1245 77

Recent evidence suggests that the susceptibility to respiratory distress syndrome (RDS) is partly explained by genetic variation in the surfactant proteins (SP) SP-A and SP-B. The present study was designed to evaluate the concordance difference method and candidate gene analysis, in parallel, for the investigation of genetic susceptibility to RDS. We studied 100 same-sex twin pairs with established RDS in at least one twin. The difference in RDS concordance rates between the monozygotic (MZ) and dizygotic (DZ) twin pairs as evidence of a genetic influence was evaluated, and the SP-A and SP-B genes were investigated for potential associations with the susceptibility to RDS. The concordance rates of RDS were 54 and 44% in the MZ and DZ pairs, respectively. The concordance difference of 10% was not significant [95% confidence interval (CI) -0.1 to +0.3, P=0.32], suggesting a low hereditary impact. However, the SP-B Ile131Thr polymorphism was associated with RDS. The threonine allele was associated with an increased risk of RDS [odds ratio (OR) 2.2, 95% CI 1.4-3.5, P=0.0014]. This was particularly apparent in first-born male infants (OR 6.2, 95% CI 2.4-16.3, P<0.001). The degree of prematurity (<32 weeks OR 2.0, 95% CI 1.1-3.7, P=0.021) and birth order (second-born OR 3.1, 95% CI 1.3-7.4, P=0.009) were the clinical variables affecting the risk of RDS. An association between the SP-B Ile131Thr polymorphism and RDS was found. The threonine allele was associated with the risk of RDS, particularly in the first-born twin infants. The concordance difference between MZ and DZ twin pairs underestimates the genetic impact on the risk of RDS. The traditional twin concordance study is insufficient to evaluate genetic predisposition to RDS or other diseases that are confounded by the birth order or multiple pregnancy in itself.
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PMID:Surfactant protein B polymorphism and respiratory distress syndrome in premature twins. 1248 94


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