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)

KL(4)-surfactant contains the novel KL(4) peptide, sinapultide, which mimics properties of the hydrophobic pulmonary surfactant protein SP-B, in a phospholipid formulation and may be lung protective in experimental acute respiratory distress syndrome/acute lung injury. Our objective was to determine the protective role of airway delivery of KL(4)-surfactant in murine models of hyperoxic and lipopolysaccharide (LPS)-induced lung injury and further explore the mechanisms of protection. For the hyperoxic injury model, mice exposed to 80% O(2) for 6 days received an intranasal bolus of vehicle, beractant, or KL(4)-surfactant on days 3, 4, 5, and 6 of the exposure, and lungs were evaluated on day 7. Mice in the LPS-induced lung injury model received an intratracheal bolus of LPS followed by an intranasal bolus of KL(4)-surfactant or control at 1, 3, and 19 hr post-LPS challenge, and lungs were evaluated after 24 hr. To explore the mechanisms of protection, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was evaluated. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, our data showed KL(4)-surfactant, unlike vehicle or beractant, blocked neutrophil influx into alveoli and suppressed lung injury. Furthermore, in vitro assays showed KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant decreased inflammation and lung permeability compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is through inhibition of PMN transmigration through the endothelium.
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PMID:KL4-surfactant prevents hyperoxic and LPS-induced lung injury in mice. 1687 29

Here, we describe the approach of defining the genetic contribution to disease and discuss the polymorphisms of some genes that are associated with respiratory disease. The common allelic variants of SP-A1, SP-A2, SP-B, SP-C, and SP-D genes are associated with respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), or respiratory syncytial virus (RSV) bronchiolitis. The main SP-A haplotype, interactively with SP-B Ile131Thr polymorphism and with constitutional and environmental factors, influences the risk of RDS. The polymorphisms of SP-A2 and SP-D are associated with the risk of severe RSV. The polymorphism may turn out to be important in susceptibility to influenza virus. The SP-B intron 4 deletion variant is the risk factor of BPD. Understanding the molecular mechanisms behind the hereditary risk may lead to new focused treatment strategies.
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PMID:Surfactant protein polymorphisms and neonatal lung disease. 1714 61

Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3-/- knock-out mice died soon after birth, whereas most of the wild type, Abca3+/+, and heterozygous, Abca3+/-, neonates survived. The lungs from E18.5 and E19.5 Abca3-/- mice were less mature than wild type. Alveolar type 2 cells from Abca3-/- embryos contained no lamellar bodies, and expression of mature SP-B protein was disrupted when compared with the normal lung surfactant system of wild type embryos. Small structural and functional differences in the surfactant system were seen in adult Abca3+/- compared with Abca3+/+ mice. The heterozygotes had fewer lamellar bodies, and the incorporation of radiolabeled substrates into newly synthesized disaturated phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine in both lamellar bodies and surfactant was lower than in Abca3+/+ mouse lungs. In addition, since the fraction of near term Abca3-/- embryos was significantly lower than expected from Mendelian inheritance ABCA3 probably plays roles in development unrelated to surfactant. Collectively, these findings strongly suggest that ABCA3 is necessary for lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation.
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PMID:ABCA3 is critical for lamellar body biogenesis in vivo. 1754 Jul 62

This study investigates the activity and inhibition resistance in excised rat lungs of a novel synthetic surfactant containing the phospholipase-resistant diether phosphonolipid DEPN-8 plus 1.5% bovine surfactant protein (SP)-B/C compared to calf lung surfactant extract (CLSE). DEPN-8 + 1.5% SP-B/C surpassed CLSE in normalizing surfactant-deficient pressure-volume (P-V) deflation mechanics in lavaged excised lungs in the presence of phospholipase A(2) (PLA(2)) or C18:1 lyso-phosphatidylcholine (LPC). DEPN-8 + 1.5% SP-B/C had activity equal to CLSE in normalizing P-V mechanics in the absence of inhibitors or in the presence of serum albumin. These physiologic activity findings were directly consistent with surface activity measurements on the pulsating bubble surfactometer. In the absence of inhibitors, DEPN-8 + 1.5% SP-B/C and CLSE rapidly reached minimum surface tensions < 1 mN/m (0.5 and 2.5 mg surfactant phospholipid/ml). DEPN-8 + 1.5% SP-B/C maintained its high surface activity in the presence of PLA(2), while the surface activity of CLSE was significantly inhibited by exposure to this enzyme. DEPN-8 + 1.5% SP-B/C also had greater surface activity than CLSE in the presence of LPC, and the two surfactants had equivalent surface activity in the presence of albumin. DEPN-8 + 1.5% SP-B/C also had slightly greater surface activity than CLSE when exposed to peroxynitrite in pulsating bubble studies. These results support the potential of developing highly active and inhibition-resistant synthetic exogenous surfactants containing DEPN-8 + apoprotein/peptide constituents for use in treating direct pulmonary forms of clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS).
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PMID:Activity and inhibition resistance of a phospholipase-resistant synthetic surfactant in rat lungs. 1755 74

Lung surfactant is a complex mixture of phospholipids and four surfactant-associated proteins (SP-A, SP-B, SP-C and SP-D). Its major function in the lung alveolus is to reduce surface tension at the air-water interface in the terminal airways by the formation of a surface-active film enriched in surfactant lipids, hence preventing cellular collapse during respiration. Surfactant therapy using bovine or porcine lung surfactant extracts, which contain only polar lipids and native SP-B and SP-C, has dramatically improved the therapeutic outcomes of preterm infants with respiratory distress syndrome (RDS). One important goal of surfactant researchers is to replace animal-derived therapies with fully synthetic preparations based on SP-B and SP-C, produced by recombinant technology or peptide synthesis, and reconstituted with selected synthetic lipids. Here, we review recent research developments with peptide analogues of SP-B and SP-C, designed using either the known primary sequence and three-dimensional (3D) structure of the native proteins or, alternatively, the known 3D structures of closely homologous proteins. Such SP-B and SP-C mimics offer the possibility of studying the mechanisms of action of the respective native proteins, and may allow the design of optimized surfactant formulations for specific pulmonary diseases (e.g., acute lung injury (ALI) or acute respiratory distress syndrome (ARDS)). These synthetic surfactant preparations may also be a cost-saving therapeutic approach, with better quality control than may be obtained with animal-based treatments.
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PMID:Hydrophobic surfactant proteins and their analogues. 1757 74

We investigated the influence of load impedance on ventilator performance and the resulting effects of reduced tidal volume (Vt) on lung physiology during a 30-min ventilation of normal mice and 10 min of additional ventilation following lavage-induced injury at two positive end-expiratory pressure (PEEP) levels. Respiratory mechanics were regularly monitored, and the lavage fluid was tested for the soluble E-cadherin, an epithelial cell adhesion molecule, and surfactant protein (SP) B. The results showed that, due to the load dependence of the delivered Vt from the small-animal ventilator: 1) uncontrolled ventilation in normal mice resulted in a lower delivered Vt (6 ml/kg at 3-cmH(2)O PEEP and 7 ml/kg at 6-cmH(2)O PEEP) than the prescribed Vt (8 ml/kg); 2) at 3-cmH(2)O PEEP, uncontrolled ventilation in normal mice led to an increase in lung parenchymal functional heterogeneity, a reduction of SP-B, and an increase in E-cadherin; 3) at 6-cmH(2)O PEEP, ventilation mode had less influence on these parameters; and 4) in a lavage model of acute respiratory distress syndrome, delivered Vt decreased to 4 ml/kg from the prescribed 8 ml/kg, which resulted in severely compromised lung function characterized by increases in lung elastance, airway resistance, and alveolar tissue heterogeneity. Furthermore, the low Vt ventilation also resulted in poor survival rate independent of PEEP. These results highlight the importance of delivering appropriate Vt to both the normal and injured lungs. By leaving the Vt uncompensated, it can significantly alter physiological and biological responses in mice.
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PMID:Effects of reduced tidal volume ventilation on pulmonary function in mice before and after acute lung injury. 1769 Feb 3

Surfactant preparations, which are effective in the treatment of respiratory distress syndrome (RDS), contain phospholipids and small amounts of the 2 hydrophobic surfactant proteins SP-B and SP-C. At present, surfactant preparations are obtained from animal lungs. However, since information concerning the structure of SP-B and SP-C is now available, it appears possible to design analogues that can replace the native proteins and so formulate a synthetic peptide/lipid surfactant. This would circumvent problems associated with current purification procedures and also facilitate the production of quantities sufficient for evaluation of surfactant therapy in other respiratory diseases. SP-C analogues which effectively accelerate the spreading of surfactant lipids and exhibit physiological activity in animal models of RDS have been developed. However, the in vivo activity of surfactant preparations based on SP-C analogues are inferior to those of surfactant preparations derived from natural sources. This may be caused by lack of covalently linked palmitoyl groups in the SP-C analogues tested and/or that SP-B is required for full activity. The larger size of SP-B compared to SP-C makes the design of SP-B analogues more demanding. Surfactant preparations containing single peptides that may resemble SP-B have shown promising results in vitro and in vivo. Identification of further SP-B analogues as well as suitable combinations of SP-B and SP-C analogues appear to be important topics for future studies.
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PMID:Pulmonary surfactant: emerging protein analogues. 1803 Nov 16

Studies of different fragments and mutants of SP-B suggest that the function related structural and compositional characteristics in SP-B are its positive charges with intermittent hydrophobic domains. KL4 ([lysine-(leucine)4]4-lysine) is a synthetic peptide based on SP-B structure and is the major constituent of Surfaxin, a potential therapeutic agent for respiratory distress syndrome in premature infants. There is, however, no clear understanding about the possible lipid-KL4 interactions behind its function, which is an inevitable knowledge to design improved therapeutic agents. To examine the phase behavior, topography, and lipid specificity of KL4/lipid systems, we aimed to study different surfactant model systems containing KL4, neutral dipalmitoylphosphatidylcholine (DPPC) and/or negatively charged dipalmitoylphosphatidylglycerol (DPPG) in the presence of Ca2+ ions. Surface pressure-area isotherms, fluorescence microscopic images, scanning force microscopy as well as time-of-flight secondary ion mass spectrometry suggest (i) that KL4 is not miscible with DPPC and therefore forms peptide aggregates in DPPC/KL4 mixtures; (ii) that KL4 specifically interacts with DPPG via electrostatic interactions and induces percolation of DPPG-rich phases; (iii) that existing DPPG-Ca2+ interactions are too strong to be overcome by KL4, the reason why the peptide remains excluded from condensed DPPG domains and passively colocalizes with DPPC in a demixed fluid phase; and (iv) that the presence of negatively charged lipid is necessary for the formation of bilayer protrusions. These results indicate that the capability of the peptide to induce the formation of a defined surface-confined reservoir depends on the lipid environment, especially on the presence of anionic lipids.
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PMID:The surfactant peptide KL4 in lipid monolayers: phase behavior, topography, and chemical distribution. 1809 83

The metabolism, composition, structure and functions of the alveolar surfactant (AS) are described. The most adequate biophysical models for investigation of AS are considered. The principals and possibilities of three mostly used models are described in details: Monolayers, Spinning drop method and Thin liquid films. Some of the studies of Bulgarian biophysical, physicochemical, biochemical and medical groups on the structure and mechanism of action of AS in vivo using samples of amniotic fluid (AF), animal pulmonary lavages (PL) and tracheal aspirates (TA) of newborns and adults are summarized. The role of specific surfactant proteins (SP-A, SP-B, SP-C and SP-D) on the properties and function of AS is demonstrated. The opportunities of the model investigations for application in laboratory pre- and postnatal diagnosis of the respiratory distress syndrome (RDS), as well as for the efficiency of RDS therapy during exogenous surfactant therapy with ALEC (UK), Survanta (USA), Exosurf (USA), Curosurf (Italy) u Alveofact (Germany) are considered.
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PMID:[Pulmonary surfactants: in vivo structure and in vitro biophysical models for investigation and its perspectives]. 1817 10

Surfactant therapy leads to significant clinical improvement in infants at risk for, or having, respiratory distress syndrome (RDS). The development of exogenous surfactant (ES) as a therapy for neonatal respiratory disorders was a significant advance in neonatal intensive care that has led to a decrease in neonatal mortality. Two broad categories of surfactants are available for exogenous therapy: surfactants derived from animal sources or 'natural' surfactants; and synthetic surfactants. The physical properties of natural and synthetic surfactants have been studied using techniques such as the Wilhelmy surface balance and the bilayer black film (BBF) method. Here we report some data from a comparative study of ES (Exosurf, Survanta, Curosurf and Alveofact) and clinical samples of tracheal aspirate (TA) of newborns with RDS treated with Curosurf. Measured interfacial physico-chemical parameters prove "better" properties in vitro of the surfactant proteins (SP-B and SP-C) containing preparations Curosurf and Alveofact. Their properties are similar, Alveofact showing a higher surface tension lowering capacity under dynamic conditions. A compendious comparison of results for dynamic surface properties of monolayers of TA from newborns treated with Curosurf with data for newborns treated with Exosurf is presented. Both ES yield the desired lowering of the surface tension during cyclic film compression, being larger after treatment with Curosurf. Observations concerning the properties of BFF of ES (dependence on surfactant concentration, adsorption time, film drainage time and BFF formation time) are also reported and discussed.
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PMID:[Biophysical models in investigations of exogenous surfactant activities on the surface tension and their theurapeutic effectiveness]. 1817 92


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