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Lung surfactant-associated protein interaction with lipid matrices and the effects on lipid thermotropic phase behavior are areas of active research. Many studies limit the lipids to a single or two-component system. The current investigation utilizes a three-lipid component matrix (DPPC:POPG:palmitic acid) to investigate the impact of a synthetic surfactant protein B fragment (SP-B 53-78 DiACM) on the dynamic surface activity of the lipid admixture as measured by a Wilhelmy surface balance. Also, the modulation of the individual lipid acyl chain order by the peptide within the lipid matrix is studied through the use of thermal perturbation FTIR spectroscopy. The data clearly demonstrate a concentration-dependent effect of the peptide on the surface activity with an improvement in the dynamic surface tension diagram characteristics (decreased surface tension and increased collapse plateau) especially at low, 0.36 M%, peptide concentrations. These effects are diminished upon further addition of the peptide. FTIR spectral data demonstrate that the peptide addition results in a significant increase in the acyl chain order of the DPPC and POPG components as measured by the position of the methylene stretching vibrational bands. DPPC is most sensitive to the peptide presence, while the palmitic acid is least affected. The transition temperatures of the individual lipids are also increased with the addition of the peptide. The presence of POPG in the matrix achieves the surface activity similarly seen with natural lung surfactant relative to a DPPC/palmitic acid lipid matrix alone. Its presence increases the sensitivity of the DPPC acyl chains to the presence of the peptide. These effects on the chain order are most probably related to the increased acyl chain fluidity which POPG imparts to the lipid matrix because of the presence of the cis double bond. The phosphatidylglycerol headgroup also adds a negative charge to the lipid matrix which enhances the peptide-lipid interaction. Although the palmitic acid is minimally affected by the peptide, its presence, as suggested by surface balance measurements, results in the establishment of a stable lipid film with DPPC, capable of achieving low surface tension values.
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PMID:Pulmonary lung surfactant synthetic peptide concentration-dependent modulation of DPPC and POPG acyl chain order in a DPPC:POPG:palmitic acid lipid mixture. 803 57

Genetic ablation of the murine SP-B gene in transgenic mice caused lethal perinatal respiratory distress in homozygous offspring, whereas heterozygous SP-B (+/-) mice survived postnatally. In adult SP-B(+/-) mice, surfactant protein B mRNA and the alveolar lavage SP-B protein were reduced by 50% compared with wild-type littermates, consistent with the inactivation of a single SP-B allele. Expression of SP-A, SP-C, and SP-D proteins was not affected in SP-B(+/-) mice. Heterozygous SP-B(+/-) mice reached maturity in numbers expected by Mendelian inheritance of a recessive gene. Lung morphology and both intracellular and extracellular phospholipid pool size and composition were unaltered in the SP-B(+/-) mice. Despite normal survival, pulmonary function studies demonstrated a consistent decrease in lung compliance in SP-B(+/-) mice. Abnormalities of inflation/deflation curves demonstrated airway collapse at low deflation pressures. Residual volumes were increased in the SP-B(+/-) mice. In summary, SP-B mRNA and SP-B protein were reduced by 50% in SP-B(+/-) mice, resulting in abnormalities of lung compliance and air trapping, suggesting a potential susceptibility to pulmonary dysfunction associated with SP-B deficiency.
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PMID:Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice. 899 78

Near-term newborn rabbits were exposed via the airways to a monoclonal antibody to surfactant protein B and ventilated for 0-120 min. Control animals received nonspecific rabbit or mouse immunoglobulin G, saline, or no material via the airways. Administration of the antibody at > or = 40 mg/kg elicited an immediate, significant fall in lung-thorax compliance associated with progressive intra-alveolar edema and/or alveolar collapse and necrosis and desquamation of airway epithelium, and hyaline membranes. The vascular-to-alveolar leak of human albumin and human immunoglobulin G, injected intravenously at birth and determined in lung lavage fluid 60-120 min after instillation of the antibody, was 1.8% for the left lung, with no difference between the markers. The average leak in control animals ventilated for 120 min was < 0.3% (P < 0.05). Cytospin preparations of lung lavage fluid from animals exposed to the antibody showed significantly increased recruitment of neutrophilic granulocytes. The pathology and pathophysiology of neonatal lung injury induced by the monoclonal antibody to surfactant protein B probably reflect a combination of direct inactivation of surfactant and an inflammatory response triggered by the immune reaction.
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PMID:Pathophysiology of neonatal lung injury induced by monoclonal antibody to surfactant protein B. 917 70

The mechanisms that direct positive-stranded RNA virus replication complexes to plant and animal cellular membranes are poorly understood. We describe a specific interaction between a replication protein of an RNA plant virus and membranes in vitro and in live cells. The tobacco etch virus (TEV) 6 kDa protein associated with membranes as an integral protein via a central 19 amino acid hydrophobic domain. In the presence or absence of other viral proteins, fluorescent fusion proteins containing the 6 kDa protein associated with large vesicular compartments derived from the endoplasmic reticulum (ER). Infection by TEV was associated with a collapse of the ER network into a series of discrete aggregated structures. Viral RNA replication complexes from infected cells were also associated with ER-like membranes. Targeting of TEV RNA replication complexes to membranous sites of replication is proposed to involve post-translational interactions between the 6 kDa protein and the ER.
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PMID:Formation of plant RNA virus replication complexes on membranes: role of an endoplasmic reticulum-targeted viral protein. 923 14

The acid-labile poly(ethyleneglycol)-diorthoester-distearoylglycerol lipid (POD), was used with a cationic lipid-phosphatidylethanolamine mixture to prepare stabilized plasmid-lipid nanoparticles (POD SPLP) that could mediate gene transfer in vitro by a pH triggered escape from the endosome. Nanoparticles of 60 nm diameter were prepared at pH 8.5 using a detergent dialysis method. The DNA encapsulation efficiency in the nanoparticles was optimal between 10 and 13 mol % ratio of cationic lipid and at a POD content of 20 mol %. The apparent zeta potential of the nanoparticles at 1 mM salt and pH 7.5 was positive, indicating cationic lipid on the external surface. However, the external layer of the nanoparticles was depleted in the cationic component compared to the starting mole ratio. Low pH sensitivity of the POD SPLP was characterized by a lag phase followed by a rapid collapse; at pH 5.3 the nanoparticles collapsed in 100 min. Nanoparticles prepared from a pH-insensitive PEG-lipid, PEG-distearoylglycerol had similar physicochemical characteristics as the POD SPLP but did not collapse at low pH. The POD SPLP had up to 3 orders of magnitude greater gene transfer activity than did the pH-insensitive nanoparticles. Both the pH-sensitive and pH-insensitive nanoparticles were internalized to a qualitatively similar extent in a punctate pattern into cultured cells within 2 h of incubation with the cells; thus, increased gene transfer of the POD SPLP was due to a more rapid escape from the endosome rather than to greater cell association of these nanoparticles. These results suggest that the pH-sensitive stabilized plasmid-lipid nanoparticles may be a useful component of a synthetic vector for parenterally administered gene therapy.
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PMID:Low-pH-sensitive PEG-stabilized plasmid-lipid nanoparticles: preparation and characterization. 1264 53

Diving mammals that descend to depths of 50-70 m or greater fully collapse the gas exchanging portions of their lungs and then reexpand these areas with ascent. To investigate whether these animals may have evolved a uniquely developed surfactant system to facilitate repetitive alveolar collapse and expansion, we have analyzed surfactant in bronchoalveolar lavage fluid (BAL) obtained from nine pinnipeds and from pigs and humans. In contrast to BAL from terrestrial mammals, BAL from pinnipeds has a higher concentration of phospholipid and relatively more fluidic phosphatidylcholine molecular species, perhaps to facilitate rapid spreading during alveolar reexpansion. Normalized concentrations of hydrophobic surfactant proteins B and C were not significantly different among pinnipeds and terrestrial mammals by immunologic assay, but separation of proteins by gel electrophoresis indicated a greater content of surfactant protein B in elephant seal surfactant than in human surfactant. Remarkably, surfactant from the deepest diving pinnipeds produced moderately elevated in vitro minimum surface tension measurements, a finding not explained by the presence of protein or neutral lipid inhibitors. Further study of the composition and function of pinniped surfactants may contribute to the design of optimized therapeutic surfactants.
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PMID:Surfactant from diving aquatic mammals. 1468 33

The authors have recently reported the presence of characteristic foamy swelling/degeneration (giant lamellar body degeneration, GLBD) of type II pneumocytes in the lungs affected by Hermansky-Pudlak syndrome (HPS)-associated interstitial pneumonia (HPSIP), and proposed the hypothesis that GLBD may be the triggering factor in the development of HPSIP (Virchows Arch 2000; 437: 304-13). The purpose of the present paper was to investigate the lung pathology of pale ear (ep) mouse, a mouse model of HPS1, and of beige (bg) mouse, a mouse model of Chediak-Higashi syndrome (CHS) with a reference to GLBD and associated pathologic changes. GLBD was found in both ep and bg mice soon after birth, and increased in severity as the mice grew older. Younger mice had only GLBD with no evidence of interstitial change. Aged bg mice showed the most prominent GLBD and patchy areas of alveolar collapse accompanied by lymphocytic infiltration and slight fibrosis. Aged ep mice with less severe GLBD than bg mice of comparable ages also had a slight tendency to develop interstitial inflammation but no fibrosis. The pneumocytes with GLBD were immunoreactive for surfactant protein B and composed of giant lamellar bodies ultrastructurally, findings which were almost identical to those of human GLBD. The results of the present study support the hypothesis that GLBD may play an important role in the development of HPSIP. Ep and bg mice, especially the latter, may be useful mouse models of HPSIP.
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PMID:Lung pathology of pale ear mouse (model of Hermansky-Pudlak syndrome 1) and beige mouse (model of Chediak-Higashi syndrome): severity of giant lamellar body degeneration of type II pneumocytes correlates with interstitial inflammation. 1574 22

Harlequin ichthyosis (HI), which is the most severe genodermatosis, is caused by loss-of-function mutations in ABCA12, a member of the ATP-binding cassette transporter family. To investigate the pathomechanism of HI and the function of the ABCA12 protein, we generated ABCA12-deficient mice (Abca12(-/-)) by targeting Abca12. Abca12(-/-) mice closely reproduce the human HI phenotype, showing marked hyperkeratosis with eclabium and skin fissure. Lamellar granule abnormalities and defective ceramide distribution were remarkable in the epidermis. Skin permeability assay of Abca12(-/-) fetuses revealed severe skin barrier dysfunction after the initiation of keratinization. Surprisingly, the Abca12(-/-) mice also demonstrated lung alveolar collapse immediately after birth. Lamellar bodies in alveolar type II cells of the Abca12(-/-) mice lacked normal lamellar structures. The level of surfactant protein B, an essential component of alveolar surfactant, was reduced in the Abca12(-/-) mice. Fetal therapeutic trials with systemic administration of retinoid or dexamethasone, which are effective for HI and respiratory distress, respectively, to the pregnant mother mice neither improved the skin phenotype nor extended the survival period. Our HI model mice reproduce the human HI skin phenotype soon after the initiation of fetal skin keratinization and provide evidence that ABCA12 plays pivotal roles in lung and skin barrier functions.
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PMID:Harlequin ichthyosis model mouse reveals alveolar collapse and severe fetal skin barrier defects. 1863 86

Mutations in the genes encoding the surfactant proteins B and C (SP-B and SP-C) and the phospholipid transporter, ABCA3, are associated with respiratory distress and interstitial lung disease in the pediatric population. Expression of these proteins is regulated developmentally, increasing with gestational age, and is critical for pulmonary surfactant function at birth. Pulmonary surfactant is a unique mixture of lipids and proteins that reduces surface tension at the air-liquid interface, preventing collapse of the lung at the end of expiration. SP-B and ABCA3 are required for the normal organization and packaging of surfactant phospholipids into specialized secretory organelles, known as lamellar bodies, while both SP-B and SP-C are important for adsorption of secreted surfactant phospholipids to the alveolar surface. In general, mutations in the SP-B gene SFTPB are associated with fatal respiratory distress in the neonatal period, and mutations in the SP-C gene SFTPC are more commonly associated with interstitial lung disease in older infants, children, and adults. Mutations in the ABCA3 gene are associated with both phenotypes. Despite this general classification, there is considerable overlap in the clinical and histologic characteristics of these genetic disorders. In this review, similarities and differences in the presentation of these disorders with an emphasis on their histochemical and ultrastructural features will be described, along with a brief discussion of surfactant metabolism. Mechanisms involved in the pathogenesis of lung disease caused by mutations in these genes will also be discussed.
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PMID:Genetic disorders of surfactant dysfunction. 1922 77

Pulmonary surfactant protein B (SP-B) facilitates the rapid transfer of phospholipids from bilayer stores into air-liquid interfacial films along the breathing cycle, and contributes to the formation of a surface-associated multilayer reservoir of surfactant to optimize the stability of the respiratory interface. To obtain more insights into the mechanisms underlying this transfer and multilayer formation, we established a simple model system that captures different features of SP-B action. We monitored the formation of supported planar bilayers from the collapse of intact phospholipid vesicles on a silica surface using a technique called quartz crystal microbalance with dissipation, which provides information on changes in membrane thickness and viscosity. At physiologically relevant concentrations, SP-B dramatically alters vesicle collapse. This manifests itself as a reduced buildup of intact vesicles on the surface before collapse, and allows the stepwise buildup of multilayered deposits. Accumulation of lipids in these multilayer deposits requires the presence of SP-B in both the receptor and the arriving membranes, surrounded by a comparable phospholipid charge. Thus, the quartz crystal microbalance with dissipation system provides a useful, simplified way to mimic the effect of surfactant protein on vesicle dynamics and permits a detailed characterization of the parameters governing reorganization of surfactant layers.
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PMID:Surfactant protein SP-B strongly modifies surface collapse of phospholipid vesicles: insights from a quartz crystal microbalance with dissipation. 1965 Oct 35


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