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PubMed2003

Preparation of a stable phospholipid monolayer grafted onto a methacryloyl-terminated substrate as blood compatible materials.

We have prepared a surface-grafted phospholipid monolayer by in situ polymerization carried out at the interface between a pre-assembled phospholipid monolayer and a methacryloyl-terminated substrate. The phospholipid containing an acryloyl moiety, 1-stearoyl-2-[12-(acryloyloxy)-dodecanoyll-sn-glycero-3-phosphocholine (acryloyl-PC), was pre-assembled by vesicle fusion onto methacryloyl-terminated substrates which were silanized with 3-(trimethoxysilyl)propyl methacrylate (TSM). The acryloyl-PC monolayer and methacryloyl-terminated substrates were then polymerized in situ by adding a water-soluble initiator, 2,2-azobis(2-methylpropionamidine) dihydrochloride (AAPD), at 60 degrees C for 15 min. Atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) measurements indicated that the polymerized phospholipid surface on the TSM-silanized substrates formed a lipid monolayer structure with some defects. The polymerized phospholipid surfaces also showed good stability in methanol due to chemical bonding to solid surfaces. The grafting efficiency of acryloyl-PC monolayer on the TSM substrate, which was calculated by the relative carbon ratio of the polymerized acryloyl-PC monolayer on TSM substrate before and after methanol washing, was 94.5%. For comparative analysis, the acryloyl-PC monolayer was also polymerized onto dimethyl-terminated substrates silanized with dichlorodimethylsilane (DCM). In the absence of surface grafting moieties on solid substrates, the laterally polymerized acryloyl-PC monolayer physically adsorbed on substrates was easily removed in an organic solvent. The surface-grafted phospholipid monolayer was also greatly effective in the prevention of platelet adhesion.

Animals↗
PubMed1997

Primary importance of zwitterionic over anionic phospholipids in the surface-active function of calf lung surfactant extract.

The relative contributions of zwitterionic and anionic phospholipids to the surface-active function of calf lung surfactant extract (CLSE) were assessed by measurements of surface properties in vitro and pressure-volume (P-V) mechanics in excised rat lungs in situ. Surface activity and mechanical effects were compared for chromatographically purified CLSE subfractions containing the complete mix of phospholipids (PPL) or modified phospholipids depleted in anionic components (mPPL), alone or combined with 1.3% (by weight) of hydrophobic surfactant proteins (SP-B and SP-C). Surface pressure-time (pi-t) adsorption isotherms at 37 degrees C were very similar for dispersions of PPL and mPPL in a Teflon dish with a stirred subphase to minimize diffusion resistance. Combination of either PPL or mPPL with hydrophobic SP substantially improved adsorption, but mixtures of PPL:SP and mPPL:SP had only small differences in pi-t isotherms and reached the same final equilibrium pi of approximately 47 mN/m achieved by CLSE. Surface pressure-area (pi-A) isotherms and maximum surface pressures were also very similar for spread films of PPL versus mPPL and PPL:SP versus mPPL:SP on the Wilhelmy balance (23 degrees C and 37 degrees C). Respreading based on pi-A isotherm area calculations was slightly better in surface-excess films of PPL versus mPPL and PPL:SP versus mPPL:SP, but differences were minor and were smaller at 37 degrees C than at 23 degrees C. Overall dynamic surface activity in oscillating bubble studies was not significantly different for PPL versus mPPL or for PPL:SP versus mPPL:SP, and the latter two mixtures both reached minimum surface tensions < 1 mN/m (37 degrees C, 20 cycles/min, 0.5 mM phospholipid). Dispersions of PPL:SP, mPPL:SP, and CLSE were also not significantly different in improving P-V mechanics almost to normal when instilled in lavaged, excised rat lungs at 37 degrees C (30 mg/2.5 ml saline). These data suggest that zwitterionic phospholipids have a major role over anionic phospholipids in interacting with hydrophobic SP in the adsorption, dynamic surface tension lowering, film respreading, and pulmonary mechanical activity of the hydrophobic components of calf lung surfactant in CLSE.

Absorption↗
PubMed1986

Reconstitution of surfactant activity using purified human apoprotein and phospholipids measured in vitro and in vivo.

The major apoprotein of human lung surfactant was isolated from amniotic fluid obtained at term gestation. It was found to be a disulfide-linked oligomer composed of polypeptide chains of 35,000 daltons. The monomeric unit was shown to be a glycoprotein, and treatment with peptide: N-glycosidase F resulted in a decrease in molecular weight to 31,000 daltons. The isolated apoprotein could be recombined in the presence of Ca++ with the phospholipids dipalmitoylphosphatidylcholine and phosphatidylglycerol (3:1) at a weight ratio of 1:100. The surface tension (gamma min) measured on a pulsating bubble formed in 4 mg/ml of phospholipids was reduced from 32.3 +/- 2.0 dyn X cm-1 to 18.0 +/- 0.6 dyn X cm-1 after 15 s when 1% apoprotein was present. Reduction of disulfide bonds and deglycosylation of the apoprotein did not alter its ability to lower gamma min. Fetal rabbits of 27 days gestation had instilled intratracheally at delivery, saline, phospholipids, phospholipids plus apoprotein, or natural human surfactant. The latter 2 resulted in increased lung compliance and striking improvement in homogeneous alveolar expansion when the lungs were expanded to 10 cm H2O pressure, fixed, and viewed histologically. This effect was also shown to be independent of the disulfide-dependent oligomeric structure of the apoprotein or its state of glycosylation. The surfactant produced by recombination of the phospholipids with the isolated apoprotein was, therefore, shown to be biophysically active both in vitro and in vivo. These data suggest that apoprotein can be recombined with phospholipids to produce a biologically active surfactant for use in clinical trials of human surfactant replacement.

Animals↗
PubMed1968

Hereditary nonspherocytic hemolytic disease associated with an altered phospholipid composition of the erythrocytes.

A hemolytic disorder with mild hyperbilirubinemia and reticulocytosis of 6 to 15% was documented in eight members of a large family from the Dominican Republic and was presumed to be present in eight other members. The disorder appeared to be inherited as an autosomal dominant characteristic. Analysis of phospholipids by quantitative thinlayer chromatography revealed a distinct increase in phosphatidyl choline (lecithin) to 35.5 +/- SD 1.3% of the total (normal: 28.2 +/- 1.4%) in erythrocytes of affected members of the family, but not in the cells of unaffected relatives. The alteration appeared to constitute an absolute increase in lecithin content, rather than a decrease in other phospholipids. Erythrocytes from patients with other varieties of hereditary hemolytic disorders and comparable levels of reticulocytosis had normal phospholipid compositions. Plasma lipids of six affected members of the family were not unusual with respect to total lipid weight, total phospholipid, and cholesterol. Three patients with liver disease and jaundice were found to have marked increases in the lecithin content of the erythrocytes, but they also had extremely high plasma levels of total lipid, phospholipids, and cholesterol. Osmotic fragility of the erythrocytes of affected patients was decreased and the increase in fragility after incubation for 24 hr was less than that observed with normal erythrocytes. Autohemolysis after 48 hr was slightly increased and was corrected to nearly normal by the addition of glucose. The activities of 15 enzymes of the erythrocytes of the propositus were normal or elevated and the adenosine triphosphate content was normal. An abnormal hemoglobin could not be demonstrated. The life span of isologous erythrocytes in the propositus was reduced, but homologous erythrocytes survived normally.A causal relationship between the altered phospholipid composition and the hemolytic disorder has not been established.

Adenosine Triphosphate↗
PubMed1990

Bacterial phospholipid hydrolysis enhances the destruction of Escherichia coli ingested by rabbit neutrophils. Role of cellular and extracellular phospholipases.

Escherichia coli ingested by PMN are promptly growth arrested but undergo limited destruction. We have studied bacterial phospholipid hydrolysis as a possible limiting factor in the disassembly of ingested E. coli, comparing the fates, during phagocytosis by rabbit peritoneal exudate PMN, of three isogenic strains, differing in their content of the pldA gene encoding the principal E. coli phospholipase A (PLA), i.e., pldA-, pldA+, pldA (the latter strain bearing the pldA gene in a multicopy plasmid resulting in a 20-fold increase in PLA content). Ingestion and growth inhibition (greater than 99% within 15 min) were the same for the three strains, but phospholipid degradation differed according to bacterial PLA content: pldA up to 60%, pldA+ up to 30%, and pldA- up to 20%. Since the pldA- strain has no activatable PLA, phospholipid degradation in this strain demonstrates the action of a PMN PLA. Added PLA2-rich ascitic fluid (AF) or purified AF PLA2 increased the rate and extent of degradation of the pldA- strain, provided the enzyme was added before ingestion was complete. 125I-AF-PLA2 binds to both E. coli and PMN and thus can enter the vacuole during phagocytosis. Although up to 50-fold more AF-PLA2 than the PLA2 content of the PMN could be loaded into the PMN in this way, degradation of pldA- E. coli did not exceed 30%. Increased phospholipid degradation had no effect on the degradation of bacterial macromolecules. In contrast, bacterial disassembly manifest as structural disorganization, release of bacterial protein derived material, and inhibition of protein synthesis were markedly enhanced when greater than 50% of prelabelled bacterial phospholipids were degraded. These findings reveal a link between envelope phospholipid degradation and overall bacterial destruction, suggesting therefore that factors limiting PLA action limit the destruction of E. coli ingested by PMN.

Animals↗
PubMed1997

Anti-beta2-glycoprotein I (beta2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta2GPI binding to phospholipids.

beta2-Glycoprotein I (beta2GPI), a plasma glycoprotein with phospholipid-binding property, is known to be the actual target antigen for autoimmune type anticardiolipin antibodies (aCLs). Certain groups of aCLs (anti-beta2GPI antibodies) exert lupus anticoagulant (LA) activity and perturb the function of vascular endothelial cells. This investigation aimed at highlighting some insights into the molecular basis by which aCLs exert their biological effects by using anti-beta2GPI mAbs with well-characterized epitopes from mice and from patients with antiphospholipid syndrome. Anti-beta2GPI mAbs directed against the third domain (Cof-20 and Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of beta2GPI inhibited the thrombin generation induced by Russell's viper venom in diluted plasma and that induced by the prothrombinase complex reconstituted with purified clotting factors. This anticoagulant activity was abrogated in the presence of an excess amount of phospholipids, thus resembling the LA activity. In stark contrast, anti-beta2GPI mAbs directed against the fifth domain and the carboxy-terminal region of the fourth domain showed no LA-like activity. These findings suggest that the LA activity of anti-beta2GPI antibodies depends on their epitope specificity. Experiments carried out to clarify the mechanism of the LA activity showed that anti-beta2GPI mAbs with LA-like activity, but not those without this effect, enhance the beta2GPI binding to phospholipids. In addition, the F(ab')2 fragment, but not the Fab' fragment, of the anti-beta2GPI mAbs was found to enhance the LA activity and the beta2GPI binding to phospholipids, suggesting that anti-beta2GPI antibodies induce formation of multiple complexes of beta2GPI on the surface of phospholipids because of their bivalent property. This clustering of beta2GPI molecules induced by anti-beta2GPI antibodies, probably because of their multivalent property and epitope specificity, might hinder the lateral mobility and activation of clotting factors on the surface of phospholipids and thus exert LA activity. Clustering of beta2GPI molecules may also explain the molecular mechanism by which anti-beta2GPI antibodies alter the function of leukocytes and endothelial cells. The well-documented heterogeneous LA activity of aCLs (anti-beta2GPI antibodies) may also be explained by their epitope specificity.

Animals↗
PubMed1997

Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy.

Hepatocellular secretion of bile salts into the biliary space induces phospholipid and cholesterol secretion, but the mechanism for integrated lipid secretion is poorly understood. Knockout mice unable to make the canalicular membrane mdr2 P-glycoprotein exhibit normal rates of bile salt secretion, yet are virtually incapable of secreting biliary phospholipid and cholesterol. As the mdr2 P-glycoprotein is thought to mediate transmembrane movement of phospholipid molecules, this mouse model was used to examine the mechanism for biliary phospholipid secretion. In wild-type mdr2 (+/+) mice, ultrarapid cryofixation of livers in situ revealed abundant unilamellar lipid vesicles within bile canalicular lumina. Although 74% of vesicles were adherent to the external aspect of the canalicular plasma membrane, bilayer exocytosis was not observed. Vesicle numbers in mdr2 (+/-) and (-/-) mice were 55 and 12% of wild-type levels, respectively. In a strain of mdr2 (-/-) mice which had been "rescued" by heterozygous genomic insertion of the MDR3 gene, the human homologue of the murine mdr2 gene, vesicle numbers returned to 95% of wild-type levels. Our findings indicate that biliary phospholipid is secreted as vesicles by a process largely dependent on the action of the murine mdr2 P-glycoprotein or human MDR3 P-glycoprotein. We conclude that mdr2-mediated phospholipid translocation from the internal to external hemileaflet of the canalicular membrane permits exovesiculation of the external hemileaflet, a vesiculation process promoted by the detergent environment of the bile canalicular lumen.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1995

Clinical significance of phospholipid-dependent anti-beta 2-glycoprotein I (beta 2-GPI) antibodies in systemic lupus erythematosus.

We investigated the clinical significance of IgG phospholipid-dependent anti-beta 2-glycoprotein I (beta 2-GPI) antibodies in patients with SLE. The study population consisted of 140 patients with SLE. Sera were examined for IgG phospholipid-dependent anti-beta 2-GPI antibodies by ELISA. IgG phospholipid-dependent anti-beta 2-GPI antibodies were detected in 21 of 140 patients (15%) and remained positive from 4 to 98 months. Significantly higher incidences of thrombosis, intrauterine fetal loss, thrombocytopenia, patients with antiphospholipid syndrome (APS), prolonged APTT, BFP-STS and hemolytic anemia were found in SLE patients with phospholipid-dependent anti-beta 2-GPI antibodies. Moreover, significantly lower incidences of malar rash and serositis were found in SLE patients with phospholipid-dependent anti-beta 2-GPI antibodies, and the majority of these patients satisfied four or five of the revised criteria items of the American Rheumatism Association. These differences were not observed when we compared clinical manifestations in anticardiolipin antibody-positive patients with those in antibody-negative patients by conventional ELISA. These results indicated that SLE patients with IgG phospholipid-dependent anti-beta 2-GPI antibodies show an unique form of SLE.

Adult↗
PubMed1998

Lupus anticoagulant antibodies: recognition of phospholipid-binding protein complexes.

Lupus anticoagulant antibodies form a heterogeneous group of antiphospholipid antibodies with rather poorly defined antigens. The role that phospholipid-binding proteins play in lupus anticoagulant antibody activity is a subject of current investigation. Several candidate proteins have been proposed, including beta2-glycoprotein I (beta2GPI), prothrombin, and annexin V. As beta2GPI-dependent lupus anticoagulants will be reviewed elsewhere in this issue, this paper will focus on the involvement of prothrombin and annexin V in lupus anticoagulant activity. Evidence for a role for these proteins in the reactivity and induction of lupus anticoagulant antibodies will be discussed, as well as an apparent requirement for both phospholipid and phospholipid-binding protein. The data presented here suggest that some lupus anticoagulant antibodies recognize and may be induced by complexes of phospholipid and phospholipid-binding proteins, in particular, phospholipid and prothrombin or annexin V.

Animals↗
PubMed2003

Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development.

The C2 domain of factor VIII (FVIII) mediates FVIII binding to von Willebrand factor (VWF) and phospholipids (PLs), thereby determining the stability and the activity of FVIII. A deletion of Ala2201 (Del2201) was identified in the FVIII C2 domain of 2 unrelated patients with mild hemophilia A (FVIII:C 11%-33%). This mutation prevents FVIII binding to a human monoclonal antibody recognizing the C2 domain and inhibiting FVIII binding to VWF and phospholipids. By comparison to healthy FVIII, Del2201 FVIII had a significantly reduced binding to VWF, which likely contributes to reduced FVIII levels in plasma. Del2201 FVIII interaction with phospholipids was evaluated in an FXa generation assay, using various concentrations of synthetic phospholipid vesicles mimicking an activated platelet surface. At the lowest phospholipid concentration allowing FXa generation, Del2201 FVIII activity was reduced 3-fold. This is the first report of a mutation altering FVIII binding to phospholipids and occurring in patients with hemophilia A.

Alanine↗
PubMed2006

Saposin B binds and transfers phospholipids.

Saposin B (Sap B) is a member of a family of four small glycoproteins, Sap A, B, C, and D. Like the other three saposins, Sap B plays a physiological role in the lysosomal degradation of sphingolipids (SLs). Although the interaction of Sap B with SLs has been investigated extensively, that with the main membrane lipid components, namely phospholipids and cholesterol (Chol), is scarcely known. Using large unilamellar vesicles (LUVs) as membrane models, we have now found that Sap B simultaneously extracts from the lipid surface neutral [phosphatidylcholine (PC)] and anionic [phosphatidylinositol (PI)] phospholipids, fewer SLs [ganglioside GM1 (GM1) or cerebroside sulfate (CS)], and no Chol. More PI than SL (GM1 or CS) was solubilized from LUVs containing equal amounts of PI and SLs. An increase in PI level had a poor effect on the Sap B-induced solubilization of GM1 or CS but strongly inhibited that of PC. Sap B was able not only to bind, but also to transfer phospholipids between lipid surfaces. Both the phospholipid binding and transfer activities were optimal at low pH values. These results represent the first biochemical analysis of the Sap B interaction with phospholipids. The capacity of Sap B to bind and transfer phospholipids occurs under conditions mimicking the interior of the late endosomal/lysosomal compartment and thus might have physiological relevance.

Chromatography, Gel↗
PubMed2003

Molecular species compositions of lung and pancreas phospholipids in the cftr(tm1HGU/tm1HGU) cystic fibrosis mouse.

Fatty acid analysis of phospholipid compositions of lung and pancreas cells from a cystic fibrosis transmembrane regulator (CFTR) negative mouse (cftr(-/-))suggested that a decreased concentration of docosahexaenoate (22:6(n-3)) and increased arachidonate (20:4(n-6)) may be related to the disease process in cystic fibrosis (CF). Consequently, we have determined compositions of the major phospholipids of lung, pancreas, liver, and plasma from a different mouse model of CF, the cftr(tm1HGU/tm1HGU) mouse, compared with ZTM:MF-1 control mice. Electrospray ionization mass spectrometry permitted the quantification of all of the individual molecular species of phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylglycerol (PtdGly), phosphatidylserine (PtdSer), and phosphatidylinositol (PtdIns). There was no deficiency of 22:6(n-3) in any phospholipid class from lung, pancreas, or liver from mice with the cftr(tm1HGU/tm1HGU). Instead, the concentration of 20:4(n-6) was significantly decreased in plasma PtdCho species and in pancreas and lung species of PtdEtn, PtdSer, and PtdIns. These results demonstrate the variability of membrane phospholipid compositions in different mouse models of CF and suggest that in cftr(tm1HGU/tm1HGU) mice, the apparent deficiency was of 20:4n-6- rather than of 22:6n-3-containing phospholipid species. They highlight a need for detailed phospholipid molecular species analysis of cells expressing mutant CFTR from children with CF before the therapeutic effects of administering high doses of 22:6(n-3)-containing oils to children with CF can be fully evaluated.

Animals↗
PubMed1981

Stimulation of phospholipid labeling and steroidogenesis by luteinizing hormone in isolated bovine luteal cells.

The present study was conducted to examine the effect of LH on phospholipid metabolism in corpora luteal tissue. Collagenase-dispersed cells obtained from bovine corpora lutea of early pregnancy were incubated with 32PO4 in the presence or absence of LH and examined for their ability to incorporate this label into phospholipids. LH (1 microgram/ml) significantly increased 32P incorporation into total lipid extracts, with a time course similar to that of progesterone synthesis. This stimulation of 32P incorporation was dependent on the concentrations of LH, and this dose-response relationship correlated well with the dose response of LH-induced progesterone production. Bovine serum albumin and ACTH had no apparent effect on 32P incorporation into phospholipids or progesterone production. Separation of luteal cell phospholipid extracts by thin layer chromatography revealed that LH stimulated the incorporation 32PO4, mainly into phosphatidic acid and phosphatidylinositol, with small increases occurring in the polyphosphoinositide fraction. The LH-induced labeling of these individual phospholipids also appeared to be temporally and dose-related to the LH-induced increases in progesterone synthesis. LH had no effect on the labeling of phosphatidylcholine, phosphatidylserine, sphingomyelin, or cardiolipin. These results indicate that LH has selective effects on phospholipid metabolism in bovine luteal cells which may be a part of the mechanism of action of LH on steroidogenesis.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1981

Kinetic aspects of cycloheximide-induced reversal of adrenocorticotropin effects on steroidogenesis and phospholipid metabolism in rat adrenal sections in vitro.

We examined the rate of cycloheximide-induced reversal of ACTH effects on steroidogenesis and phospholipid metabolism in adrenal sections in vitro. In the absence of cycloheximide, ACTH treatment elicited sustained increases in steroidogenesis (approximately 3- to 5-fold) and adrenal concentrations (approximately 2-fold) of phosphatidic acid, phosphatidylinositol, and polyphosphoinositides. These increases in phospholipids were not dependent on steroidogenesis, since they were also apparent in aminoglutethimide-blocked adrenal sections. The addition of cycloheximide 30 min after ACTH treatment reversed the stimulatory effects of ACTH on steroidogenesis and phospholipids, and the rates of decay for both processes were identical, viz 28 min. This relatively slow turnover in adrenal sections in vitro contrasts with a much more rapid turnover observed previously in vivo and presently in dispersed adrenal cells in vitro; thus, it appears that an artefact of the in vitro adrenal section system stabilizes the putative labile protein. More importantly, the identical rates of decay for steroidogenesis and phospholipids suggest that the same labile protein is required for both phospholipid metabolism and steroidogenesis. These findings are in keeping with our postulate that the labile protein is required for phospholipid metabolism, which, in turn, is required for steroidogenesis.

Adrenal Glands↗
PubMed2003

Mechanical constraint imposed on plasma membrane through transverse phospholipid imbalance induces reversible actin polymerization via phosphoinositide 3-kinase activation.

Platelets were used to explore the effect of membrane curvature induced by phospholipid excess on cell shape and on organization of the actin cytoskeleton. We showed that the addition of short chain analogues of phospholipids to the outer leaflet of plasma membrane of resting platelets immediately induced a shape change with long filopodia formation containing newly polymerized actin. Cells recovered rapidly their discoid shape and their initial F-actin content only with the phosphatidylserine analogue, which was transported to the inner leaflet by aminophospholipid translocase. Filopodia formation and actin polymerization were inhibited in platelets pre-incubated with cytochalasin D. Both wortmannin and LY294002, two unrelated inhibitors of phosphoinositide 3-kinase, considerably reduced actin polymerization and filopodia formation. Phospholipid imbalance was accompanied by a reversible translocation of phosphoinositide 3-kinase from cytoplasm to plasma membrane. In agreement with a role for PI 3-kinase, when phospholipids were added to platelets, PtdIns(3,4)P2 increased two-fold and Akt protein was partly phosphorylated. A similar shape change was also observed in nocodazole-treated L929 fibroblasts which were incubated with the similar phospholipid analogues. In those nucleated cells, where the microtubule cytoskeleton was disrupted, a major actin-dependent membrane extension was induced by addition of short chain phospholipids that required the functional integrity of PI 3-kinase. We conclude that any physical constraint acting on plasma membrane and resulting on local changes in membrane curvature is sufficient to initiate transient actin polymerization via phosphoinositide 3-kinase activation.

Actin Cytoskeleton↗
PubMed1986

A possible contribution of phospholipids in tissue distribution of quinidine in rats.

The tissue distribution of quinidine was investigated at three different steady-state plasma concentrations of quinidine in rats. The tissue distribution of quinidine (tissue-to-plasma concentration ratio, Ct/Cp) was studied in the liver, lung, kidney and heart and the highest distribution was found in the lung. Tissue binding characteristics of quinidine was determined in normal tissue homogenates and lipid-depleted tissue homogenates in vitro. No correlation was observed between the tissue bindings (product of association constant (K1) and number of binding sites (n), nK1) estimated in each normal tissue homogenate and the values of Ct/Cp in vivo. However, a marked decrease in the tissue binding of quinidine was observed in all lipid-depleted tissue homogenates, and the largest decrease was observed in the lung tissue. This result suggested that lipid may have an important role in the tissue binding of quinidine. However, no good relationship was observed between the values of Ct/Cp and the phospholipid contents in each tissue. In order to investigate the role of lipid in the tissue binding of quinidine, phospholipids extracted from each tissue were used for binding study. The phospholipids binding of quinidine (nK2) increased in the following order; heart less than liver less than kidney less than lung, and the plots of the values of Ct/Cp obtained in vivo against the binding ability of phospholipids (product of nK2 and the content of phospholipid in each tissue) gave a good linear relationship. Based on these observations, it was concluded that some species of phospholipids had an important and determining role in the tissue distribution of quinidine in vivo.

Animals↗
PubMed2005

Effects of phospholipids on the oligomeric state of phospholamban of the cardiac sarcoplasmic reticulum.

BACKGROUND: Phospholamban is a reversible inhibitor of the Ca(2+)-ATPase of the cardiac sarcoplasmic reticulum (SR) and contributes to the regulation of heart muscle contractility. Because only the monomeric form, not the pentameric form, of phospholamban inhibits the Ca2+-pumping activity of the SR, it is important to understand the dynamic equilibrium between these 2 forms. METHODS AND RESULTS: The effects of various detergents and phospholipids on the oligomeric state of phospholamban were examined. Among the detergents examined, 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) stabilized the pentameric form whereas octylglucoside was an effective inducer of dissociation into the monomer. On the basis of these properties of the 2 detergents, the effects of various phospholipids on the oligomeric state of phospholamban with the use of mixed micelles containing octylglucoside or CHAPS were examined. Among the 8 phospholipids examined, phosphatidic acid was an effective inducer of pentamer dissociation, whereas the other phospholipids exhibited pentamer-stabilizing activity. Lysophosphatidylcholine, lysophosphatidylethanolamine, and phosphatidylglycerol were highly effective stabilizers of the pentamer. CONCLUSIONS: The phospholipids in the SR membrane are important determinants of the equilibrium between the monomeric and pentameric forms of this protein. The results suggest that the metabolism of phospholipids in the cardiac SR may contribute to regulation of heart muscle contractility by shifting this equilibrium.

Animals↗
PubMedDate not supplied

Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion.

BACKGROUND: Lipids and lipoproteins have been shown to bind and neutralize endotoxin and to improve outcomes in animal models of sepsis. OBJECTIVE: To provide safety and pharmacokinetic data for a protein-free, phospholipid-rich emulsion developed as an agent to neutralize endotoxin, and to study the changes in lipids and lipoproteins following emulsion administration. METHODS: Thirty healthy male volunteers (aged 18-45 y) were given an emulsion containing 92.5% soy phospholipid, 7.5% soy triglyceride, and 18 mM sodium cholate using a double-blind, placebo-controlled crossover protocol. Emulsion at 3 escalating doses (75, 150, 300 mg/kg) based on phospholipid content was administered by intravenous infusion over 2 hours in the low- and mid-dose groups and 6 hours in the high-dose group. RESULTS: All subjects completed the protocol without significant toxicities. A slight dose-dependent increase in indirect bilirubin at the 24-hour time point was observed in the emulsion treatment period, with a maximum difference between placebo and emulsion of 0.9 mg/dL. Mean +/- SD peak phospholipid levels were 316 +/- 30, 533 +/- 53, and 709 +/- 86 mg/dL, and phospholipid half-lives were 5.4 +/- 0.6, 5.4 +/- 0.5, and 8.0 +/- 0.8 hours for the low, mid, and high doses, respectively. Increases in total cholesterol, low-density lipoprotein cholesterol and apolipoprotein A-I and B levels were observed. High-density lipoprotein cholesterol decreased immediately following emulsion infusion, but rebounded to above placebo levels by 24 hours. CONCLUSIONS: A unique phospholipid-rich emulsion was shown to have a favorable safety profile and to expand the blood lipid and lipoprotein pool without the use of human-derived blood products. Lipid levels expected to protect against the physiologic effects of bacterial endotoxin were achieved.

Adolescent↗