Publications
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Bernardino de la Serna J, Hansen S, Berzina Z, et al., 2013, Compositional and structural characterization of monolayers and bilayers composed of native pulmonary surfactant from wild type mice, BBA: Biomembranes, Vol: 1828, Pages: 2450-2459, ISSN: 0005-2736
This work comprises a structural and dynamical study of monolayers and bilayers composed of native pulmonary surfactant from mice. Spatially resolved information was obtained using fluorescence (confocal, wide field and two photon excitation) and atomic force microscopy methods. Lipid mass spectrometry experiments were also performed in order to obtain relevant information on the lipid composition of this material. Bilayers composed of mice pulmonary surfactant showed coexistence of distinct domains at room temperature, with morphologies and lateral packing resembling the coexistence of liquid ordered (lo)/liquid disordered (ld)-like phases reported previously in porcine lung surfactant. Interestingly, the molar ratio of saturated (mostly DPPC)/non-saturated phospholipid species and cholesterol measured in the innate material corresponds with that of a DOPC/DPPC/cholesterol mixture showing lo/ld phase coexistence at a similar temperature. This suggests that at quasi-equilibrium conditions, key lipid classes in this complex biological material are still able to produce the same scaffold observed in relevant but simpler model lipid mixtures. Also, robust structural and dynamical similarities between mono- and bi-layers composed of mice pulmonary surfactant were observed when the monolayers reach a surface pressure of 30 mN/m. This value is in line with theoretically predicted and recently measured surface pressures, where the monolayer–bilayer equivalence occurs in samples composed of single phospholipids. Finally, squeezed out material attached to pulmonary surfactant monolayers was observed at surface pressures near the beginning of the monolayer reversible exclusion plateau (~ 40 mN/m). Under these conditions this material adopts elongated tubular shapes and displays ordered lateral packing as indicated by spatially resolved LAURDAN GP measurements.
Eggeling C, Mueller V, Honigmann A, et al., 2013, New Insight into Lipid-Protein Membrane Organization and its Functionality with Super-Resolution STED Microscopy, 57th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 5A-5A, ISSN: 0006-3495
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Bernardino de la Serna J, Vargas R, Picardi V, et al., 2013, Segregated ordered lipid phases and protein-promoted membrane cohesivity are required for pulmonary surfactant films to stabilize and protect the respiratory surface, FARADAY DISCUSSIONS, Vol: 161, Pages: 535-548, ISSN: 1359-6640
Caschera F, de la Serna JB, Loffler PMG, et al., 2011, Stable vesicles composed of monocarboxylic or dicarboxylic fatty acids and trimethylammonium amphiphiles, Langmuir: the ACS journal of surfaces and colloids, Vol: 27, Pages: 14078-14090, ISSN: 0743-7463
The self-assembly of cationic and anionic amphiphile mixtures into vesicles in aqueous media was studied using two different systems: (i) decanoic acid and trimethyldecylammonium bromide and (ii) hexadecanedioic acid (a simple bola-amphiphile) and trimethyldecylammonium bromide. The resulting vesicles with varying amphiphile ratios were characterized using parameters such as the critical vesicle concentration, pH sensitivity, and encapsulation efficiency. We also produced and observed giant vesicles from these mixtures using the electroformation method and confocal microscopy. The mixed catanionic vesicles were shown to be more stable than those formed by pure fatty acids. Those containing bola-amphiphile even showed the encapsulation of a small hydrophilic solute (8-hydroxypyrene-1,3,6-trisulfonic-acid), suggesting a denser packing of the amphiphiles. Compression and kinetics analysis of monolayers composed of these amphiphiles mixtures at the air/water interface suggests that the stabilization of the structures can be attributed to two main interactions between headgroups, predominantly the formation of hydrogen bonds between protonated and deprotonated acids and the additional electrostatic interactions between ammonium and acid headgroups.
Brown NJ, Dohm MT, de la Serna JB, et al., 2011, Biomimetic N-terminal alkylation of peptoid analogues of surfactant protein C, Biophysical Journal, Vol: 101, Pages: 1076-1085, ISSN: 0006-3495
Surfactant protein C (SP-C) is a hydrophobic lipopeptide that is critical for lung function, in part because it physically catalyzes the formation of surface-associated surfactant reservoirs. Many of SP-C's key biophysical properties derive from its highly stable and hydrophobic α-helix. However, SP-C's posttranslational modification with N-terminal palmitoyl chains also seems to be quite important. We created a new (to our knowledge) class of variants of a synthetic, biomimetic family of peptide mimics (peptoids) that allow us to study the functional effects of biomimetic N-terminal alkylation in vitro. Mimics were designed to emulate the amphipathic patterning, helicity, and hydrophobicity of SP-C, and to include no, one, or two vicinal amide-linked, N-terminal octadecyl chains (providing a reach equivalent to that of natural palmitoyl chains). Pulsating bubble surfactometry and Langmuir-Wilhelmy surface balance studies showed that alkylation improved biomimetic surface activities, yielding lower film compressibility and lower maximum dynamic surface tensions. Atomic force microscopy studies indicated that alkyl chains bind to and retain segregated interfacial surfactant phases at low surface tensions by inducing 3D structural transitions in the monolayer's fluid-like phase, forming surfactant-associated reservoirs. Peptoid-based SP-C mimics are easily produced and purified, and offer much higher chemical and secondary structure stability than polypeptide-based mimics. In surfactant replacements intended for medical use, synthetic SP mimics reduce the odds of pathogen contamination, which may facilitate the wider use of surfactant treatment of respiratory disorders and diseases.
de la Serna JB, Hansen S, Berzina Z, et al., 2011, Respiration: An Immiscibility Interfacial Phenomenon, 55th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 19-19, ISSN: 0006-3495
Steimle KL, Mogensen ML, Karbing DS, et al., 2011, A model of ventilation of the healthy human lung, Computer Methods and Programs in Biomedicine, Vol: 101, Pages: 144-155, ISSN: 0169-2607
This paper presents a model of the lung mechanics which simulates the pulmonary alveolar ventilation. The model includes aspects of: the alveolar geometry; pressure due to the chest wall; pressure due to surface tension determined by surfactant activity; pressure due to lung tissue elasticity; and pressure due to the hydrostatic effects of the lung tissue and blood. The cross-sectional area of the lungs in the supine position derived from computed tomography is used to construct a horizontally layered model, which simulates heterogeneous ventilation distribution from the non-dependent to the dependent layers of the lungs. The model is in agreement with experimentally measured hysteresis of the pressure–volume curve of the lungs, static lung compliance, changes in lung depth during breathing and density distributions at total lung capacity (TLC) and residual volume (RV). In the dependent layers of the lungs, alveolar collapse may occur at RV, depending on the assumptions concerning lung tissue elasticity at very low alveolar volumes. The model simulations showed that ventilation increased with depth in the lungs, although not as pronounced as observed experimentally. The model simulates alveolar ventilation including all of the mentioned components of the respiratory system and to be validated against all the above mentioned experimental data.
Andreassen S, Steimle KL, Mogensen ML, et al., 2010, The effect of tissue elastic properties and surfactant on alveolar stability, Journal of Applied Physiology, Vol: 109, Pages: 1369-1377, ISSN: 1522-1601
This paper presents a novel mathematical model of alveoli, which simulates the effects of tissue elasticity and surfactant on the stability of human alveoli. The model incorporates a spherical approximation to the alveolar geometry, the hysteretic behavior of pulmonary surfactant and tissue elasticity. The model shows that the alveolus without surfactant and the elastic properties of the lung tissue are always at an unstable equilibrium, with the capability both to collapse irreversibly and to open with infinite volume when the alveolus has small opening radii. During normal tidal breathing, the alveolus can becomes stable, if surfactant is added. Including the passive effect of tissue elasticity stabilizes the alveolus, further allowing the alveoli to be stable, even for lung volumes below residual volume. The model is the first to describe the combined effects of tissue elasticity and surfactant on alveolar stability. The model may be used as an integrated part of a more comprehensive model of the respiratory system, since it can predict opening pressures of alveoli.
Javanainen M, Monticelli L, de la Serna JB, et al., 2010, Free volume theory applied to lateral diffusion in Langmuir monolayers: atomistic simulations for a protein-free model of lung surfactant, Langmuir: the ACS journal of surfaces and colloids, Vol: 26, Pages: 15436-15444, ISSN: 0743-7463
We hereby present a study on lateral diffusion of lipids in Langmuir monolayers. We apply atomistic molecular dynamics simulations to a model system whose composition is consistent with protein-free lung surfactant. Our main focus is on the assessment of the validity of the free volume theory for lateral diffusion and on the interpretation of the cross-sectional area and activation energy parameters appearing in the theory. We find that the diffusion results can be fitted to the description given by the free volume theory, but the interpretation of its parameters is not straightforward. While the cross-sectional area appears to be related to the hard-core cross-sectional area of a lipid, its role in the lateral diffusion process is unclear. Also, the activation energy derived using the free volume theory is different from the activation energy found through Arrhenius analysis, and its physical interpretation remains elusive. Finally, we find that lipid diffusion does not occur via rapid single-particle “jumps”. Instead, lipids move in a concerted manner as loosely defined transient clusters, as observed earlier for lipid bilayers.
Dohm MT, Brown NJ, Seurynck-Servoss SL, et al., 2010, Mimicking SP-C palmitoylation on a peptoid-based SP-B analogue markedly improves surface activity, BBA: Biomembranes, Vol: 1798, Pages: 1663-1678, ISSN: 0005-2736
Hydrophobic lung surfactant proteins B and C (SP-B and SP-C) are critical for normal respiration in vertebrates, and each comprises specific structural attributes that enable the surface-tension-reducing ability of the lipid–protein mixture in lung surfactant. The difficulty in obtaining pure SP-B and SP-C on a large scale has hindered efforts to develop a non-animal-derived surfactant replacement therapy for respiratory distress. Although peptide-based SP-C mimics exhibit similar activity to the natural protein, helical peptide-based mimics of SP-B benefit from dimeric structures. To determine if in vitro surface activity improvements in a mixed lipid film could be garnered without creating a dimerized structural motif, a helical and cationic peptoid-based SP-B mimic was modified by SP-C-like N-terminus alkylation with octadecylamine. “Hybridized” mono- and dialkylated peptoids significantly decreased the maximum surface tension of the lipid film during cycling on the pulsating bubble surfactometer relative to the unalkylated variant. Peptoids were localized in the fluid phase of giant unilamellar vesicle lipid bilayers, as has been described for SP-B and SP-C. Using Langmuir–Wilhelmy surface balance epifluorescence imaging (FM) and atomic force microscopy (AFM), only lipid-alkylated peptoid films revealed micro- and nanostructures closely resembling films containing SP-B. AFM images of lipid-alkylated peptoid films showed gel condensed-phase domains surrounded by a distinct phase containing “nanosilo” structures believed to enhance re-spreading of submonolayer material. N-terminus alkylation may be a simple, effective method for increasing lipid affinity and surface activity of single-helix SP-B mimics.
Possmayer F, Hall SB, Haller T, et al., 2010, Recent advances in alveolar biology: some new looks at the alveolar interface, Respiratory Physiology and Neurobiology, Vol: 173, Pages: S55-S64, ISSN: 1569-9048
This article examines the manner in which some new methodologies and novel concepts have contributed to our understanding of how pulmonary surfactant reduces alveolar surface tension. Investigations utilizing small angle X-ray diffraction, inverted interface fluorescence microscopy, time of flight-secondary ion mass spectroscopy, atomic force microscopy, two-photon fluorescence microscopy and electrospray mass spectroscopy are highlighted and a new model of ventilation-induced acute lung injury described. This contribution attempts to emphasize how these new approaches have resulted in a fuller appreciation of events presumably occurring at the alveolar interface.
de la Serna JB, Hansen S, Berzina Z, et al., 2010, Lipid composition can predict mice native pulmonary surfactant membranes. 2. Fluid phase coexistence in bilayers and monolayers, 51st International Conference of the Bioscience of Lipids (ICBL), Publisher: ELSEVIER IRELAND LTD, Pages: S5-S5, ISSN: 0009-3084
de la Serna JB, Hansen S, Berzina Z, et al., 2010, Native pulmonary surfactant membranes show similar phase segregation in bilayers and monolayers, both qualitatively and quantitatively, as predicted by lipid composition analysis, 51st International Conference of the Bioscience of Lipids (ICBL), Publisher: ELSEVIER IRELAND LTD, Pages: S31-S31, ISSN: 0009-3084
Brewer J, de la Serna JB, Wagner K, et al., 2010, Multiphoton excitation fluorescence microscopy in planar membrane systems, BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, Vol: 1798, Pages: 1301-1308, ISSN: 0005-2736
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- Citations: 45
de la Serna JB, Hansen S, Hannibal-Bach HK, et al., 2010, Native Pulmonary Surfactant Membranes in Mice Show Coexistence of Two Different Phases in Bilayers and Monolayers: When the Lipid Composition can Predict the Structural Phase Segregations, Publisher: CELL PRESS, Pages: 287A-287A, ISSN: 0006-3495
Bernardino de la Serna J, Oradd G, Bagatolli LA, et al., 2009, Segregated phases in pulmonary surfactant membranes do not show coexistence of lipid populations with differentiated dynamic properties, Biophysical Journal, Vol: 97, Pages: 1381-1389, ISSN: 0006-3495
The composition of pulmonary surfactant membranes and films has evolved to support a complex lateral structure, including segregation of ordered/disordered phases maintained up to physiological temperatures. In this study, we have analyzed the temperature-dependent dynamic properties of native surfactant membranes and membranes reconstituted from two surfactant hydrophobic fractions (i.e., all the lipids plus the hydrophobic proteins SP-B and SP-C, or only the total lipid fraction). These preparations show micrometer-sized fluid ordered/disordered phase coexistence, associated with a broad endothermic transition ending close to 37°C. However, both types of membrane exhibit uniform lipid mobility when analyzed by electron paramagnetic resonance with different spin-labeled phospholipids. A similar feature is observed with pulse-field gradient NMR experiments on oriented membranes reconstituted from the two types of surfactant hydrophobic extract. These latter results suggest that lipid dynamics are similar in the coexisting fluid phases observed by fluorescence microscopy. Additionally, it is found that surfactant proteins significantly reduce the average intramolecular lipid mobility and translational diffusion of phospholipids in the membranes, and that removal of cholesterol has a profound impact on both the lateral structure and dynamics of surfactant lipid membranes. We believe that the particular lipid composition of surfactant imposes a highly dynamic framework on the membrane structure, as well as maintains a lateral organization that is poised at the edge of critical transitions occurring under physiological conditions.
de la Serna JB, Hansen S, Hannibal-Bach HK, et al., 2009, Biophysical, Structural and Compositional characterization at the molecular level of Native Pulmonary Surfactant Membranes directly isolated from mice Wild-type and Knocked-out Protein D Bronco-alveolar Lavage Fluid, Publisher: CELL PRESS, Pages: 451A-451A, ISSN: 0006-3495
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Brewer J, de la Sern JBDLSB, Bagatolli L, 2009, Implementation of Two Photon Excitation Fluorescence Microscopy Techniques in Langmuir Films, Publisher: CELL PRESS, Pages: 149A-149A, ISSN: 0006-3495
Steimle KL, Mogensen ML, Karbing DS, et al., 2009, A mathematical physiological model of the pulmonary ventilation, Pages: 222-227, ISSN: 1474-6670
This paper presents a model of the lung mechanics and simulates the pulmonary alveolar ventilation. The model includes the alveolar geometry and distribution and pressures exerted by the chest wall, due to surface tension affected by surfactant activity, due to lung tissue elasticity and due to the hydrostatic effects of the lung tissue and blood utilizing a stratified subdivision of the lungs. The model simulates a heterogenous ventilation distribution down the lungs in agreement with experimental studies. Furthermore the model is in agreement with experimentally measured hysteresis, static lung compliance, lung volumes and density distribution at different lung volumes. The presented model is the first to simulate alveolar ventilation including all of the above mentioned components of the respiratory system. © 2009 IFAC.
Zasadzinski JA, Alig TF, Alonso C, et al., 2005, Inhibition of pulmonary surfactant adsorption by serum and the mechanisms of reversal by hydrophilic polymers: theory, Biophysical Journal, Vol: 89, Pages: 1621-1629, ISSN: 0006-3495
A theory based on the Smolukowski analysis of colloid stability shows that the presence of charged, surface-active serum proteins at the alveolar air-liquid interface can severely reduce or eliminate the adsorption of lung surfactant from the subphase to the interface, consistent with the observations reported in the companion article (pages 1769–1779). Adding nonadsorbing, hydrophilic polymers to the subphase provides a depletion attraction between the surfactant aggregates and the interface, which can overcome the steric and electrostatic resistance to adsorption induced by serum. The depletion force increases with polymer concentration as well as with polymer molecular weight. Increasing the surfactant concentration has a much smaller effect than adding polymer, as is observed. Natural hydrophilic polymers, like the SP-A present in native surfactant, or hyaluronan, normally present in the alveolar fluids, can enhance adsorption in the presence of serum to eliminate inactivation.
Taeusch HW, de la Serna JB, Perez-Gil J, et al., 2005, Inactivation of pulmonary surfactant due to serum-inhibited adsorption and reversal by hydrophilic polymers: experimental, Biophysical Journal, Vol: 89, Pages: 1769-1779, ISSN: 0006-3495
The rate of change of surface pressure, p, in a Langmuir trough following the deposition of surfactant suspensions on subphases containing serum, with or without polymers, is used to model a likely cause of surfactant inactivation in vivo:inhibition of surfactant adsorption due to competitive adsorption of surface active serum proteins. Aqueous suspensions ofnative porcine surfactant, organic extracts of native surfactant, and the clinical surfactants Curosurf, Infasurf, and Survantaspread on buffered subphases increase the surface pressure, p, to ;40 mN/m within 2 min. The variation with concentration,temperature, and mode of spreading confirmed Brewster angle microscopy observations that subphase to surface adsorption ofsurfactant is the dominant form of surfactant transport to the interface. However (with the exception of native porcine surfactant),similar rapid increases in p did not occur when surfactants were applied to subphases containing serum. Components of serumare surface active and adsorb reversibly to the interface increasing p up to a concentration-dependent saturation value, pmax.When surfactants were applied to subphases containing serum, the increase in p was significantly slowed or eliminated.Therefore, serum at the interface presents a barrier to surfactant adsorption. Addition of either hyaluronan (normally found inalveolar fluid) or polyethylene glycol to subphases containing serum reversed inhibition by restoring the rate of surfactantadsorption to that of the clean interface, thereby allowing surfactant to overcome the serum-induced barrier to adsorption
de la Serna JB, Perez-Gil J, Simonsen AC, et al., 2004, Cholesterol rules - direct observation of the coexistence of two fluid phases in native pulmonary surfactant membranes at physiological temperatures, Journal of Biological Chemistry, Vol: 279, Pages: 40715-40722, ISSN: 0021-9258
Pulmonary surfactant, the lipid-protein material that stabilizes the respiratory surface of the lungs, contains approximately equimolar amounts of saturated and unsaturated phospholipid species and significant proportions of cholesterol. Such lipid composition suggests that the membranes taking part in the surfactant structures could be organized heterogeneously in the form of inplane domains, originating from particular distributions of specific proteins and lipids. Here we report novel results concerning the lateral organization of bilayer membranes made of native pulmonary surfactant where the coexistence of two distinct micrometer sized fluid phases (fluid ordered and fluid disordered-like phases) is observed at physiological temperatures by using fluorescence microscopy and atomic force microscopy. Additional experiments using fluorescent-labeled proteins SP-B and SP-C show that at physiological temperatures these hydrophobic proteins are located exclusively in the fluid disordered-like phase. Most interestingly, the microscopic coexistence of fluid phases is maintained up to 37.5 °C, where most fluid ordered phases melt. This observation suggests that the particular composition of this material is naturally designed to be at the “edge” of a lateral structure transition under physiological conditions, likely providing particular structural and dynamic properties for its mechanical function. The observed lateral structure in native pulmonary surfactant membranes is dramatically affected by the extraction of cholesterol, an effect not observed upon extraction of the surfactant proteins. Furthermore, the spreading properties of the native surfactant material at the air-liquid interface were also greatly affected by cholesterol extraction, suggesting a connection between the observed lateral structure and a physiologically relevant function of the material. We suggest that the particular lipid composition of surfactant could be finely tuned to provi
Taeusch W, de la Serna JB, Alonso C, et al., 2004, Spreading of pulmonary surfactants with and without subphase inhibitors and polymers, Annual Meeting of the Pediatric-Academic-Societies, Publisher: INT PEDIATRIC RESEARCH FOUNDATION, INC, Pages: 513A-513A, ISSN: 0031-3998
Taeusch HW, de la Serna JB, Alonso C, et al., 2004, Spreading of pulmonary surfactants with and without subphase inhibitors and polymers., 227th National Meeting of the American-Chemical Society, Publisher: AMER CHEMICAL SOC, Pages: U864-U864, ISSN: 0065-7727
Simonsen AC, de la Serna JB, Bagatolli L, et al., 2004, Lateral organization in native pulmonary surfactant films visualized by combined AFM and fluorescence imaging, 48th Annual Meeting of the Biophysical Society, Publisher: BIOPHYSICAL SOCIETY, Pages: 203A-203A, ISSN: 0006-3495
de la Serna JB, Simonsen AC, Perez-Gil J, et al., 2004, Coexistence of two fluid phases in native porcine pulmonary surfactant membranes: cholesterol rules, 48th Annual Meeting of the Biophysical Society, Publisher: BIOPHYSICAL SOCIETY, Pages: 335A-335A, ISSN: 0006-3495
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de la Serna JB, Perez-Gil J, Bagatolli LA, 2004, Role of hydrophobic proteins, SP-B and SP-C, and cholesterol in the lateral structure of native porcine pulmonary surfactant giant unilamellar vesicles., 48th Annual Meeting of the Biophysical Society, Publisher: BIOPHYSICAL SOCIETY, Pages: 203A-203A, ISSN: 0006-3495
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