More Than a Monolayer: Relating Lung Surfactant Structure and Mechanics to Composition

Alonso, Coralie; Alig, Tim; Yoon, Joonsung; Bringezu, Frank; Warriner, Heidi E.; Zasadzinski, Joseph A.

doi:10.1529/biophysj.104.051201

Cited by 150 publications

(262 citation statements)

References 68 publications

(176 reference statements)

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“…The multilayer structure has been proposed to have arrangements similar to the bulk phases formed in LS extracts (LSEs) (6,(12)(13)(14) and in clinical multivesicular dispersions (15,16). Two types of multilayer structures have been observed: lamellar bodies with spherically concentric bilayers and a tetragonal structure called tubular myelin (6,17).…”

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confidence: 99%

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Effect of cholesterol on the molecular structure and transitions in a clinical-grade lung surfactant extract

Andersson

Grey

Larsson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The lipid-protein film covering the interface of the lung alveolar in mammals is vital for proper lung function and its deficiency is related to a range of diseases. Here we present a molecular-level characterization of a clinical-grade porcine lung surfactant extract using a multitechnique approach consisting of 1 H-13 C solid-state nuclear magnetic spectroscopy, small-and wide-angle X-ray scattering, and mass spectrometry. The detailed characterization presented for reconstituted membranes of a lung extract demonstrates that the molecular structure of lung surfactant strongly depends on the concentration of cholesterol. If cholesterol makes up about 11% of the total dry weight of lung surfactant, the surfactant extract adopts a single liquid-ordered lamellar phase, L α(o) , at physiological temperatures. This L α(o) phase gradually changes into a liquid-disordered lamellar phase, L α(d) , when the temperature is increased by a few degrees. In the absence of cholesterol the system segregates into one lamellar gel phase and one L α(d) phase. Remarkably, it was possible to measure a large set of order parameter magnitudes |S CH | from the liquiddisordered and -ordered lamellar phases and assign them to specific C-H bonds of the phospholipids in the biological extract with no use of isotopic labeling. These findings with molecular details on lung surfactant mixtures together with the presented NMR methodology may guide further development of pulmonary surfactant pharmaceuticals that better mimic the physiological selfassembly compositions for treatment of pathological states such as respiratory distress syndrome.T he air-alveoli interface of human lungs consists of ∼100 m 2 of surface area covered by a 1-to 2-µm-thick film rich in lipids, generally referred to as lung surfactant (LS) (1, 2). The alveolar interfacial film has several important functions, including stabilizing the interface, allowing for area expansions and controlling diffusional transport (3-7). These functions strongly rely on the self-assembly structure, as well as on the mechanical, barrier, and surface properties of the dynamic LS interfacial layer, which in turn depend on its chemical composition and external conditions in terms of compression, hydration, and so on. The main components of LS are phospholipids, cholesterol, and the so-called surfactant proteins representing ∼80, 10, and 10 wt %, respectively (2).Deficiency of LS in the alveoli, or an imbalance of its chemical composition, induces a number of pathological conditions (8). For instance, neonatal respiratory distress syndrome affects prematurely born infants when LS is not yet matured or is completely lacking; this deficiency may be lethal if left untreated. In these cases, the most common treatment is intratracheal administration of an exogenous LS into the lungs (9). In case of acute respiratory distress syndrome the mortality is 35 to 45% (10) and an effective treatment is clearly lacking (8). An accurate characterization of the molecular structure and dynamics of endogenous an...

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“…10 wt % cholesterol (2). LSE samples with low cholesterol content have also been commonly used in biophysical characterization studies (11,13,15,16,(21)(22)(23)(24). We aim for an overview picture of the self-assembly in LS mixtures, and we explore phase structure, transitions, and molecular dynamics for a range of cholesterol contents and temperatures.…”

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confidence: 99%

Effect of cholesterol on the molecular structure and transitions in a clinical-grade lung surfactant extract

Andersson

Grey

Larsson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…6B). The similar saturated alkyl chains of both PA and hexadecanol drive cocrystallization with DPPC, and therefore greater surface viscosities (27,30,31). By contrast, the sterol ring of cholesterol cannot pack into the alkane lattice of DPPC and thus degrades the DPPC crystal, leading to disordered, low-viscosity nanodomains, which lowers the surface viscosity of the mixed films as ln η s ∝ ϕ DPPC ln η DPPC .…”

Section: (Details In Supporting Information)mentioning

confidence: 99%

Effect of cholesterol nanodomains on monolayer morphology and dynamics

Kim

Choi

Zell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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At low mole fractions, cholesterol segregates into 10-to 100-nmdiameter nanodomains dispersed throughout primarily dipalmitoylphosphatidylcholine (DPPC) domains in mixed DPPC:cholesterol monolayers. The nanodomains consist of 6:1 DPPC:cholesterol "complexes" that decorate and lengthen DPPC domain boundaries, consistent with a reduced line tension, λ. The surface viscosity of the monolayer, η s , decreases exponentially with the area fraction of the nanodomains at fixed surface pressure over the 0.1-to 10-Hz range of frequencies common to respiration. At fixed cholesterol fraction, the surface viscosity increases exponentially with surface pressure in similar ways for all cholesterol fractions. This increase can be explained with a free-area model that relates η s to the pure DPPC monolayer compressibility and collapse pressure. The elastic modulus, G′, initially decreases with cholesterol fraction, consistent with the decrease in λ expected from the line-active nanodomains, in analogy to 3D emulsions. However, increasing cholesterol further causes a sharp increase in G′ between 4 and 5 mol% cholesterol owing to an evolution in the domain morphology, so that the monolayer is elastic rather than viscous over 0.1-10 Hz. Understanding the effects of small mole fractions of cholesterol should help resolve the controversial role cholesterol plays in human lung surfactants and may give clues as to how cholesterol influences raft formation in cell membranes.surface rheology | isotherms | free-volume model | AFM M inute fractions of cholesterol lead to dramatic changes in dipalmitoylphosphatidylcholine (DPPC) monolayer morphology (Figs. 1-3) (1, 2) and have equally dramatic effects on monolayer dynamic properties. One weight percent cholesterol reduces the surface viscosity, η s , of DPPC monolayers by an order of magnitude, and 2 wt% reduces η s by two orders of magnitude . Atomic force microscopy (AFM) images and microrheological data show that the cholesterol is segregated to lineactive, locally disordered nanodomains that are dispersed in and separate ordered, primarily DPPC domains. As a result, the monolayer retains many of the features of pure DPPC monolayers including a high collapse pressure, high compressibility, and so on, while having significantly lower surface viscosity. This surface viscosity effect suggests a role for cholesterol in lung surfactant (LS), a lipid-protein monolayer necessary to reduce the surface tension in the lung alveoli during respiration (Fig. S1) (3, 4). At present, even the existence of cholesterol in native LS is questioned, because the lung lavage required to harvest LS inevitably causes blood and cell debris to be coextracted, potentially contaminating LS with cholesterol (5). This lack of consensus over the role of cholesterol is reflected in the composition of replacement lung surfactants for neonatal respiratory distress syndrome (NRDS), which occurs in 20,000-30,000 premature births each year (6). Survanta and Curosurf, two clinically approved animalextract replacement surfact...

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“…This charged phospholipid has shown to provide specific interactions with the hydrophobic proteins, especially SP-B, contributing to optimize their biophysical activity [25,26]. A classical and substantially the stability of interfacial films, which are thus able to maintain very low surface tensions when repeatedly compressed [43,44]. The problem is that these palmitic-containing mixtures reach and maintain low surface tensions at the cost of bearing a high viscosity, both as lipid/protein or lipid/peptide suspensions and as interfacial films.…”

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Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Mingarro¹,

Lukovic²,

Vilar³

et al. 2008

CMC

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Pulmonary surfactant is a lipid-protein complex that coats the interior of the alveoli and enables the lungs to function properly. Upon its synthesis, lung surfactant adsorbs at the interface between the air and the hypophase, a capillary aqueous layer covering the alveoli. By lowering and modulating surface tension during breathing, lung surfactant reduces respiratory work of expansion, and stabilises alveoli against collapse during expiration.Pulmonary surfactant deficiency, or dysfunction, contributes to several respiratory pathologies, such as infant respiratory distress syndrome (IRDS) in premature neonates, and acute respiratory distress syndrome (ARDS) in children and adults. The main clinical exogenous surfactants currently in use to treat some of these pathologies are essentially organic extracts obtained from animal lungs. Although very efficient, natural surfactants bear serious defects: i) they could vary in composition from batch to batch; ii) their production involves relatively high costs, and sources are limited; and iii) they carry a potential risk of transmission of animal infectious agents and the possibility of immunological reaction. All these caveats justify the necessity for a highly controlled synthetic material.In the present review the efforts aimed at new surfactant development, including the modification of existing exogenous surfactants by adding molecules that can enhance their activity, and the progress achieved in the production of completely new preparations, are discussed. Pulmonary surfactant function and dysfunctionThe respiratory surface of lungs constitutes the largest area of the human body exposed to the environment. Efficient gas exchange requires a large enough surface to be continuously exposed to air while minimising the barriers for oxygen and carbon dioxide to diffuse between air and the blood compartment [1]. At the same time, a selection of combined defence mechanisms is required to help keep such an essentially exposed area sterile of potential pathogenic microorganisms. Pulmonary surfactant, a lipid-protein complex produced by the alveolar epithelium of lungs, has been optimised to coordinate two main activities through natural evolution. On the one hand, it stabilises the respiratory surface against physical forces, therefore minimising the work required to maintain the large respiratory surface open to air [2][3][4]. On the other hand, pulmonary surfactant contains elements responsible for establishing a primary innate antipathogenic barrier, essential to ensure an intrinsically low pathogen load in the absence of induced defence mechanisms [5]. Extensive research in the last few decades has revealed some of the molecular mechanisms involved in pulmonary surfactant action. However, the manner in which both the biophysical and defence activities are intermingled and coordinately modulated in the alveolar spaces is now only beginning to be envisioned.Pulmonary surfactant is composed of approximately 90% lipids and 8-10% proteins, although only around 5% ...

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More Than a Monolayer: Relating Lung Surfactant Structure and Mechanics to Composition

Cited by 150 publications

References 68 publications

Effect of cholesterol on the molecular structure and transitions in a clinical-grade lung surfactant extract

Effect of cholesterol on the molecular structure and transitions in a clinical-grade lung surfactant extract

Effect of cholesterol nanodomains on monolayer morphology and dynamics

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

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