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* Systèmes Organisés Fluorés à Finalités Thérapeutiques (SOFFT), Institut Charles Sadron (UPR CNRS 22), 67083 Strasbourg Cedex, France; Laboratoire de Chimie Bioorganique (UMR CNRS 7514), Université Louis Pasteur, 67401 Illkirch, France; Institut des NanoSciences de Paris (INSP), Campus Boucicaut, 75015 Paris, France; and Synchrotron SOLEIL, l'Orme des Merisiers, Saint Aubin, BP 48 91192 Gif-sur-Yvette Cedex, France
Correspondence: Address reprint requests to Dr. Marie Pierre Krafft, Institut Charles Sadron (CNRS, UPR 22), 6 rue Boussingault, 67083 Strasbourg Cedex, France. Tel.: 33-3-88-41-40-60; Fax: 33-3-88-41-40-99. E-mail: krafft{at}ics.u-strasbg.fr.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCES |
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), in particular for intravascular oxygen transport (2) and for the stabilization of gaseous microbubbles used as contrast agent in ultrasound imaging (3). Partial liquid ventilation (PLV) with FCs has been explored as a treatment of acute respiratory distress syndrome (ARDS). Improved oxygenation and lung compliance were achieved in preterm animal models (4) as well as in premature infants (5,6). FC-based PLV was also reported to have an antiinflammatory effect in the alveolar environment of trauma patients (7). The fact that FCs attenuate the proinflammatory and procoagulatory responses of activated monocytes and of alveolar macrophages may contribute to the protective role of FCs in injuries associated with local activation of inflammatory processes (8). Delivery of vaporized FCs to oleic acid-injured ARDS sheep resulted in significant and sustained improvements of gas exchange and of lung compliance (9,10). Although these results suggest that FCs may be useful in pulmonary disease therapy, no study aiming at determining the influence of FCs on LS or LS models appears to have been reported so far, to our knowledge.
The native LS is a complex mixture of lipids and proteins that forms a monolayer at the alveolus/air interface of mammalian species (11,12). LS is secreted into the alveolar space by epithelial type II pneumocytes via exocytosis (13,14). It contains several lipids, primarily DPPC, small fractions of polyunsaturated fatty-acid-containing phospholipids (PUFA-PL), anionic PLs such as phosphatidylglycerols (PGs), neutral lipids such as diacyl- and triacylglycerols, free fatty acids such as palmitic acid (PA), plasmalogens, and cholesterol (15). LS also contains four specific proteins (SP-A, SP-B, SP-C, and SP-D). One key role of LS is to form a monolayer that lowers the air/alveoli surface tension upon compression (i.e., during expiration), reduces the work of breathing, and respreads easily on expansion (i.e., during inspiration) (16,17).
The LS function has been described by the "squeeze out" model (18). Upon compression, the minor components (predominantly nonphosphatidylcholine compounds) are squeezed out from the monolayer, which results in an enrichment of the monolayer in phosphatidylcholine compounds. Surface tension is then reduced and alveolar collapse is prevented. However, the physicochemical properties of the major surfactant-PL fraction were not in accordance with the predicted requirements of this model (19). A new concept involving a "surface-associated reservoir" was suggested as an improved model (20,21). In this model of surfactant function, layers of LS are folded in the subphase and remain in contact with the monolayer at the air/liquid interface. One key role of the minor components of LS is to decrease the surface viscosity of the monolayer (19). SP-B and SP-C are small amphiphilic proteins that were recently shown to play an important role in the surface activity of the LS (22,23). Recent work has focused on designing lipid mixtures that combine the surface activity of PLs (and neutral lipids) and the fluidizing properties of plasmalogens, PUFA-PL, and SP-B (15).
Although DPPC can generate near-zero surface tension at the air/water interface during compression, it is a poor LS when used alone. This is because it tends to form rigid, multilamellar structures in solution and does not adsorb efficiently at the air/water interface. When present at the interface, DPPC forms a monolayer that is in the semicrystalline liquid-condensed (LC) state (24). Moreover, DPPC does not respread upon expansion because of the formation of stable, two-dimensional crystalline domains at the air/water interface.
Several LS substitutes (for example, Curosurf (Chiesi Pharmaceutici, Parma, Italy) and Survanta (Ross Laboratories, Columbus, OH)) have been developed and are being clinically used in the treatment of neonatal respiratory distress syndrome (NRDS). These replacement LS consist of purified preparations of bovine (Survanta) or porcine (Curosurf) LS. Being natural extracts, these preparations are, however, not devoid of potential viral contamination and inherent immunological risks. Other drawbacks include a costly purification procedure and the difficulty of achieving batch-to-batch consistency. Therefore, there is a clear need for alternative synthetic LS substitutes (25).
We found that FC gases have a strong effect on the physical state of DPPC Langmuir monolayers upon compression. Langmuir monolayers provide useful model systems for studying LS. Great care is necessary when extrapolating Langmuir monolayer behavior to LS behavior in vivo. General correlations between in vitro and in vivo behavior start, however, to emerge (26). The behavior of surfactants in monolayers is characterized by surface pressure – molecular area (
– A) compression isotherms. Compression isotherms of DPPC monolayers were measured under an atmosphere saturated with various gFCs. Fluorescence microscopy (FM) and grazing incidence x-ray diffraction (GIXD) were used to determine the presence, morphology, and degree of order of the organized domains within the monolayers. Because FCs have low intermolecular cohesiveness, their vapor pressures are high with regard to their molecular weights (27). The FCs selected for this study, perfluorooctyl bromide (PFOB), perfluorooctylethane (PFOE), bis(perfluorobutyl)ethene (F-44E), perfluorodecalin (FDC), and perfluorooctane (PFO), were chosen among those most thoroughly investigated for biomedical applications, in particular for intravascular oxygen transport (2). Both the ability of gFCs to prevent the formation of crystalline DPPC domains and their ability to dissolve such domains once formed were determined. We have also compared the behavior of DPPC monolayers contacted with gFCs with that of monolayers of the commercial LS substitutes Curosurf and Survanta.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCES |
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-1,2-dipalmitoyl-sn-3-glycero-phosphatidylcholine (DPPC, purity >99%) were purchased from Sigma (St. Louis, MO). Samples of Curosurf and Survanta were a gift from Prof. J. Messer (Service de Néonatalogie, Hôpital de Hautepierre, Strasbourg, France). Water was purified using a Millipore system (pH = 5.5; surface tension: 72.1 mN m–1 at 20°C, resistivity: 18 M
cm). The fluorescent dye (2-[6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino] hexanoyl-1-hexadecanoyl-sn-glycero-3-phosphocholine, NBDC6-HPC) was purchased from Molecular Probes (Eugene, OR).
Methods
Compression of DPPC monolayers under FC gases
Surface pressure, , versus molecular area, A, isotherms were recorded on a Langmuir minitrough (Riegler & Kirstein, Potsdam, Germany) equipped with two movable barriers (speed: 2.0 mm min–1, which corresponds to a reduction of the total area of 3% min–1). The surface pressure was measured using the Wilhelmy plate method. The trough was enclosed in a gas-tight box (volume = 9 L). The gas-tight box was flushed either with pure N2 or with N2 saturated with the chosen FC. In the latter case, N2 was allowed to bubble at room temperature through the liquid FC before being flushed into the gas-tight box. The flow rate of the gas phase (N2 or N2 saturated with the FC) was set to 1.2 L min–1 for PFOB, PFOE, F-44E, and FDC and 0.5 L min–1 for PFO. The evaporation rate of these FCs was then 
6 mL h–1. The temperature measured inside the gas-tight box was 26°C ± 0.5°C. The errors on and A were estimated to be ± 1 mN m–1 and ± 1 Å2, respectively. The molecular formula and physical characteristics of the FCs investigated are collected in Table 1. Spreading solutions of DPPC (1.0 mmol L–1 for minitrough experiments and 2.0 mmol L–1 for GIXD experiments) were prepared in chloroform (analytical grade). A total of 15 µL of DPPC solution was spread on the water surface.
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Grazing incidence x-ray diffraction
GIXD experiments were achieved at the D41B beamline of the LURE-DCI synchrotron source (Orsay, France). The x-ray wavelength 
= 1.646 Å of the incoming x-ray beam was selected using a focusing Ge (111) monochromator. The monocrystalline surface of a Ge plate (
111
) is used to select a monochromatic beam of wavelength 1.646 Å from the white synchrotron beam (28). The grazing angle of incidence 
i = 2.08 mrad was set slightly below the critical angle for total external reflection of the x-rays at the air/water interface (2.8 mrad at 1.646 Å). For the acquisition of the diffracted intensity, we used a new setup composed of a two-dimensional detector and a single vertical slit positioned between the sample and the detector (28). The resulting qxy resolution was 0.007 Å–1 for the q-range explored here. The shape of the Bragg rods gave information about the tilt angle t and tilt azimuth 
(29). In the following, the rectangular description of the chain lattice will be used (30). The diffraction pattern exhibits two peaks. The peak located at low qxy corresponds to the degenerate [11] and [
1] out-of-plane reflections, and the other peak to the [02] in-plane reflection. Since the maximum of intensity along the Bragg rods [11] and [1] is located out of the plane and in the scattering plane along the Bragg rod [02], the chains are tilted to the nearest neighbor. Thus, the observed phase is L2d (t 
0, = 0), according to the nomenclature introduced in Kaganer et al. (30).
The Teflon Langmuir trough mounted on the diffractometer was equipped with a movable single barrier. The surface pressure, , measured using the Wilhelmy plate method, was kept constant throughout a given scan. The trough was enclosed in a gas-tight box with Kapton windows flushed with water-saturated helium. Helium is the only gas that exerts sufficiently low absorption and scattering of the incident and diffracted x-ray beam to allow measurement of the diffraction of the monolayer at the interface. It is noteworthy that the diffraction and scattering level by N2 is too high to enable the diffraction measurement. When appropriate, helium was saturated with the chosen FC. With this chamber, the partial pressure of the FC was readily controlled. The temperature was regulated to 20°C ± 0.5°C. A total of 50 µL of DPPC solution were spread on the water surface. The film was compressed stepwise, and Bragg peaks were recorded at each set pressure step. The total duration of a scan was typically 10 min.
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RESULTS |
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,32). The phase transition surface pressure, eq, at a given temperature is a characteristic quantity for a given lipid in a monolayer on a given subphase. The eq value determined for DPPC from the isotherm was 10 mN m–1. This value is in agreement with the literature, which reports for DPPC on pure water, a eq value of 4 mN m–1 at 20°C shifted by 
eq/T + 1.5 mN m–1 K–1, until a tricritical point is reached at Tt 43°C (32). Enclosing the trough in the gas-tight box resulted in an increase of temperature of 1°C (26°C ± 0.5°C), which results in an increase of eq to 13 mN m–1. The LE/LC coexistence region is identified by the observation, by FM, of discrete domains of LC phase within a continuous LE phase (Fig. 2). When increases, the LC domains increase in size, become more numerous, and progressively merge into a continuous LC phase.
Compressing the DPPC monolayer under a N2 atmosphere saturated with a gFC changes the phase behavior drastically. The LE/LC transition at 13 mN m–1 (Fig. 1) disappears. The compression isotherm is now characterized by two kinks at 28 and 38 mN m–1. Below 38 mN m–1, the isotherm is shifted toward larger molecular areas, which indicates that FC molecules are incorporated into the DPPC monolayer. It is also noteworthy that, even at the beginning of the compression, the surface pressure is not zero as in the case of pure DPPC, but 2–4 mN m–1, which also shows that FC molecules are inserted into the DPPC monolayers.
The transition observed at 28 mN m–1 is no longer of the LE/LC type, as assessed by the fluorescence images that are bright and featureless (Fig. 2), not only at 28 mN m–1, but up to 35 mN m–1 (Fig. 2 c'). This suggests a conformational change of the FC molecules inserted in the DPPC monolayer. For higher than 38 mN m–1, the isotherm becomes steeper, and the limiting area (50 Å2) is then very comparable to the limiting area of the DPPC monolayer compressed in the absence of gFC. This indicates that the FC molecules are progressively squeezed out on the top of the DPPC monolayer. At such high surface pressures, FM images show the presence of very small crystalline domains, suggesting that the LE/LC transition occurred at 38 mN m–1. However, for these values, the images are not focused, probably due to the presence of PFOB molecules expelled from the DPPC monolayer, which likely form a thin liquid film with small droplets on top of the monolayer. It is noteworthy that for higher than 38 mN m–1, i.e., after squeeze out of the FC molecules, only small LC domains are seen as compared to the essentially continuous LC phase observed for DPPC under pure N2 at the same values. It is likely that the presence of a thin liquid FC film on top of the DPPC monolayer also disorganizes the DPPC molecules and contributes to the fluidization process at high surface pressures. Finally, it should be noticed that the presence of the gFC above the DPPC monolayer does not destabilize it.
The collapse surface pressure of the DPPC monolayer in contact with gFC is 71 mN m–1 (see inset in Fig. 1), i.e., is identical to the collapse surface pressure of the DPPC monolayer in the absence of gFC. This means that combinations of DPPC and gFC allow reaching very low surface tension values, which is necessary if gFCs are to be used in exogenous LS compositions.
These experiments demonstrate that gFC molecules interact with DPPC molecules and prevent the formation of the LC phase until high values of lateral pressure and hence induce a fluidizing effect in the monolayer.
An important issue with regard to the potential LS replacement application was to ensure that there is no delipidating effect of gPFOB on the DPPC monolayer. Fig. 3 represents the compression/expansion isotherms of DPPC in an atmosphere of N2 saturated with gPFOB. It shows clearly that very few DPPC molecules have desorbed from the air/water interface during the compression/expansion cycle. However, the shape of the expansion isotherm has significantly changed. Although the compression isotherm was characterized by two kinks at 28 and 38 mN m–1, only the latter kink was observed during expansion. The plateau observed around 38 mN m–1 is more clearly visible than during compression, and the expansion isotherm is much more expanded than the compression isotherm. FM images clearly show the presence of very small crystalline domains for pressures higher than 38 mN m–1 (data not shown). For values lower than 38 mN m–1, the images were bright and featureless, demonstrating that the monolayer was in a homogeneous LE phase (Fig. 2). This confirms that the LE/LC phase transition occurs at 38 mN m–1 for the DPPC monolayer in contact with gPFOB.
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28 mN m–1 is no longer visible during expansion. We have designed another experiment aimed at detecting any delipidating effect of the gFC in which the gas-tight box that had contained gPFOB-saturated N2 was flushed with pure N2 after the first compression/expansion cycle. This allowed us to thoroughly remove gPFOB (Fig. 3). It was observed that the compression isotherm of the DPPC monolayer after removal of gPFOB is similar to that obtained when compression was achieved in the absence of gPFOB. This indicates that the PFOB molecules are easily removed from the DPPC monolayer by evaporation. It also establishes that the fluidizing effect of gPFOB is a reversible phenomenon. The fact that, during the second compression, the limiting area is nearly identical to that observed during the first compression further indicates that the presence of gPFOB molecules does not provoke any significant loss of DPPC molecules to the subphase.
Similar results were obtained with the other FCs investigated. All gFCs interacted with DPPC, thus preventing the formation of the LC phase and inducing a fluidizing effect in the monolayer. This fluidizing effect was always reversible; removal of the gFC by N2 flushing of the gas-tight box resulted in the restoration of the isotherm of a pure DPPC monolayer, with the same limiting molecular area, which further demonstrates that no significant amount of DPPC molecules had been desorbed by the gFC.
Effect of gFCs on preformed LC domains
To assess the effect of gFCs on the DPPC semicrystalline domains that are already formed, DPPC monolayers were first compressed to 13 mN m–1 and gFC-saturated N2 was then allowed to flow into the gas-tight box that encloses the trough. The fluorescence images of Fig. 4 clearly show that, 3 min after the introduction of gPFOB, the LC domains have become significantly smaller. After 7 min, these domains have totally disappeared, indicating that the DPPC monolayer has become totally fluid. When the DPPC monolayer was contacted with gPFOE at 13 mN m–1, total fluidization of the monolayer was observed after 5 min (Fig. 5).
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5 min. The effect of F-44 E was comparable to that of PFOB (total fluidization in 7 min). The effect was slower with FDC (fluidization required 10 min). The lesser fluidizing capacity of the bicyclic FDC may be assigned to lesser affinity for hydrocarbon oils, as indicated by a higher critical solubility temperature (CST) in hexane (Table 1) and to its globular, bulky molecular shape.
FM provides information on a local scale. Small crystalline domains present at the interface may escape from the investigation field and not be taken into account. To have a definitive, independent assessment of any possible crystalline regions present in the monolayer, we performed GIXD using synchrotron radiation. An x-ray beam that hits the surface of water at an incidence lower than the critical angle of water (2.5 mrad) is totally reflected. Under these conditions, an evanescent wave is formed that is scattered by the monolayer. If the monolayer is ordered (i.e., crystalline), the wave is diffracted and Bragg peaks are obtained. GIXD thus provides global information on the zones of the monolayer that are ordered.
Fig. 6 a shows the integrated diffracted intensity (I/I0) as a function of the in-plane component of the scattering wave vector (qxy) of a DPPC monolayer compressed at 20 mN m–1. At this surface pressure, two Bragg peaks were obtained, indicating a rectangular unit cell (NN tilted, L2d phase). The calculated area per chain of 23 Å2 and the tilt angle obtained from Bragg rod analysis are in agreement with published data for DPPC. When the He atmosphere was saturated with gPFOB, the diffraction peaks disappeared within a few minutes (Fig. 6 b), establishing the dissolution of the LC domains and the rapid respreading of the DPPC molecules.
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It is noteworthy that total fluidization has not been obtained in the case of FDC (Fig. 7). The DPPC peak at qxy = 1.51 Å–1 is less intense but still visible even if the gas-tight box of the trough has been saturated with gFDC for over 1 h. This indicates that parts of the monolayer still retain some weak organization. The fact that FDC is not as efficient as the other FCs with respect to the DPPC monolayer fluidization may be ascribed to the globular shape of the FDC molecule, which is expected to be less favorable to insertion between the hydrophobic fatty chains of DPPC than the linear shape of the other FCs investigated.
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), demonstrating a lower compressibility (comparable to that of the LC phase of DPPC). A slight kink is observed for Curosurf at 28 mN m–1, and the isotherm becomes steeper at higher surface pressures. FM images (Fig. 9, left panel) indeed show that the Curosurf monolayer is in the fluid LE state, except at the highest lateral pressures (i.e., 45 mN m–1), for which some small crystalline domains can be observed (Fig. 9 c). By contrast, definite crystalline domains are already seen in the Survanta monolayer at low surface pressures, actually even at zero surface pressure for A = 80 Å2 (Fig. 9 a'). The number of these domains increases rapidly with , until they practically form a continuous LC phase at 45 mN m–1 (Fig. 9 c').
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCES |
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). It is likely that the FC condenses upon compression and forms a thin liquid film on top of the DPPC molecules. The FC molecules are reincorporated into the monolayer upon expansion. The fluidizing effect of gFCs that is established here results from the inhibition by the gFCs of the formation of an LC phase and from the fact that an LE phase is more fluid than a crystalline LC phase.
Improving our understanding of the interactions between FCs and PL interfaces is a key issue for the medical use of FCs since several FC-based systems are being developed (1). One can note the growing interest for gaseous microbubbles as contrast agents for ultrasound diagnosis (echosonography) and therapy (3,35). The most recent commercial microbubbles have a shell made of PLs and are osmotically stabilized by an FC gas (3). A synergistic effect between shell and internal gas components has recently been demonstrated (36).
We believe that the observations reported here are important because they suggest that a gFC/PLs combination could be the basis for the development of new synthetic LS replacement compositions. One advantage of this new approach is that the acting components (FC + DPPC) are synthetic. Another is that the fluidizing effect induced by gFCs is highly reproducible. During expansion (inspiration) the gFC molecules are likely inserted into the monolayer, thus preventing the formation of crystalline domains of DPPC and facilitating DPPC respreading. During compression (expiration), the FC molecules are expelled, leaving a DPPC-rich monolayer capable of producing near zero surface tension, but remain readily available, probably as a condensed thin liquid film on top of the DPPC monolayer. We have also established that the contact of the DPPC monolayer with gFC does not induce any detectable desorption of the PLs to the subphase. Such a mechanism of action would not require a "reservoir" effect provided by folded layers of PLs and proteins.
Replacing the air/water interface by a gFC-saturated air/water interface appears to have a significant impact on the adsorption of DPPC molecules at the interface. We have recently shown that the interfacial tension was much lower at a gPFOB/water interface than at the air/water interface and that the kinetics of adsorption of DPPC molecules at the interface were strongly accelerated (F. Gerber, M. Sanchez-Dominguez, T. F. Vandamme, and M. P. Krafft, unpublished). We can thus infer that, in vivo, the presence of gFC in the lung will help recruit DPPC molecules at the alveolar interface, thus decreasing the interfacial tension and improving the pulmonary function. This function would be combined and develop a synergy with the LS function, which will provide a further advantage over the commercial LS compositions.
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CONCLUSIONS AND PERSPECTIVES |
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ACKNOWLEDGEMENTS |
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Submitted on November 1, 2005; accepted for publication January 10, 2006.
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