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Methods and models to investigate the physico-chemical functionality of pulmonary surfactant

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Abstract

The pulmonary surfactant (PS) is a complex mixture of lipids and proteins dispersed in the aqueous lining layer of the alveolar surface. Such a layer plays a key role in maintaining the proper lung functionality. It acts as a barrier against inhaled particles and pathogens, including viruses, and may represent an important entry point for drugs delivered via aerosols. Understanding the physico-chemical properties of PS is therefore of importance for the comprehension of pathophysiological mechanisms affecting the respiratory system. That can be of particular relevance for supporting the development of novel therapeutic interventions against COVID-19-induced acute respiratory distress syndrome. Due to the complexity of the in vivo alveolar lining layer, several in vitro methodologies have been developed to investigate the functional and structural properties of PS films or interfacial films made by major constituents of the natural PS. As breathing is a highly dynamic interfacial process, most applied methodologies for studying pulmonary surfactants need to be capable of dynamic measurements, including the study of interfacial dilational rheology. We provide here a review of the most frequently and successfully applied methodologies that have proven to be excellent tools for understanding the biophysics of the PS and of its role in the respiratory mechanics. This overview also discusses recent findings on the dynamics of pulmonary surfactant layers and on the impact of inhalable particles or pathogens, such as the novel coronavirus, on its functionality.

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... The use of models based on fluid films of different lipids or mixtures of lipids and proteins at water/vapor interfaces, or their deposits onto solid surfaces as Langmuir-Blodgett or Langmuir-Schaefer films, is widespread for the evaluation of the impact of specific chemicals on the activity of different biological systems under physiological relevant conditions [49,[53][54][55][56][57][58][59][60][61][62][63][64]. Therefore, the use of interfacial science may help in the evaluation of the effect of inhaled pollutants or particles in LS films [58,59,[65][66][67][68] by exploiting the importance of different physical and chemical aspects of the liquid/vapor interface formed between the alveolar lining and the gas contained in the alveolar cavity in LS physiology [69,70]. It should be stressed that studies using model systems are in most of the cases an oversimplification, allowing mimicking of only some specific physico-chemical aspects related to the complex biophysical function of LS film. ...
... The highly dynamic character of the alveoli during breathing requires deepening of the mechanical characterization of LS layers under dilational deformations mimicking the expiration-inspiration cycles [116,151]. This information is difficult to obtain by using Langmuir film balances as was stated above (further details can be found in the recent review by Ravera et al. [68]). However, the use of techniques based on oscillating drops or bubbles, e.g., pulsating bubble surfactometer or captive bubble tensiometer [152][153][154][155][156], help in the evaluation of the potential impact of the particle incorporation in the mechanics of LS films under realistic simulations of the physiological situation. ...
... Conventional oscillating bubbles have also been used for exploring the effect of particles in LS [159,160]. This approach relies on the oscillation of the bubble surface at a frequency close to that corresponding to the breathing rate (around 15 min −1 ), allowing the evaluation of different relevant properties for the breathing cycle, including the minimum surface tension reached under compression and the area of the hysteresis loop associated with the compression-expansion of the area available, and how these parameters are influenced as a result of the incorporation of particles [68]. Oscillating drops in pendant drop tensiometers also allow obtaining information about the mechanical performance of LS layers under sinusoidal changes of the interfacial area [159,161,162]. ...
Article
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Pollution is currently a public health problem associated with different cardiovascular and respiratory diseases. These are commonly originated as a result of the pollutant transport to the alveolar cavity after their inhalation. Once pollutants enter the alveolar cavity, they are deposited on the lung surfactant (LS) film, altering their mechanical performance which increases the respiratory work and can induce a premature alveolar collapse. Furthermore, the interactions of pollutants with LS can induce the formation of an LS corona decorating the pollutant surface, favoring their penetration into the bloodstream and distribution along different organs. Therefore, it is necessary to understand the most fundamental aspects of the interaction of particulate pollutants with LS to mitigate their effects, and design therapeutic strategies. However, the use of animal models is often invasive, and requires a careful examination of different bioethics aspects. This makes it necessary to design in vitro models mimicking some physico-chemical aspects with relevance for LS performance , which can be done by exploiting the tools provided by the science and technology of interfaces to shed light on the most fundamental physico-chemical bases governing the interaction between LS and particulate matter. This review provides an updated perspective of the use of fluid films of LS models for shedding light on the potential impact of particulate matter in the performance of LS film. It should be noted that even though the used model systems cannot account for some physiological aspects, it is expected that the information contained in this review can contribute on the understanding of the potential toxicological effects of air pollution.
... Along with the surface tension, the dynamic surface elasticity is often measured. It characterizes the behavior of the monolayer during periodic expansions and compressions [14,17,[21][22][23]. Various types of microscopies are also used to study the structure of surface layers [24][25][26][27][28]. Hydrophobic nano-and microparticles strongly influence the surface properties of the lung surfactant [29]. ...
... Most of the published works consider the effect of particles on lipid monolayers in the region of high surface tension, while much lower values of surface tension are achieved in the lungs [14,21]. This paper presents the results of the measurements of surface properties under a wide range of surface pressures, including values characteristic of the pulmonary and 3.0 µC/cm 2 (5.4 nm 2 per one charged group), respectively (Molecular Probes). ...
Article
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The application of surface rheology and Brewster angle microscopy on mixed monolayers of DPPC and polymeric nanoparticles (cationic and anionic) showed that the sign of the particle charge affects the dynamic properties of the monolayers less than the nanoparticles’ ability to aggregate. Under almost physiological conditions, the effect of nanoparticles on the elasticity of DPPC monolayer is insignificant. However, the particles prevent the surface tension from decreasing to extremely low values. This effect could affect the functionality of pulmonary surfactants.
... The underlying mechanisms behind inhibition are not fully understood but progress is ongoing using microscopy, spectroscopy, proteomics, and other classes of techniques. (Zuo et al., 2008;Ravera et al., 2021). ...
... The common concept behind these methods is to simulate an alveolus and empirically determine the surface tension of LS at initial adsorption, minimum, and maximum values. (Ravera et al., 2021). ...
Article
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Lung surfactant (LS) is a mixture of lipids and proteins that forms a thin film at the gas-exchange surfaces of the alveoli. The components and ultrastructure of LS contribute to its biophysical and biochemical functions in the respiratory system, most notably the lowering of surface tension to facilitate breathing mechanics. LS inhibition can be caused by metabolic deficiencies or the intrusion of endogenous or exogenous substances. While LS has been sourced from animals or synthesized for clinical therapeutics, the biofluid mixture has also gained recent interest as a biophysical model for inhalation toxicity. Various methods can be used to evaluate LS function quantitatively or qualitatively after exposure to potential toxicants. A narrative review of the recent literature was conducted. Studies focused whether LS was inhibited by various environmental contaminants, nanoparticles, or manufactured products. A review is also conducted on synthetic lung surfactants (SLS), which have emerged as a promising alternative to conventional animal-sourced LS. The intrinsic advantages and recent advances of SLS make a strong case for more widespread usage in LS-based toxicological assays.
... The slow progress in this scientific area can be explained by the significant difficulties connected with the measurements of dynamic surface properties at conditions relevant to the physiological state inside the lungs, with low surface tension values (lower than 30 mN/m). Several experimental methods were developed for measuring extremely low surface tension values at periodic compression and expansion levels [81]. One of the frequently used methods involves a captive bubble surfactometer, which is based on an analysis of bubble shapes in solutions of pulmonary surfactants. ...
... Most recently, an overview of the role of lung surfactants was published by Ravera et al. [81]. The various functionalities of the various liquids involved in the digestion process were discussed and the methods were analyzed to ensure they are suitable for systematic investigations in order to find optimum solutions for the detected problems. ...
Article
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The input of chemical and physical sciences to life sciences is increasingly important. Surface science as a complex multidisciplinary research area provides many relevant practical tools to support research in medicine. The tensiometry and surface rheology of human biological liquids as diagnostic tools have been very successfully applied. Additionally, for the characterization of pulmonary surfactants, this methodology is essential to deepen the insights into the functionality of the lungs and for the most efficient administration of certain drugs. Problems in ophthalmology can be addressed using surface science methods, such as the stability of the wetting films and the development of artificial tears. The serious problem of obesity is fast-developing in many industrial countries and must be better understood, while therapies for its treatment must also be developed. Finally, the application of fullerenes as a suitable system for detecting cancer in humans is discussed.
... To evaluate if the incorporation of GRR10W4-F could compromise surfactant function, we investigated surfactant performance using a captive bubble surfactometer (CBS). As described by Ravera et al. [37], there are different methodologies to study the function and structure of surfactant, providing information about different aspects. CBS is, as the constrained drop surfactometer, one of the preferred methods to study the interfacial properties of PS under controlled and reproducible conditions, but the former is actually considered the most effective technique to study dynamic changes in surface tension under breathing-like conditions [38]. ...
... European Journal of Pharmaceutics and Biopharmaceutics 180 (2022)[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] ...
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This work evaluates interaction of pulmonary surfactant (PS) and antimicrobial peptides (AMPs) in order to investigate (i) if PS can be used to transport AMPs, and (ii) to what extent PS interferes with AMP function and vice versa. This, in turn, is motivated by a need to find new strategies to treat bacterial infections in the airways. Low respiratory tract infections (LRTIs) are a leading cause of illness and death worldwide that, together with the problem of multidrug-resistant (MDR) bacteria, bring to light the necessity of developing effective therapies that ensure high bioavailability of the drug at the site of infection and display a potent antimicrobial effect. Here, we propose the combination of AMPs with PS to improve their delivery, exemplified for the hydrophobically end-tagged AMP, GRR10W4 (GRRPRPRPRPWWWW-NH2), with previously demonstrated potent antimicrobial activity against a broad spectrum of bacteria under various conditions. Experiments using model systems emulating the respiratory interface and an operating alveolus, based on surface balances and bubble surfactometry, served to demonstrate that a fluorescently labelled version of GRR10W4 (GRR10W4-F), was able to interact and insert into PS membranes without affecting its biophysical function. Therefore, vehiculization of the peptide along air-liquid interfaces was enabled, even for interfaces previously occupied by surfactants layers. Furthermore, breathing-like compression-expansion dynamics promoted the interfacial release of GRR10W4-F after its delivery, which could further allow the peptide to perform its antimicrobial function. PS/GRR10W4-F formulations displayed greater antimicrobial effects and reduced toxicity on cultured airway epithelial cells compared to that of the peptide alone. Taken together, these results open the door to the development of novel delivery strategies for AMPs in order to increase the bioavailability of these molecules at the infection site via inhaled therapies.
... A simpler lipid mixture, lacking cholesterol and sphingomyelin, was also prepared in order to characterize a monolayer uniquely composed of three natural phospholipids, PC-PE-PS (Fig. 1A shows the molar lipid compositions). Previously, synthetic lipid monolayers, for example using DPPC (1,2dipalmitoyl-sn-glycerol-3-phosphocholine) and POPC (1palmitoyl-2-oleoyl-glycero-3-phosphocholine), or complex mixtures such as the so-called canonical mixture (containing POPC, sphingomyelin and cholesterol), were employed to mimic cellular membranes as well as lung surfactants [17][18][19][20][21][22][23][24][25][26]. Even though Langmuir monolayers are not well suited to address transmembrane processes, their versatility allows the investigation of lipid structure and organization of single membrane leaflets at the air/water interface, by exploiting a plethora of interfacial in situ techniques [27][28][29], thus offering the possibility of untangling different questions of biophysical interest. ...
Article
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Hypothesis Unravelling the structural diversity of cellular membranes is a paramount challenge in life sciences. In particular, lipid composition affects the membrane collective behaviour, and its interactions with other biological molecules. Experiments Here, the relationship between membrane composition and resultant structural features was investigated by surface pressure-area isotherms, Brewster angle microscopy and neutron reflectometry on in vitro membrane models of the mammalian plasma and endoplasmic-reticulum-Golgi intermediate compartment membranes in the form of Langmuir monolayers. Natural extracted yeast lipids were used because, unlike synthetic lipids, the acyl chain saturation pattern of yeast and mammalian lipids are similar. Findings The structure of the model membranes, orthogonal to the plane of the membrane, as well as their lateral packing, were found to depend strongly on their specific composition, with cholesterol having a major influence on the in-plane morphology, yielding a coexistence of liquid-order and liquid-disorder phases.
... In addition to the above-mentioned studies, a wide range of wetlab methods have also been investigated to study the structure and physicochemical characteristics of the LSM, including Langmuir trough, [38][39][40][41][42][43] atomic force microscopy (AFM), 35 electron resonance spectroscopy 33 and captive bubble surfactometer experiments. 44 These techniques can be used to study the interaction of the LSM with steroids 45-47 and non-steroid drugs, 29,48,49 but they do not provide proper molecular-level mechanistic interaction between drugs and LSM. To gain better insight into molecular level mechanistic interaction of corticosteroid drugs and surfactant monolayer, it is preferable to use coarse-grained lung surfactant models because coarsegrained simulations provide precise insights into molecular level interaction. ...
Article
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Understanding the adsorption mechanism of corticosteroids in the lung surfactant requires the knowledge of corticosteroid molecular interactions with lung surfactant monolayer (LSM). We employed coarse-grained molecular dynamics simulation to explore the action of hydrocortisone on an LSM comprised of a phospholipid, cholesterol and surfactant protein. The structural and dynamical morphology of the lung surfactant monolayer at different surface tensions were investigated to assess the monolayer compressibility. The simulations were also conducted at the two extreme ends of breathing cycles: exhalation (0 mN m-1 surface tension) and inhalation (20 mN m-1 surface tension). The impact of surface tension and hydrocortisone concentration on the monolayer compressibility and stability are significant, resulting the monolayer expansion at higher surface tension. However, at low surface tension, the highly compressed monolayer induces monolayer instability in the presence of the drug due to the accumulation of surfactant protein and drug. The constant area per lipid simulation results demonstrate that the surface pressure-area isotherms show a decrease in area-per-lipid with increased drug concentration. The drug-induced expansion causes considerable instability in the monolayer after a specific drug concentration is attained at inhalation breathing condition, whereas, for exhalation breathing, the monolayer gets more compressed, causing the LSM to collapse. The monolayer collapse occurs for inhalation due to the higher drug concentration, whereas for exhalation due to the accumulation of surfactant proteins and drugs. The findings from this study will aid in enhancing the knowledge of molecular interactions of corticosteroid drugs with lung surfactants to treat respiratory diseases.
... The last few years have been very fruitful in terms of the development of suitable tools to measure the response of planar fluid/fluid interfaces against dilational deformation [48,49]. Unfortunately, many of such tools provide information of the response against deformations within the linear response regime, which does not provide, in most cases, a suitable representation of some of the phenomena occurring in complex fluid/fluid interfaces, which are of technological and scientific interest [6,9]. ...
Article
Full-text available
Fluid/fluid interfaces are ubiquitous in science and technology, and hence, the understanding of their properties presents a paramount importance for developing a broad range of soft interface dominated materials, but also for the elucidation of different problems with biological and medical relevance. However, the highly dynamic character of fluid/fluid interfaces makes shedding light on fundamental features guiding the performance of the interfaces very complicated. Therefore, the study of fluid/fluid interfaces cannot be limited to an equilibrium perspective, as there exists an undeniable necessity to face the study of the deformation and flow of these systems under the application of mechanical stresses, i.e., their interfacial rheology. This is a multidisciplinary challenge that has been evolving fast in recent years, and there is currently available a broad range of experimental and theoretical methodologies providing accurate information of the response of fluid/fluid interfaces under the application of mechanical stresses, mainly dilational and shear. This review focused on providing an updated perspective on the study of the response of fluid/fluid interfaces to dilational stresses; to open up new avenues that enable the exploitation of interfacial dilational rheology and to shed light on different problems in the interest of science and technology.
... DPPC was chosen because its structure is well known to form stable monolayers and bears structural similarities to a large diversity of phospholipids in biological membranes. Indeed, Langmuir monolayers have been widely used to mimic cellular membranes in vitro [24][25][26][27][28][29][30]. The lipid monolayer configuration in a Langmuir trough allows the in situ use of neutron reflectometry (NR), ellipsometry and Brewster angle microscopy (BAM). ...
Article
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Hypothesis: Inositol phospholipids are well known to form clusters in the cytoplasmic leaflet of the plasma membrane that are responsible for the interaction and recruitment of proteins involved in key biological processes like endocytosis, ion channel activation and secondary messenger production. Although their phosphorylated inositol ring headgroup plays an important role in protein binding, its orientation with respect to the plane of the membrane and its lateral packing density has not been previously described experimentally. Experiments: Here, we study phosphatidylinositol 4,5-bisphosphate (PIP2) planar model membranes in the form of Langmuir monolayers by surface pressure-area isotherms, Brewster angle microscopy and neutron reflectometry to elucidate the relation between lateral (in-plane) and perpendicular (out-of-plane) molecular organization of PIP2. Findings: Different surface areas were explored through monolayer compression, allowing us to correlate the formation of transient PIP2 clusters with the change in orientation of the inositol-biphosphate headgroup, which was experimentally determined by neutron reflectometry.
... A wide range of wet-lab techniques have been employed to analyse the structure and physico-chemical features of the LSM, including Langmuir trough [19][20][21][22][23][24], atomic force microscopic (AFM) [25], electron resonance spectroscopy [26] and captive bubble surfactometer experiments [27]. These techniques can also be used to study the interaction of the LSM with steroids [28][29][30][31] and non-steroid drugs [32,33]. ...
Article
Corticosteroids are drugs used to treat inflammatory conditions. In the case of lung diseases, corticosteroids can be administered by inhalation. The main barrier for inhaled particles is the lung surfactant monolayer (LSM) that lines the alveolar air–water interface and reduces surface tension during breathing. In this study, we use coarse-grained molecular dynamics simulations to study the concentration-dependent interaction of cortisone with an LSM composed of neutral and negatively charged phospholipids, cholesterol, and surfactant proteins. Simulations were carried out at surface tensions mimicking inhalation and exhalation conditions and different compressibilities. In-depth analysis shows that cortisone causes a concentration-dependent expansion of the monolayer that at high surface tension and high drug concentrations results in the monolayer collapsing. This instability is associated with the accumulation of drugs and surfactant proteins that prevent adsorption into the monolayer. Our findings help to improve the understanding of how corticosteroids alter lung surfactants structure and assist efforts to improve drug adsorption.
... A simpler lipid mixture, lacking cholesterol and sphingomyelin, was also prepared in order to characterize a monolayer uniquely composed of three natural phospholipids, PC-PE-PS ( Figure 1A shows the molar lipid compositions). Previously, synthetic lipid monolayers, for example using DPPC (1,2-dipalmitoylsn-glycerol-3-phosphocholine) and POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), or complex mixtures such as the so-called canonical mixture (containing POPC, sphingomyelin and cholesterol), were employed to mimic cellular membranes as well as lung surfactants [17][18][19][20][21][22][23][24][25][26] . Even though Langmuir monolayers are not well suited to address transmembrane processes, their versatility allows the investigation of lipid' structure and organisation of single membrane leaflets at the air/water interface, by exploiting a plethora of interfacial in situ techniques [27][28][29] , thus offering the possibility of untangling different questions of biophysical interest. ...
Preprint
Unravelling the structural diversity of cellular membranes is a paramount challenge in life sciences. In particular, lipid composition affects the membrane collective behaviour, and its interactions with other biological molecules. Here, the relationship between membrane composition and resultant structural features was investigated by surface pressure-area isotherms, Brewster angle microscopy and neutron reflectometry on in vitro membrane models of the mammalian plasma and endoplasmic-reticulum-Golgi intermediate compartment membranes in the form of Langmuir monolayers. Natural extracted yeast lipids were used because, unlike synthetic lipids, the acyl chain saturation pattern of yeast and mammalian lipids are similar. The structure of the model membranes, orthogonal to the plane of the membrane, as well as their lateral packing, was found to depend strongly on their specific composition, with cholesterol having a major influence on the in-plane morphology, yielding a coexistence of liquid-order and liquid-disorder phases.
... The knowledge of interfacial dynamic properties of surfactant-adsorbed layers in the presence of inorganic electrolytes is essential for many industries dealing with foaming, emulsification and coating, such as pharmaceuticals [1], mining [2][3][4], environmental remediation [5,6], food [7,8] and biology [9,10], enhanced oil recovery [11] and gas well deliquification [12][13][14][15]. The stability of foam/emulsion is strongly influenced by surface properties of gas-fluid interfaces containing adsorbed surface-active compounds such as surfactants. ...
Article
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This study presents the equilibrium surface tension (ST), critical micelle concentration (CMC) and the dilational viscoelasticity of sodium dodecylbenzene sulfonate (SDBS)-adsorbed layers in the presence of NaCl, KCl, LiCl, CaCl2 and MgCl2 at 0.001–0.1 M salt concentration. The ST and surface dilational viscoelasticity were determined using bubble-shape analysis technique. To capture the complete profile of dilational viscoelastic properties of SDBS-adsorbed layers, experiments were conducted within a wide range of SDBS concentrations at a fixed oscillating frequency of 0.01 Hz. Salts were found to lower the ST and induce micellar formation at all concentrations. However, the addition of salts increased dilational viscoelastic modulus only at a certain range of SDBS concentration (below 0.01–0.02 mM SDBS). Above this concentration range, salts decreased dilational viscoelasticity due to the domination of the induced molecular exchange dampening the ST gradient. The dilational viscoelasticity of the salts of interest were in the order CaCl2 > MgCl2 > KCl > NaCl > LiCl. The charge density of ions was found as the corresponding factor for the higher impact of divalent ions compared to monovalent ions, while the impact of monovalent ions was assigned to the degree of matching in water affinities, and thereby the tendency for ion-pairing between SDBS head groups and monovalent ions.
... Carnitine causes lung maturation via membrane phospholipid repair activity and has been reported to have surfactant like properties so its deficiency may have a further negative effect on decreased surfactant synthesis in lung tissue; hence the infant quickly consumes carnitine for fatty acid oxidation and surfactant synthesis [14] . ...
Article
Background: Carnitine is one of hydrophilic amino acid derivatives participating in pulmonary surfactant production in infants. The deficiency of Carnitine might lead to the incidence and severity of respiratory distress syndrome [RDS] in preterm infants. Aim of the work: The aim of this work is the assessment and evaluation of L- carnitine therapy effect on the prognosis of respiratory distress syndrome.Patients and Methods: The study included a total number of 90 preterm infants with RDS, categorized into two groups; group I [40 cases] with sufficient level of l-carnitine and group II [50 cases] with deficient l-carnitine. Both groups are subdivided into two subgroups; intervention group [received carnitine] and control group. Patients with sufficient carnitine levels received Carnitine supplementation at a dose of 10 mg/kg/day. Patients with deficient carnitine levels received Carnitine therapy at a dose of 30 mg/kg/day Follow-up was carried out to assess the need of respiratory support, oxygenation, hospital stay and mortality.Results: The mean gestational age was 31.62 ± 2.18 wks. The mean birth weight was 1.58 ± 0.41 Kg. Newborns with deficient carnitine level were had lower birth weight [1.68 ± 0.42 Kg vs. 1.50 ± 0.39 Kg; P=0.046] and exhibited more frequency of mechanical ventilation [P=0.021]. In the sufficient Carnitine group, carnitine supplementation was associated with improvement of weight [P
... Over the years, excellent reviews concerning these studies have been published. The most recent of them can be found in references [12][13][14][15][16][17]. In the last decades, great progress has been made in the field of computational modelling of biological systems, especially by means of molecular dynamics simulations (MD). ...
Article
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The surface of pulmonary alveolar subphase is covered with a mixture of lipids and proteins. This lung surfactant plays a crucial role in lung functioning. It shows a complex phase behavior which can be altered by the interaction with third molecules such as drugs or pollutants. For studying multicomponent biological systems, it is of interest to couple experimental approach with computational modelling yielding atomic-scale information. Simple two, three, or four-component model systems showed to be useful for getting more insight in the interaction between lipids, lipids and proteins or lipids and proteins with drugs and impurities. These systems were studied theoretically using molecular dynamic simulations and experimentally by means of the Langmuir technique. A better understanding of the structure and behavior of lung surfactants obtained from this research is relevant for developing new synthetic surfactants for efficient therapies, and may contribute to public health protection.
... Interfacial layers of surfactants are building blocks of foams and emulsions and are present in ubiquitous applications in many areas including mining [1], oil and gas production [2,3], environmental remediation [4], waste water treatment [5], food [6,7] and biology [8,9]. The stability of foams and emulsions are determined by the equilibrium and dynamic properties of interfacial layers, which are dictated by the composition and structure of the adsorbed surfaceactive compounds at the interface and the inherent relaxation processes. ...
Article
Interfacial rheology of adsorbed layers of surfactants, demonstrating the response of the interface to interfacial deformations, plays a key role in formation and stability of foams and emulsions. It also provides insights into complex surfactant systems in different applications; in particular, medical treatments and diagnostics. The response of the interface is mainly determined by the composition of a surfactant system, the equilibrium and kinetic adsorption properties of the included surface-active compounds, and their interaction within the adsorption layer. The subject of on-going investigations is interfacial rheology of surfactant layers in the presence of inorganic ions. Although these ions have no surface activity, they can strongly influence the interfacial rheological properties due to their interaction with the surface-active molecules. This work aims to present recent developments in the interfacial rheology of surfactant adsorbed layers at liquid-fluid interfaces in the presence and absence of salts, highlighting the state of the art of experimental and theoretical works in this area. We highlight drawbacks of recently developed techniques for measuring dilational interfacial properties of surfactant layers, compared with previous techniques. Moreover, this review shows the dearth of research in the ion-specific effect on the interfacial rheology of surfactant layers. This demonstrates the necessity of further investigation of the effect of ion-specificity on interfacial viscoelasticity.
... A number of contributions is dedicated to the molecular aspects of the interaction between the virus and other system compounds. Various experimental methods for the characterization of viruses and other particles interacting at fluid interfaces with pulmonary surfactants are summarised by Ravera et al. 5 . Simon et al. 6 give an overview of the basic properties of classical surfactants for combatting viruses in general and the Corona virus in particular. ...
Preprint
COVID-19 is transmitted by inhaling SARS-CoV-2 virions, which are enveloped by a lipid bilayer decorated by a crown of Spike protein protrusions. In the respiratory tract, virions interact with surfactant films composed of phospholipids and cholesterol that coat lung airways. Here, we explore by using coarse-grained molecular dynamics simulations the physico-chemical mechanisms of surfactant adsorption on Spike proteins. With examples of zwitterionic dipalmitoyl phosphatidyl choline, cholesterol, and anionic sodium dodecyl sulfate, we show that surfactants form micellar aggregates that selectively adhere to the specific regions of S1 domain of the Spike protein that are responsible for binding with ACE2 receptors and virus transmission into the cells. We find high cholesterol adsorption and preferential affinity of anionic surfactants to Arginine and Lysine residues within S1 receptor binding motif. These findings have important implications for informing the search for extraneous therapeutic surfactants for curing and preventing COVID-19 by SARS-CoV-2 and its variants.
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The interaction of hydrophobic silicon dioxide particles (fumed silicon dioxide), as model air pollutants, and Langmuir monolayers of a porcine lung surfactant extract has been studied in order to try to shed light on the physicochemical bases underlying the potential adverse effects associated with pollutant inhalation. The surface pressure−area isotherms of lung surfactant (LS) films including increasing the particle mass fractions revealed that particle incorporation into LS monolayers modifies the organization of the molecules at the water/vapor interface, which alters the mechanical resistance of the interfacial films, hindering the ability of LS layers for reducing the surface tension, and reestablishing the interface upon compression. This influences the normal physiological function of LS as is inferred from the analysis of the response of the Langmuir films upon the incorporation of particles against harmonic changes of the interfacial area (successive compression−expansion cycles). These experiments evidenced that particles alter the relaxation mechanisms of LS films, which may be correlated to a modification of the transport of material within the interface and between the interface and the adjacent fluid during the respiratory cycle.
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Carbonaceous particles are accounted among the most common environmental pollutants. This makes necessary a careful examination of their potential impact on the physico-chemical properties of different biological films, e.g. tear film, skin, or lung surfactant. This work analyzes the interaction of three different types of carbonaceous particles with Langmuir monolayers of 1,2-Dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC) spread at the water/vapor interface. This type of studies can be exploited as preliminary in vitro tests for evaluating the potential risks and hazards of this type of pollutants for human health, which requires to study the effect of the particles on the ability of lipid layers for reducing the surface tension under static and dynamics conditions. The obtained results have shown that the insertion of particles into lipid films leads to the emergence of excluded area-like effects which modify the interfacial cohesion and packing. This hinders partially the ability of the lipid films for reducing the surface tension, which may present important adverse effects for the normal physiological performance of lipid membranes, and in particular for the performance of lung surfactant layers. Furthermore, the analysis of the response of lipid layers including carbonaceous particles against mechanical stresses also evidenced that particle incorporation worsens the mechanical performance of lipid layers, which may alter both their functional and structural roles.
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Hypothesis: Fluorocarbon gases introduced above monolayers of phospholipids at the air/water interface were recently found to promote the adsorption of diverse molecular compounds, with potential application in drug-loaded microbubble design. Quantitative determination of the fluorocarbon present in the monolayers is strongly needed for the development of such applications. We hypothesized that neutron reflectometry (NR) and ellipsometry experiments would allow quantification of the fluorocarbon trapped in the monolayers. Experiments: We report the first quantitative determination of the extents of adsorption of perfluorohexane (F-hexane) on different phospholipid monolayers with respect to both their phase and isotopic form. To this aim, we applied an approach based on co-modeling the data obtained from NR and ellipsometry. Findings: We found that F-hexane adsorbs strongly in monolayers of dipalmitoylphosphatidylcholine (DPPC) when they are both in the liquid expanded (LE) and liquid condensed (LC) phases, but to different extents according to the isotopic form of the phospholipid. Kinetic resolution of the interfacial composition from data on both isotopic contrasts (assuming chemical identicality) was therefore not possible using NR alone, so an alternative NR/ellipsometry co-modeling treatment was applied to data from each isotopic contrast. F-hexane adsorbs more abundantly on monolayers of hydrogenous DPPC than chain-deuterated DPPC when they are in the LE phase, whilst the opposite was observed when they monolayers are in the LC phase. The extents of adsorption of F-hexane in monolayers of dimyristoylphosphatidylcholine (DMPC, LE phase) and distearoylphosphatidylcholine (DSPC, LC phase) concurs with the strong dependence of those with phospholipids of different isotopic contrasts according to the monolayer phase. This new methodology can lead to advances in the novel characterization of fluorocarbons interacting with phospholipid monolayers of relevance to applications such as in the shells of fluorocarbon-stabilized medically-oriented microbubbles.
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Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown. Here, the interfacial structure and the composition of lung surfactant films have been analysed in vitro under TH as well as the molecular basis of its improved performance both under physiological and inhibitory conditions. The biophysical activity of a purified porcine surfactant was tested under slow and breathing-like dynamics by constrained drop surfactometry (CDS) and in the captive bubble surfactometer (CBS) at both 33 and 37 °C. Additionally, the temperature-dependent surfactant activity was also analysed upon inhibition by plasma and subsequent restoration by further surfactant supplementation. Interfacial performance was correlated with lateral structure and lipid composition of films made of native surfactant. Lipid/protein mixtures designed as models to mimic different surfactant contexts were also studied. The capability of surfactant to drastically reduce surface tension was enhanced at 33 °C. Larger DPPC-enriched domains and lower percentages of less active lipids were detected in surfactant films exposed to TH-like conditions. Surfactant resistance to plasma inhibition was boosted and restoration therapies were more effective at 33 °C. This may explain the improved respiratory outcomes observed in cooled patients with acute respiratory distress syndrome and opens new opportunities in the treatment of acute lung injury.
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Introduction The dramatic impact of COVID-19 on humans worldwide has initiated an extraordinary search for effective treatment approaches. One of these is the administration of exogenous surfactant, which is being tested in ongoing clinical trials. Areas covered Exogenous surfactant is a life-saving treatment for premature infants with neonatal respiratory distress syndrome. This treatment has also been tested for acute respiratory distress syndrome (ARDS) with limited success possibly due to the complexity of that syndrome. The 60-year history of successes and failures associated with surfactant therapy distinguishes it from many others treatment currently being tested for COVID-19 and provides the opportunity to discuss the factors that may influence the success of this therapy. Expert opinion Clinical data provides a strong rationale for using exogenous surfactant in COVID-19 patients. Success of this therapy may be influenced by the mechanical ventilation strategy, the timing of treatment, the doses delivered, the method of delivery and the preparations utilized. In addition, future development of enhanced preparations may improve this treatment approach. Overall, results from ongoing trials may not only provide data to indicate if this therapy is effective for COVID-19 patients, but also lead to further scientific understanding and improved treatment strategies.
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This work explores the potential for strategizing pulmonary surfactant (PS) for drug delivery over the respiratory air-liquid interface: the interfacial delivery. The efficacy of PS- and interface-assisted drug vehiculization was determined both in vitro and in vivo using a native purified porcine PS combined with the hydrophobic anti-inflammatory drug Tacrolimus (TAC), a calcineurin inhibitor. In vitro assays were conducted in a novel double surface balance setup designed to emulate compression-expansion dynamics applied to interfacially connected drug donor and recipient compartments. In this setup, PS transported TAC efficiently over air-liquid interfaces, with compression/expansion breathing-like dynamics enhancing rapid interface-assisted diffusion and drug release. The efficacy of PS-assisted TAC vehiculization was also evaluated in vivo in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In anesthetized mice, TAC combined with PS was intra-nasally (i.n) instilled prior administering i.n. LPS. PS/TAC pre-treatment caused greater TAC internalization into a higher number of lung cells obtained from bronchoalveolar lavages (BAL) than TAC pre-treatment alone. Additionally, the PS/TAC combination but not TAC or PS alone attenuated the LPS-induced pro-inflammatory effects reducing cells and proteins in BAL fluid. These findings indicated that PS-mediated increase in TAC uptake blunted the pro-injurious effects of LPS, suggesting a synergistic anti-inflammatory effect of PS/drug formulations. These in vitro and in vivo results establish the potential utility of PS to open novel effective delivery strategies for inhaled drugs.
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Lung surface is the first line of contact between inhaled carbon nanomaterials, CNMs, and the organism, so this is the place where pulmonary health effects begin. The paper analyzes the influence of several CNMs (single- and multi-walled nanotubes with various surface area: 90–1,280 m²/g and aspect ratio: 8–3,750) on the surface-active properties of the lung surfactant, LS, model (Survanta). Effects of CNM concentration (0.1–1 mg/ml) and surface oscillation rate were determined using the oscillating drop method at simulated breathing conditions (2–10 s per cycle, 37 °C). Based on the values of apparent elasticity and viscosity of the interfacial region, new parameters: Sε and Sμ were proposed to evaluate potential effect of particles on the LS at various breathing rates. Some of tested CNMs (e.g., COOH- functionalized short nanotubes) significantly influenced the surfactant dynamics, while the other had weaker effects even at high particle concentration. Analysis of changes in Sε and Sμ provides a new way to evaluate of a possible disturbance of the basic functions of LS. The results show that the expected pulmonary effects caused by inhaled CNMs at variable breathing rate depend not only on particle concentration (inhaled dose) but also on their size, structure and surface properties.
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Lipid layers are considered among the first protective barriers of the human body against pollutants, e.g., skin, lung surfactant, or tear film. This makes it necessary to explore the physico-chemical bases underlying the interaction of pollutants and lipid layers. This work evaluates using a pool of surface-sensitive techniques, the impact of carbon black and fumed silica particles on the behavior of Langmuir monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). The results show that the incorporation of particles into the lipid monolayers affects the surface pressure–area isotherm of the DPPC, modifying both the phase behavior and the collapse conditions. This is explained considering that particles occupy a part of the area available for lipid organization, which affects the lateral organization of the lipid molecules, and consequently the cohesion interactions within the monolayer. Furthermore, particles incorporation worsens the mechanical performance of lipid layers, which may impact negatively in different processes presenting biological relevance. The modification induced by the particles has been found to be dependent on their specific chemical nature. This work tries to shed light on some of the most fundamental physico-chemical bases governing the interaction of pollutants with lipid layers, which plays an essential role on the design of strategies for preventing the potential health hazards associated with pollution.
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CHF5633 is a novel synthetic clinical pulmonary surfactant preparation composed by two phospholipid species, dipalmitoyl phosphatidylcholine (DPPC) and palmitoyloleoyl phosphatidylglycerol (POPG), and synthetic analogues of the hydrophobic surfactant proteins SP-B and SP-C. In this study, the interfacial properties of CHF5633 in the absence and in the presence of inhibitory serum proteins have been assessed in comparison with a native surfactant purified from porcine lungs and with poractant alpha, a widely used clinical surfactant preparation. The study of the spreading properties of CHF5633 in a Wilhelmy balance, its ability to adsorb and accumulate at air-liquid interfaces as revealed by a multiwell fluorescence assay, and its dynamic behavior under breathing-like compression-expansion cycling in a Captive Bubble Surfactometer (CBS), all revealed that CHF5633 exhibits a good behavior to reduce and sustain surface tensions to values below 5 mN/m. CHF5633 shows somehow slower initial interfacial adsorption than native surfactant or poractant alpha, but a better resistance to inhibition by serum proteins than the animal-derived clinical surfactant, comparable to that of the full native surfactant complex. Interfacial CHF5633 films formed in a Langmuir-Blodgett balance coupled with epifluorescence microscopy revealed similar propensity to segregate condensed lipid domains under compression than films made by native porcine surfactant or poractant alpha. This ability of CHF5633 to segregate condensed lipid phases can be related with a marked thermotropic transition from ordered to disordered membrane phases as exhibited by differential scanning calorimetry (DSC) of CHF5633 suspensions, occurring at similar temperatures but with higher associated enthalpy than that shown by poractant alpha. The good interfacial behavior of CHF5633 tested under physiologically meaningful conditions in vitro and its higher resistance to inactivation by serum proteins, together with its standardized and well-defined composition, makes it a particularly useful therapeutic preparation to be applied in situations associated with lung inflammation and edema, alone or in combined strategies to exploit surfactant-facilitated drug delivery.
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Due to its branching structure, drug delivery to the peripheral areas of the lung is a major challenge. Consequently, most pulmonary therapies utilize large systemic dosing, with the potential for adverse side effects. One proposed strategy to overcome this challenge is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle. The objective was to develop and test an in vitro system to rapidly assess surfactant based therapies prior to animal studies. The Wet Bridge Transfer System consisted of two connected wells in which drugs were instilled into a delivery well and function was tested in a remote well which mimicked the remote areas of the lung where drug activity would be required. The system was used to assess surfactant as a carrier for antibiotics (Gentamicin, Ciprofloxacin, and Colistin) by measuring their ability to kill Pseudomonas aeruginosa bacteria in the remote well. Anti-inflammatory agents (Budesonide and a host defense peptide, CATH-2) with and without exogenous surfactant were examined using stimulated macrophages in the remote well and IL-6 concentration as an outcome. The results showed that being paired with surfactant, Gentamicin and Ciprofloxacin, but not Colistin, had significantly greater bacterial killing in the remote wells. Similarly, when combined with a surfactant, both Budesonide and CATH-2 significantly lowered IL-6 concentrations. We conclude that the wet-bridge system can be used to rapidly screen surfactant-based therapies prior to their assessment in vivo. Furthermore, exogenous surfactant was an effective delivery vehicle for several antimicrobial and anti-inflammatory therapeutics.
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Following the first successful trial of surfactant replacement therapy for preterm infants with respiratory distress syndrome (RDS) by Fujiwara in 1980, several animal-derived natural surfactants and synthetic surfactants have been developed. Synthetic surfactants were designed to overcome limitations of natural surfactants such as cost, immune reactions, and infections elicited by animal proteins contained in natural surfactants. However, first-generation synthetic surfactants that are protein-free have failed to prove their superiority over natural surfactants because they lack surfactant protein (SP). Lucinactant, a second-generation synthetic surfactant containing the SP-B analog, was better or at least as effective as the natural surfactant, suggesting that lucinactant could act an alternative to natural surfactants. Lucinactant was approved by the U. S. Food and Drug Administration in March 2012 as the fifth surfactant to treat neonatal RDS. CHF5633, a second-generation synthetic surfactant containing SP-B and SP-C analogs, was effective and safe in a human multicenter cohort study for preterm infants. Many comparative studies of natural surfactants used worldwide have reported different efficacies for different preparations. However, these differences are believed to due to site variations, not actual differences. The more important thing than the composition of the surfactant in improving outcome is the timing and mode of administration of the surfactant. Novel synthetic surfactants containing synthetic phospholipid incorporated with SP-B and SP-C analogs will potentially represent alternatives to natural surfactants in the future, while improvement of treatment modalities with less-invasive or noninvasive methods of surfactant administration will be the most important task to be resolved.
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Lung surfactant is a complex mixture of lipids and proteins which plays a major role in the respiratory cycle. This makes necessary to understand the effects of different external factors or agents, for example, inhaled particles, as a potential source of alteration of the normal physiological response of lung surfactant. However, in most cases, in vivo studies are difficult to perform, and preliminary studies based in model systems are required. Films of lipids or mixtures of lipids and proteins at the water–vapor interface are accounted as one of the most useful methodologies for initial assessments of the potential toxicity of inhaled particles. Thus, the study of the modifications induced by the incorporation of colloidal particles in the interfacial properties of layers mimicking some of the physicochemical features of lung surfactant might provide a first evaluation of the risks and hazards associated with the inhalation of particulate matter. Considering the importance of particles in technology and industry, it is mandatory to develop strategies providing information about toxicological aspects of these widespread materials. This review focuses its interest on the recent advancements on the application of studied bases on monolayers at the fluid interface as preliminary assay for deepening on a complex situation with biological interest.
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Predicting the non-Newtonian shear response of soft interfaces in biophysical systems and engineered products has been compromised by the use of linear (Newtonian) constitutive equations. We present a generalized constitutive equation, with tractable material properties, governing the response of Newtonian and non-Newtonian interfaces subjected to a wide range of steady shear. With experiments spanning six decades of shear rate, we capture and unify divergent reports of shear-thinning behavior of monomolecular films of the lipid dipalmitoylphosphatidylcholine, the primary constituent of mammalian cell walls and lung surfactant, at near-physiological packing densities.
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Complex fluid-fluid interfaces play an important role in a variety of application domains, from emulsion and foam stability, to thin films in biomedical applications, to coating flow phenomena. The current work reviews progress made in particular for interfaces where rheological stresses, peculiar to the interface, play an important role. The developments made in the area of constitutive modelling are briefly reviewed to clarify which material functions can be measured. For shear rheometry, progress in analyzing the flow field in the measurement device has been key, combined with advances in control over surface concentration and microstructural evaluation. For dilation/compressional rheometry much work has been done on separating changes in the surface tension from the extra rheological stresses. Finally, we discuss how “simple complex flows”, such as thin film and drainage flows, offer a first step up in complexity and seem to present a good benchmark problem for testing constitutive equations and the interplay between transport phenomena, interfacial rheology and the changes in state variables.
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Background Despite their growing popularity, the potential respiratory toxicity of electronic cigarettes (e-cigarettes) remains largely unknown. One potential aspect of e-cigarette toxicity is the effect of e-cigarette vapor on lung surfactant function. Lung surfactant is a mixture of lipids and proteins that lines the alveolar region. The surfactant layer reduces the surface tension of the alveolar fluid, thereby playing a crucial role in lung stability. Due to their small size, particulates in e-cigarette vapor can penetrate the deep lungs and come into contact with the lung surfactant. The current study sought to examine the potential adverse effects of e-cigarette vapor and conventional cigarette smoke on lung surfactant interfacial properties. Methods Infasurf®, a clinically used and commercially available calf lung surfactant extract, was used as lung surfactant model. Infasurf® films were spread on top of an aqueous subphase in a Langmuir trough with smoke particulates from conventional cigarettes or vapor from different flavors of e-cigarettes dispersed in the subphase. Surfactant interfacial properties were measured in real-time upon surface compression while surfactant lateral structure after exposure to smoke or vapor was examined using atomic force microscopy (AFM). Results E-cigarette vapor regardless of the dose and flavoring of the e-liquid did not affect surfactant interfacial properties. In contrast, smoke from conventional cigarettes had a drastic, dose-dependent effect on Infasurf® interfacial properties reducing the maximum surface pressure from 65.1 ± 0.2 mN/m to 46.1 ± 1.3 mN/m at the highest dose. Cigarette smoke and e-cigarette vapor both altered surfactant microstructure resulting in an increase in the area of lipid multilayers. Studies with individual smoke components revealed that tar was the smoke component most disruptive to surfactant function. Conclusions While both e-cigarette vapor and conventional cigarette smoke affect surfactant lateral structure, only cigarette smoke disrupts surfactant interfacial properties. The surfactant inhibitory compound in conventional cigarettes is tar, which is a product of burning and is thus absent in e-cigarette vapor.
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The surface chemistry of engineered nanoparticles (ENPs) becomes more important as their size decreases and enters the nanometer-range. This review explains the fundamental properties of the surface chemistry of nanoparticles, and argues that their agglomeration and the formation of corona around them are natural processes that reduce surface energy. ENP agglomeration and surface corona formation are further discussed in the context of inhaled ENPs, as the lung is a major port of ENP entry to the body. The pulmonary surfactant layer, which the inhaled ENPs first encounter as they land on the lung surface, represents a unique environment with a variety of well-defined biomolecules. Many factors, such as hydrophobicity, surface charge of ENPs, protein/phospholipid concentrations of the alveolar lining fluid, etc. influence the complex processes of ENP agglomeration and corona formation in the alveolar lining fluid, and these events occur even before the ENPs reach the cells. We suggest that molecular dynamic simulations can represent a promising future direction for research of the behavior of inhaled ENPs, complementing the experimental approaches. Moreover, we want to remind biologists working on ENPs of the importance relationship between ENP surface energy and size.
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The dynamic surface properties of solutions of pulmonary surfactant (PS) were investigated at various temperatures and in a broad range of surface tensions. The efficient dynamic surface elasticity was determined for the first time in case when the characteristic adsorption time is comparable with the period of surface area oscillations. The mechanical relaxation in the PS adsorption layer is accelerated strongly not only in the course of compression, but also in the course of expansion due to the formation of a sublayer. The harmonic oscillations of the surface area induce stationary oscillations of the surface tension if the characteristic adsorption time does not exceed the oscillation period and the sublayer formation is sufficiently fast. The information on the dynamic properties of the PS adsorption layer allows estimation of the PS efficiency in medical applications.
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Coronavirus disease 2019 (COVID-19), due to infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now causing a global pandemic. Aerosol transmission of COVID-19, although plausible, has not been confirmed by the World Health Organization (WHO) as a general transmission route. Considering the rapid spread of SARS-CoV-2, especially nosocomial outbreaks and other superspreading events, there is an urgent need to study the possibility of airborne transmission and its impact on the lung, the primary body organ attacked by the virus. Here, we review the complete pathway of airborne transmission of SARS-CoV-2 from aerosol dispersion in air to subsequent biological uptake after inhalation. In particular, we first review the aerodynamic and colloidal mechanisms by which aerosols disperse and transmit in air and deposit onto surfaces. We then review the fundamental mechanisms that govern regional deposition of micro- and nanoparticles in the lung. Focus is given to biophysical interactions between particles and the pulmonary surfactant film, the initial alveolar-capillary barrier and first-line host defense system against inhaled particles and pathogens. Finally, we summarize the current understanding about the structural dynamics of the SARS-CoV-2 spike protein and its interactions with receptors at the atomistic and molecular scales, primarily as revealed by molecular dynamics simulations. This review provides urgent and multidisciplinary knowledge toward understanding the airborne transmission of SARS-CoV-2 and its health impact on the respiratory system.
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Lipase is one of the most important enzymes playing a key role in many biological and chemical processes, in particular for fat hydrolysis in living systems and technological applications such as food production, medicine, and biodiesel production. As lipase is soluble in water, the major hydrolysis process occurs at the water-oil interface, where lipase can get in contact with the oil. To provide optimum conditions, the emulsification of the oil is essential to provide a large interfacial area which is generally done by adding surfactants. However, the presence of surfactants can influence the lipase activity and also cause competitive adsorption, resulting in a removal of lipase from the interface or its conformational changes in the solution bulk. Here we have studied the dynamics of competitive adsorption and interfacial elasticity of mixed solutions containing lipase and the anionic surfactant sodium dodecyl sulfate (SDS) or the cationic surfactant cetyltrimethylammonium bromide (CTAB), respectively, at the water-air interface. The experiments were performed with a special coaxial double capillary setup for drop bulk-interface exchange developed for the drop profile analysis tensiometer PAT with two protocols: sequential and simultaneous adsorption of single components and mixed systems. The results in terms of dynamic surface tension and dilational visco-elasticity illustrate fast and complete desorption of a pre-adsorbed CTAB and SDS layers via sub-phase exchange with a buffer solution. In contrast, the pre-adsorbed lipase layer cannot be removed either by SDS or CTAB from the interface during drop bulk exchange with a buffer solution due to the unfolding process and conformation evolution of the protein molecules at the interface. In the opposite case, lipase can remove pre-adsorbed SDS and CTAB. The dynamic surface tension and visco-elasticity data measured before and after sub-phase exchange show joint adsorption of lipase and CTAB in the form of complexes, while SDS is adsorbed in competition with lipase. The results are in good correlation with the determined surface charges of the lipase gained by computational simulations which show a dominant negatively charged surface for lipase that can interact with the cationic CTAB while partial positively charged regions are observed for the interaction with the anionic SDS.
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Pulmonary surfactant (PS) is a lipid-protein complex that adsorbs to the air-water surface of the lung as a thin film. Previous studies have suggested that the adsorbed PS film is composed of an interfacial monolayer, plus a functionally attached vesicular complex, called the surface-associated surfactant reservoir. However, direct visualization of the lateral structure and morphology of adsorbed PS films using atomic force microscopy (AFM) has been proven to be technically challenging. To date, all AFM studies of the PS film have relied on the model of Langmuir monolayers. Here, we showed the first AFM imaging of adsorbed PS films under physiologically relevant conditions using a novel experimental methodology called constrained drop surfactometry (CDS). In conjunction with a series of methodological innovations, including subphase replacement, in situ Langmuir-Blodgett (LB) transfer, and real-time surface tension control using closed-loop axisymmetric drop shape analysis (CL-ADSA), CDS allowed the study of lateral structure and topography of animal-derived natural PS films at physiologically relevant low surface tensions. Our data suggested that a nucleation-growth model is responsible for the adsorption-induced squeeze-out of the PS film, which likely results in an interfacial monolayer enriched in dipalmitoylphosphatidylcholine (DPPC) with the attached multilayered surface-associated surfactant reservoir. These findings were further supported by frequency-dependent measurements of surface dilational rheology. Our study provides novel biophysical insights into the understanding of the mechanisms by which the PS film attains low surface tensions and stabilizes the alveolar surface.
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The COVID-19 pandemic has seen a surge of patients with acute respiratory distress syndrome (ARDS) in intensive care units across the globe. As experience of managing patients with COVID-19-associated ARDS has grown, so too have efforts to classify patients according to respiratory system mechanics, with a view to optimising ventilatory management. Personalised lung-protective mechanical ventilation reduces mortality and has become the mainstay of treatment in ARDS. In this Viewpoint, we address ventilatory strategies in the context of recent discussions on phenotypic heterogeneity in patients with COVID-19-associated ARDS. Although early reports suggested that COVID-19-associated ARDS has distinctive features that set it apart from historical ARDS, emerging evidence indicates that the respiratory system mechanics of patients with ARDS, with or without COVID-19, are broadly similar. In the absence of evidence to support a shift away from the current paradigm of ventilatory management, we strongly recommend adherence to evidence-based management, informed by bedside physiology, as resources permit.
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Upon inhalation, nanoparticles enter the lungs where the pulmonary surfactant forms the first point of contact and plays a pivotal role for the subsequent absorption into the body. This can lead to interactions that alter the biophysical function of the surfactant monolayer. Therefore, a reliable prediction of the interaction is desired. In this study, we compared the behaviour of an artificial surfactant model with that of a natural surfactant upon exposure to chitosan nanoparticles. To simulate the physiology of the lungs, the surfactant monolayers were placed at an air/aqueous interface of a Langmuir film balance. Based on the data obtained from the experiments, the chitosan nanoparticles first integrated into the monolayer of the natural surfactant and then interact strongly with its compounds thereby moving out of the monolayer. The topographic changes in the monolayer were determined by atomic force microscopy analysis. Using this technique, the nanoparticle localisation on the monolayer could be studied. No visible interaction was observed with the artificial surfactant from surface pressure-time isotherms and atomic force microscopy analysis. Incomplete miscibility lead to instability of the artificial surfactant which left behind a DPPC rich monolayer after nanoparticle interaction. It was not stable enough to see a possible interaction (i.e. change in surface pressure) with the nanoparticles directly. These results should help understand the interactions of lipids among themselves and with the nanoparticles. Furthermore, it should help generate an efficient artificial surfactant model and to understand the underlying mechanisms of the nanoparticle interaction with the monolayer.
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Phospholipids are found throughout the natural world, including the lung surfactant (LS) layer that reduces pulmonary surface tension and enables breathing. Fibrinogen, a protein involved in the blood clotting process, is implicated in LS inactivation and the progression of disorders such as acute respiratory distress syndrome. However, the interaction between fibrinogen and LS at the air-water interface is poorly understood. Through a combined microrheological, confocal and epifluorescence microscopy approach we quantify the interfacial shear response and directly image the morphological evolution when a model LS monolayer is penetrated by fibrinogen. When injected into the subphase beneath a monolayer of the phospholipid dipalmitoylphosphatidylcholine (DPPC, the majority component of LS), fibrinogen preferentially penetrates disordered liquid expanded (LE) regions and accumulates on the boundaries between LE DPPC and liquid condensed (LC) DPPC domains. Thus, fibrinogen is line active. Aggregates grow from the LC domain boundaries, ultimately forming a percolating network. This network stiffens the interface compared to pure DPPC and imparts the penetrated monolayer with a viscoelastic character reminiscent of a weak gel. When the DPPC monolayer is initially compressed beyond LE-LC coexistence, stiffening is significantly more modest and the penetrated monolayer retains a viscous-dominated, DPPC-like character.
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Pulmonary administration is widely used for the treatment of lung diseases. The interaction between drug molecules and pulmonary surfactants affects the efficacy of the drug directly. The location and distribution of drug molecules in a model pulmonary surfactant monolayer under different surface pressures can provide vivid information on the interaction between drug molecules and the pulmonary surfactants during the pulmonary administration. Ketoprofen is a non-steroidal anti-inflammatory drug for pulmonary administration. The effect of ketoprofen molecules on the lipid monolayer containing 1,2-Dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-glycerol (DPPG) is studied by surface pressure (π)-area (A) isotherms, compressibility modulus (C_s^(-1))-surface pressure (π) isotherms. The location and distribution of ketoprofen molecules in lipid monolayer under different surface pressures are explored by surface tension, density profile, radial distribution function (RDF) as well as the potential of mean force (PMF) simulated by molecular dynamics (MD) simulation. The introduction of ketoprofen molecules affects the properties of DPPC/DPPG monolayers and the location and distribution of ketoprofen molecules in monolayers various with the surface pressure. The existence of ketoprofen molecules hinders the formation of liquid-condensed (LC) films and decreases the compressibility of DPPC/DPPG monolayers. The location and distribution of ketoprofen molecules in lipid monolayer is affected by cation-π interaction between the choline groups of lipids and the benzene ring of ketoprofen, the steric hindrance of the lipid head groups as well as the hydrophobicity of ketoprofen molecule itself, comprehensively. The contact state of lipid head group with water is determined by surface pressure, which affects the interaction between drug molecules and lipids and further dominates the location and distribution of ketoprofen in lipid monolayer. This work confirms that ketoprofen molecules can affect the property and the inner structure of DPPC/DPPG monolayers during breath. Furthermore, the results obtained using mixed monolayer containing two major pulmonary surfactants DPPC/DPPG and ketoprofen molecules will be helpful for in-depth understanding the mechanism of inhaled administration therapy.
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This work is focused on the study of the dynamic surface properties of spread monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), which is the main component of the pulmonary surfactant (PS), in the region of high surface pressures and at different temperatures. The increase of temperature from 25 to 35 °C led to a decrease of surface elasticity in the high surface pressure range corresponding to physiological conditions inside alveoli during breathing. Furthermore, the obtained results evidenced that the relaxation processes in spread DPPC monolayer were accelerated with the increase of temperature, which resulted in two different effects. On one hand, it led to the increase of hysteresis of surface pressure isotherms, which was an important condition for maximizing air penetration into alveoli; whereas on the other hand, it prevented reaching extremely high surface pressure, which could result in a premature alveolar collapse.
Article
In this work, dynamic surface properties of spread monolayers of DPPC and adsorbed layers of PS solutions were investigated in a broad range of surface pressure. Application of a modified Langmuir trough and a recently developed approach for the analysis of a non-linear response of the adsorption layer to large surface deformations gives a possibility to determine the dilational surface elasticity in the region of high surface pressures corresponding to the physiological state of the lung alveoli surface. Although DPPC is the main component of the complex pulmonary surfactant (PS)mixture, the dynamic surface properties of the adsorption layers of these two compounds are different. Other components in the PS adsorption layer lead to a decrease of the dynamic surface elasticity due to a looser packing of the layer, as confirmed by ellipsometry and infrared reflection absorption spectroscopy. Moreover, in the region of high surface pressures the main relaxation time of the surface stresses is much lower than that for spread DPPC monolayers. The fast relaxation in the adsorption layer can be connected with the redistribution of molecules between the surface and the subsurface layer in the course of compression. The acceleration of the relaxation processes can lead to a decrease of the number and size of collapsed parts of the layer and thereby to a decrease of the number of molecules with lost functional properties. This effect can be one of the reasons for the lower efficiency of synthetic pharmaceutical drugs, which do not have proteins in their composition, as compared with the natural PS extracted from animal lungs.
Article
As an organ system, the lung has unique advantages and disadvantages for localized drug delivery. Its direct contact with the external environment allows for the upper airways to be easily accessible to intrapulmonary delivery. However, its complex branching structure makes direct delivery to the peripheral airways challenging. This review will discus the utility of exogenous surfactant, a lipoprotein complex currently used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics to enhance the delivery of these drugs to the deeper regions of the lung. The focus is to provide an update on the many tools available to develop new surfactant-based therapeutics using computer modeling, in vitro approaches, and in vivo testing, which may ultimately lead to clinical trials. Two clinical conditions, Acute Respiratory Distress Syndrome and Bacterial Pneumonia are utilized throughout as prototypical examples of pulmonary conditions in which surfactant drug combination may be beneficial. Consequently, the pharmaceuticals discussed are primarily those with antimicrobial or anti-inflammatory activities.
Article
The dilational surface rheology was applied to study the properties of adsorbed layers of a fluorinated surfactant (heptadecafluoro-1-nonanol) with a surface phase transition at the water – air interface. At relatively low surface tensions (<~57 mN/m) the dynamic surface elasticity reached anomalously high values (~200 mN/m) and exhibited a local minimum at higher surface tensions in the region of a two-dimensional phase transition. A mathematical model was developed to describe dilational properties of the adsorbed layer in the region of coexistence of two surface phases. The application of this model to solutions of the fluorinated surfactant allowed estimation of the kinetic parameters of the relaxation processes in the surface layer.
Article
Pulmonary surfactant (PS) is a lipid-protein complex essential to stabilise the delicate structure of mammalian alveoli along with successive compression-expansion respiratory cycles. To do so, surfactant reduces dramatically surface tension at the air-liquid interface, an activity that depends critically on a proper lipid composition and the presence of some specific surfactant proteins. Lack or dysfunction of this system is associated with severe respiratory pathologies, which are in some cases treated by supplementation with exogenous surfactant materials. The biophysical function and performance of PS, in health and disease, are directly influenced by its composition, structure and mechanical properties. This review summarises the main biophysics concepts behind the mechanisms that define surfactant function in a healthy lung and in pathological situations. It also revises some of the most useful biophysical techniques that provide information about surfactant-related processes. Finally, translational biophysics will be invoked to illustrate how biophysical studies may contribute to understand the role of surfactant in health and disease and to design better surfactant-based therapeutic approaches.
Article
Understanding rheological properties of surfactant and protein films plays a crucial role in a variety of industrial and research areas, such as food processing, cosmetics, and pharmacology. To determine the surface dilational modulus using drop shape analysis, one needs to measure the dynamic surface tension in response to a sinusoidal oscillation of the surface area of the droplet. Despite many applications of drop shape analysis in studying interfacial rheology, oscillation of the droplet surface area is usually controlled in an indirect manner. Existing methods are only capable of controlling volume oscillations of the droplet rather than its surface area. We have developed an arbitrary waveform generator (AWG) to directly oscillate the surface area of a millimeter-sized droplet in a predefined sinusoidal waveform. Here, we demonstrated the capacity of this AWG, in conjunction with constrained drop surfactometry (CDS), in studying the surface dilational rheology of adsorbed surfactant and protein films. It is found that the surface dilational modulus determined for a dilute surfactant (C12DMPO) and two protein solutions (bovine serum albumin and β-casein) revealed their adsorption mechanisms. Our methods hold promise in studying the interfacial rheology of various thin-film materials, biomembranes, foams, and emulsions.
Article
Treatment of neonatal respiratory distress syndrome (RDS) using animal derived lung surfactant preparations has reduced the mortality of handling premature infants with RDS to a 50th of that in the 1960‐ies. The supply of animal derived lung surfactants is limited and only a part of the preterm babies is treated. Thus, there is a need to develop well‐defined synthetic replicas based on key components of natural surfactant. A synthetic product that equals natural derived surfactants would enable cost‐efficient production and could also facilitate development of treatments of other lung diseases than neonatal RDS. Recently the first synthetic surfactant that contains analogues of the two hydrophobic surfactant proteins B (SP‐B) and SP‐C entered clinical trials for treatment of neonatal RDS. Development of functional synthetic analogues of SP‐B and SP‐C, however, is considerably more challenging than anticipated 30 years ago when the first structural information of the native proteins became available. For SP‐B a complex three‐dimensional dimeric structure stabilized by several disulphides has necessitated the design of miniaturized analogues. The main challenge for SP‐C has been the pronounced amyloid aggregation propensity of its transmembrane region. Development of a functional non‐aggregating SP‐C analogue that can be produced synthetically was achieved by designing the amyloidogenic native sequence so that it spontaneously forms a stable transmembrane α‐helix. This article is protected by copyright. All rights reserved.
Article
Pulmonary surfactant (PS) has been extensively studied because of its primary role in mammalian breathing. The deposition of this surface-active material at the alveolar air-water interface is essential to lower surface tension, thus avoiding alveolar collapse during expiration. In addition, PS is involved in host defense, facilitating the clearance of potentially harmful particulates. PS has a unique composition, including 92% of lipids and 8% of surfactant proteins (SPs) by mass. Although they constitute the minor fraction, SPs to a large extent orchestrate PS-related functions. PS contains four surfactant proteins (SPs) that can be structurally and functionally divided in two groups, i.e. the large hydrophilic SP-A and SP-D and the smaller hydrophobic SP-B and SP-C. The former belong to the family of collectins and are involved in opsonization processes, thus promoting uptake of pathogens and (nano)particles by phagocytic cell types. The latter SPs regulate interfacial surfactant adsorption dynamics, facilitating (phospho)lipid transfer and membrane fusion processes. In the context of pulmonary drug delivery, the exploitation of PS as a carrier to promote drug spreading along the alveolar interface is gaining interest. In addition, recent studies investigated the interaction of PS with drug-loaded nanoparticles (nanomedicines) following pulmonary administration, which strongly influences their biological fate, drug delivery efficiency and toxicological profile. Interestingly, the specific biophysical mode-of-action of the four SPs affect the drug delivery process of nanomedicines both on the extra-and intracellular level, modulating pulmonary distribution, cell targeting and intracellular delivery. This knowledge can be harnessed to exploit SPs for the design of unique and bio-inspired drug delivery strategies.
Article
The prevalence of lung conditions, such as chronic obstructive pulmonary disease and pulmonary fibrosis, and lung infections such as pneumonia, increase sharply with age. The physiologic, cellular and immunologic changes that occur during aging contribute to the development of lung disease. Studies of age-related changes in physiology and function are not just key to preventing or ameliorating disease, they are essential for understanding healthy aging. Individuals with good lung function live longer, healthier lives, although the mechanisms by which this occurs are not understood. Herein, we review changes in the aging lung that facilitate development of disease and the evidence supporting the idea that robust lung function reduces the risk of developing chronic inflammatory conditions that occur with age.
Article
Metal-based nanomaterials (MNMs) represent a large category of the engineered nanomaterials, and have been extensively used to enhance the properties of nano-enabled consumer products. Inhaled MNMs can penetrate deeply into the peripheral lung at which they first interact with the pulmonary surfactant (PS) lining of alveoli. Here we studied the biophysical inhibitory potential of MNMs on a modified natural PS, Infasurf, using a novel in vitro experimental methodology called the constrained drop surfactometry (CDS). It was found that the biophysical inhibitory potential of six MNMs on Infasurf ranks in the order CeO2 > ZnO > TiO2 > Ag > Fe3O4 > ZrO2-CeO2. This rank of in vitro biophysical inhibition is in general agreement with the in vitro and in vivo toxicity of these MNMs. Directly imaging the lateral structure and molecular conformation of the PS film using atomic force microscopy revealed that there exists a correlation between biophysical inhibition of the PS film by the MNMs and their aggregation state at the PS film. Taking together, our study suggests that the nano-bio interactions at the PS film are determined by multiple physicochemical properties of the MNMs, including not only well-studied properties such as their chemical composition and particle size, but also properties such as hydrophobicity, dissolution rate, and aggregation state at the PS film found here. Our study provides novel insight into the understanding of nanotoxicology and metallomics of MNMs.
Article
Pulmonary surfactant protein D (SP-D) is a glycoprotein from the collectin family that is a component of the lung surfactant system. It exhibits host defense and immune regulatory functions in addition to contributing to the homeostasis of the surfactant pool within the alveolar airspaces. It is known that the SP-D monomer forms trimers, which further associate into higher order oligomers. However, the pathway and the interactions involved in the assembly of SP-D oligomers are not clearly understood. In the current study, a recombinant form of full-length human SP-D (rhSP-D) has been qualitatively and quantitatively studied by Atomic Force Microscopy (AFM) and electrophoresis, with the aim to understand the conformational diversity and the determinants defining the oligomerization of the protein. The rhSP-D preparation studied is a mixture of trimers, hexamers, dodecamers and higher order oligomeric species, with dodecamers accounting for more than 50% of the protein by mass. Similar structures were also found in hSP-D obtained from proteinosis patients, with the largest fuzzy-ball-like oligomers being more abundant in these samples. The proportion of dodecamer is increased under acidic conditions, accompanied by a conformational change into more compact configurations. Two hexamers appear to be the minimal necessary unit for dodecamer formation, with stabilization of the dodecamer occurring via non-covalent ionic and hydrophobic interactions between the individual N-terminal domains and the proximal area of the SP-D collagen stems.
Article
Discovery of lung surfactant deficiency as a main cause of neonatal respiratory distress syndrome (NRDS) has influenced a steep increase in lung surfactant research. Although this has yielded impactful scientific discoveries, much of the basic research on lung surfactants has failed to translate into clinical practices. This is attributed to insufficient information covering the entire lung surfactant ecosystem, from the basic science to economics surrounding the development and clinical practices. In this manuscript, developments related to improving therapeutic lung surfactant as well as the degree of unmet need are analyzed from both technical and economic perspectives. Two potential opportunities are emphasized: (1) aerosolized lung surfactants to treat NRDS infants, and (2) synthetic lung surfactants for acute respiratory distress syndrome (ARDS) patients. Each has a modestly projected US market size of $120 million and $4 billion, well enough to make up for the high development costs associated with investigational drug development. Both opportunities have been pursued in the past, but to date these attempts have met with no success mainly due to technical limitations. With the recent advancements in both fields, technology improvements have created opportunities to solve both decades-old problems.
Article
A new approach to the analysis of nonlinear surface dilational rheological properties was developed with the aim to enlarge the accessible range of surface pressures. The dilational surface elasticity of spread monolayers of DPPC, cholesterol, DMEA and their mixtures was determined in the region of low surface tensions (less than 10 mN/m) corresponding to the state of pulmonary surfactants at the lung interface. The dilational surface elasticity of pure DPPC monolayer proved to be high (∼200 mN/m) up to the collapse. The addition of cholesterol, DMEA or their mixture to the DPPC monolayer increased the dynamic surface elasticity, but could decrease significantly the surface pressure of the monolayer collapse if the concentration of additions exceeds an optimal value.
Article
Understanding the fundamentals of surface transport on thin viscous films has important application in pulmonary drug delivery. The human lung contains a large-area interface between its complex fluid lining and inhaled air. Marangoni flows driven by surface tension gradients along this interface would promote enhanced distribution of inhaled therapeutics by carrying them from where they are deposited in the upper airways, along the fluid interface to deeper regions of the lung. Motivated by the potential to improve therapies for acute and chronic lung diseases, we review recent progress in modeling and experimental studies of Marangoni transport induced by the deposition of surfactant-containing microliter drops and liquid aerosols (picoliter drops) onto a fluid interface. The roles of key system variables are identified, including surfactant solubility, drop miscibility with the subphase, and the thickness, composition and surface properties of the subphase liquid. Of particular interest is the unanticipated but crucial role of aerosol processing to achieve Marangoni transport via phospholipid vesicle dispersions, which are likely candidates for a biocompatible delivery system. Progress in this field has the potential to not only improve outcomes in patients with chronic and acute lung diseases, but also to further our understanding of surface transport in complex systems.
Article
The work discusses physicochemical phenomena related to interactions between the inhaled particles and the surface of pulmonary fluid which contains the lung surfactant. Dynamic surface phenomena which arise due to periodical variations of the interfacial area during breathing cycle are the extraordinary feature of this system and they are strictly related to the mechanics of ventilation and the pulmonary mass transfer processes. Presence of foreign material such as inhaled micro-and nanoparticles with different size, surface properties and morphology may alter these phenomena which may have some health consequences. This effect is discussed on two examples: mineral particles (CeO2) and carbonaceous particles emitted from diesel engine running on two different fuels. Two experimental methods of research in this field are presented: the Langmuir balance and the oscillating pendant drop. The results show the sensitivity of dynamic surface properties of the lung surfactant on exogenous materials which may be introduced to the respiratory system by inhalation of dusty air. Some physicochemical interpretation of these results is presented.
Article
The paper discusses essential engineering challenges related to the application of powder medicines for pulmonary delivery as inhaled aerosol. Starting from a physically based description of the complexity of aerosol dynamics inside the respiratory system, the paper discusses several technical factors responsible for efficient drug delivery to the lungs: (i) interparticle interactions—which can be tuned by selection and control of powder manufacturing methods, (ii) inhaler design—as a determinant of flow dynamics through the inhaling device and degree of powder dispersion, (iii) the dynamics of inhalation in a given inhaler—which is related to patient-device interaction. Basic information on the standard (compendial) methods of the quantitative evaluation of dry powder inhalers (DPIs) are presented with a special focus on the correct data interpretation and the consequences for in vivo-in vitro correlation (IVIVC) problems. Some issues regarding the development of inhalation products (including generics) are also briefly highlighted. Finally, possible strategies of powder particle functionalization to obtain the required bioavailability are outlined on the basis of knowledge on the physicochemical interactions of inhaled particles with the lung fluids.
Article
Pulmonary surfactant is a crucial system to stabilize the respiratory air-liquid interface. Furthermore, pulmonary surfactant has been proposed as an effective method for targeting drugs to the lungs. However, few studies have examined in detail the mechanisms of incorporation of drugs into surfactant, the impact of the presence of drugs on pulmonary surfactant performance at the interface under physiologically-meaningful conditions, or the ability of pulmonary surfactant to use the air-liquid interface to vehiculise drugs to long distances. This study focuses on the ability of pulmonary surfactant to interfacially vehiculize corticosteroids such as beclomethasone dipropionate (BDP) or Budesonide (BUD) as model drugs. The main objectives have been to (a) characterise the incorporation of corticosteroids into natural and synthetic surfactants; (b) evaluate whether the presence of corticosteroids affect surfactant functionality; and (c) determine whether surfactant preparations enable the efficient spreading and distribution of BDP and BUD along the air-liquid interface. We have compared the performance of a purified surfactant from porcine lungs and two clinical surfactants: Poractant alfa, a natural surfactant of animal origin extensively used to treat premature babies, and CHF5633, a new synthetic surfactant preparation currently under clinical trials. Both, natural and clinical surfactants spontaneously incorporated corticosteroids up to at least 10% by mass with respect to phospholipid content. The presence of the drugs did not interfere with their ability to efficiently adsorb into air-liquid interfaces and form surface active films able to reach and sustain very low surface tensions (<2 mN/m) under compression-expansion cycling mimicking breathing dynamics. Furthermore, the combination of clinical surfactant with corticosteroids efficiently promoted the active diffusion of the drug to long distances along the air-liquid interface. This effect could not be mimicked by vehiculisation of corticosteroids in liposomes or in micellar emulsions similar to the formulations currently in use to deliver anti-inflammatory corticosteroids through inhalation.
Article
Pulmonary surfactant is a complex of lipids and proteins assembled and secreted by the alveolar epithelium into the thin layer of fluid coating the respiratory surface of lungs. There, surfactant forms interfacial films at the air-water interface, reducing dramatically surface tension and thus stabilizing the air-exposed interface to prevent alveolar collapse along respiratory mechanics. The absence or deficiency of surfactant produces severe lung pathologies. This review describes some of the most important surfactant-related pathologies, which are a cause of high morbidity and mortality in neonates and adults. The review also updates current therapeutic approaches pursuing restoration of surfactant operative films in diseased lungs, mainly through supplementation with exogenous clinical surfactant preparations.
Article
Therapeutic pulmonary surfactants are currently investigated in clinical medicine as corticosteroids delivery vehicles into the lung. The influence of the corticosteroids Budesonide and Beclometasone dipropionate on the surface properties of aqueous solutions of the therapeutic surfactant preparation Curosurf® has been studied using the black foam film and the wetting film methods. The measurements of probability W for black foam film formation versus surfactant concentration C indicated that the two characteristics of black foam film stability − critical concentration Cc and threshold concentration Ct − for Curosurf® mixtures with 3 μg/cm³ corticosteroids practically coincide with the values for Curosurf® alone. The disjoining pressure/black film thickness isotherms for mixtures of Curosurf® + corticosteroids are slightly shifted to larger film thicknesses compared to isotherm of Curosurf® alone. The measurements of wetting film thickness and wetting contact angles showed that the hydrophobization of SiO2-solid surface by mixtures of Curosurf® + corticosteroids is slightly smaller than the hydrophobization due to Curosurf® only. Budesonide and Beclometasone dipropionate equally influence the wetting behavior of the Curosurf® solutions. These results indicate that the addition of corticosteroids does not alter significantly the surface properties of the therapeutic pulmonary surfactant.
Article
Biophysical studies of pulmonary surfactant, PS, provide the possibility to assess the roles of physicochemical phenomena in physiological functions of this mixture of biosurfactants lining the surface of lung’s alveoli. In particular they help to understand the possible alterations of PS functions by inhaled compounds (aerosols or gases). Most experimental studies are based on either multicomponent animal or human-derived PS or its essential constituents. The present study proposes a new functional experimental model of PS for studying the interfacial dynamics in the Langmuir balance and other experimental setups. The model is based on a novel application of a mixture of biosurfactants of plant origin, Quillaja bark saponins (QBS), to enhance the phospholipid mass exchange between the interface and the liquid subphase. The response of the interface during periodic variations of the gas-liquid surface area is represented by a reproducible surface tension hysteresis, which is known to be an essential marker of PS activity. The results indicate that the proposed system may be useful in further biophysical studies related to pulmonary surfactant dynamics.