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Names | |
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IUPAC name 1,2-Dipalmitoylphosphatidylcholine | |
Identifiers | |
3D model (JSmol) | |
ChemSpider | |
ECHA InfoCard | 100.018.322 |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C40H80NO8P | |
Molar mass | 734.053 g·mol−1 |
Surface tension: | |
4.6 ± 0.5 x 10−10 M [1] | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Dipalmitoylphosphatidylcholine (DPPC) is a phospholipid (and a lecithin) consisting of two C16 palmitic acid groups attached to a phosphatidylcholine head-group.
It is the main constituent of pulmonary surfactants, which reduces the work of breathing and prevents alveolar collapse during breathing. It also plays an important role in the study of liposomes and human bilayers. [2] [3]
Lung surfactant (LS) is a surface-active material produced by most air-breathing animals for the purpose of reducing the surface tension of the water layer where gas exchange occurs in the lungs, given that the movements due to inhalation and exhalation may cause damage if there is not enough energy to sustain alveolar structural integrity.
The monolayer formed by the LS on the interface is composed primarily of phospholipids (80%), in addition to proteins (12%) and neutral lipids (8%). Among the phospholipids, the most prevalent one is phosphatidylcholine (PC, or lecithin) (70–85%), which in turn is the basis of a pool of similar diacylphophatidylcholines of which 50% is dipalmitoylphosphatidylcholine or DPPC. [4]
While DPPC itself already has the ability to reduce the surface tension of the alveolar liquid, the proteins and other lipids in the surfactant further facilitate the adsorption of oxygen into the air-liquid interface.
DPPC is a variant of phosphatidylcholine. Its structure includes both a hydrophilic "head" and hydrophobic "tails", and it is this arrangement that makes it able to reduce the surface tension of the water layer. The choline radical constitutes the polar hydrophilic head; it is oriented towards and extends into the alveolar liquid. The palmitic acid (C16) chains form the nonpolar hydrophobic tails; these are oriented towards the outer side.
The synthesis of the phospholipids contained in pulmonary surfactant takes place in the endoplasmic reticulum of type II pneumocytes. Pulmonary surfactant has both protein and lipid components. More specifically, it has been found that phosphatidylcholine (PC) is the most abundant phospholipid (70%–85%), and that PC is primarily present as dipalmitoylphosphatidylcholine (DPPC).
De novo synthesis of phosphatidylcholine in the lung arises primarily from cytidine diphosphate-choline (CDP-choline). The transformation of CDP-choline to phosphatidylcholine is effected by choline phosphate cytidyltransferase. Under certain conditions the enzymes choline kinase, glycerol-3-phosphate acyltransferase and phosphatidate phosphatase may play regulatory roles.
Of the total DPPC in the pulmonary surfactant, 45% comes from de novo biosynthesis. The rest is formed by transacylation mechanisms that exchange palmitoyl groups for the unsaturated acyl chains of other related diacylphosphatidylcholines. [5] Removal of the acyl chains from these related compounds produces lysophosphatidylcholine; reacylation with palmitoyl-CoA is then facilitated by lysophosphatidylcholine acyltransferase to form DPPC.
This phospholipid is found in a solid/gel phase at 37 °C (at the effective temperature of the human body). Its melting point is around 41.3 °C. Therefore, when the temperature is above 41 °C, DPPC is no longer found in a gel phase but in a liquid one. [6]
When in contact with silica surfaces, it has been demonstrated that DPPC bilayers have different properties depending on the temperature.
Layer thickness remains the same at 25 °C and at 39 °C. However, when the temperature is further increased to 55 °C, the DPPC bilayer structure changes significantly, which causes a decrease in the layer thickness. The reason for this trait is that, in fact, at 55 °C DPPC is found in a disordered liquid state, whereas at a lower temperature it is found in a more-ordered gel state.
Temperature affects the layer's roughness too, which starts to change slightly when temperature is lowered to 25 °C.
Finally, the load-bearing capacity of the bilayer is higher when the temperature exceeds the phase transition temperature (due to its increased fluidity). When this molecule is found in a liquid state, where the fluidity is much higher, it is thought that the bilayer also develops a self-healing capacity. [7]
DPPC is an amphipathic lipid. This characteristic is due to its hydrophilic head, composed of the polar phosphatidylcholine group, and its hydrophobic tails, formed by two nonpolar palmitic acid (C16) chains. This trait allows DPPC to easily and spontaneously form micelles, monolayers, bilayers and liposomes when it is in contact with a polar solvent.
DPPC is the main phospholipid of pulmonary surfactant, and it is surface-active due to its amphipathic behaviour and its adsorption capacity. [8] However, adsorption is not optimal at human body temperature for DPPC alone, because at 37 °C it is found in a gel phase. The presence of some unsaturated phospholipids (such as dioleoylphosphatidylcholine [DOPC] or phosphatidylglycerol) and cholesterol increases the surfactant's fluidity, so it can adsorb oxygen more efficiently. [9] When this mixture contacts water, for example, it accumulates at the water-air interface and forms a thin superficial pellicule of surfactant. The polar heads of the molecules composing the surfactant are attracted by the polar molecules of the liquid (in this case, H2O molecules), causing a significant diminution of the water's surface tension.
DPPC is usually used for research purposes, such as creating liposomes and bilayers which are involved in bigger studies. The Langmuir–Blodgett technique allows the synthesis of liposomal DPPC bilayers. Currently, these liposomes are used in the study of the properties of this phosphatidylcholine and of its use as a mechanism of drug delivery in the human body.
Furthermore, because vesicle fusion dynamics are different for lipids in the gel phase versus the fluid phase, it allows scientists to use DPPC along with DOPC in Atomic Force Microscopy and Atomic Force Spectroscopy. [10] [11]
Dipalmitoylphosphatidylcholine (DPPC) is routinely used to formulate some medicines used for treatment of respiratory distress syndrome (RDS) in newborns. Current synthetic surfactants are combinations of DPPC along with other phospholipids, [12] neutral lipids and lipoproteins.
The treatment of preterm infants with RDS using surfactants was initially developed in the 1960s, and recent studies have demonstrated an improvement in clinical outcomes. [13] The first treatment given to some newborns with RDS was surfactant phospholipids, specifically DPPC, by means of an aerosol (Robillard, 1964).[ full citation needed ] This treatment proved ineffective because administration of DPPC alone did not provide any beneficial effects. Subsequently, studies were carried out to find more effective drugs for treatment of this disease.
Pulmonary surfactants can be classified into three types: [14]
The first generation of protein-free synthetic surfactants contained only DPPC. The best known is colfosceril palmitate. [14]
The second generation of surfactants were of natural (animal) origin, and were obtained from the lungs of cattle or pigs. The surfactants extracted from bovine lungs were Infasurf and Alvofact, the porcine lung extracts included Curosurf, and those made from modified bovine lung extracts included Survanta or Beraksurf (Beractant). Unlike newborns with RDS that were administered first-generation drugs, those that were treated with these second-generation surfactants required less oxygen and ventilatory support within 72 hours of drug administration.
The third generation of surfactants incorporates synthetic peptides or recombinant proteins. These use a mixture of different components. DPPC is the agent used to decrease surface tension, and the rest of the components help increase oxygen adsorption. The best known are Venicute and Surfaxin. [14] These drugs are still under development, so there is as yet no evidence as to whether they possess advantages compared to the second-generation preparations.
DPPC is also used to form liposomes that are used as components of drug delivery systems. [15]
Surfactant Dysfunction Disorder is a disease that affects newborn children whose pulmonary surfactant is insufficient for adequate breathing, resulting in respiratory distress syndrome (RDS). [16]
Despite DPPC being one of the major components of lung surfactant, most of the genetic errors that are linked with surfactant dysfunction disorder are not linked to DPPC. Rather, the main causes of this disease are differences in the production of surfactant proteins B and C due to genetic abnormalities.
However, there is a genetic condition that is related to DPPC which causes a deficiency in the production of ABCA1 protein. This protein is crucial in the transport of phospholipids – and therefore DPPC – to the lamellar bodies of the alveolar cells, where DPPC interacts with surfactant proteins to form pulmonary surfactant. [17]
Current studies cannot find a correlation between the percentage of DPPC in lung surfactant and the age of gestation, although a proven relationship has been found between the percentage of DPPC and POPC (palmitoyl-oleoyl phosphatidylcholine) in babies with respiratory distress syndrome compared with babies without this condition. These connections suggest that a particular surfactant composition will lead to respiratory distress syndrome, regardless of gestational age.
The correlation between DPPC percentage and respiratory distress syndrome is why DPPC is used to make drugs to treat newborn infants with the disease. [18]
In addition, DPPC has been shown to be related to infection of polarized cells by a specific kind of human adenovirus (HAdV-C2). Some studies have indicated that disaturated DPPC boosts infection of A59 cells with HAdV-C2 (possibly by permitting virus entry via the apical side of polarized cells). [19]
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.
A pulmonary alveolus, also known as an air sac or air space, is one of millions of hollow, distensible cup-shaped cavities in the lungs where pulmonary gas exchange takes place. Oxygen is exchanged for carbon dioxide at the blood–air barrier between the alveolar air and the pulmonary capillary. Alveoli make up the functional tissue of the mammalian lungs known as the lung parenchyma, which takes up 90 percent of the total lung volume.
Surfactants are chemical compounds that decrease the surface tension or interfacial tension between two liquids, a liquid and a gas, or a liquid and a solid. The word "surfactant" is a blend of surface-active agent, coined c. 1950. As they consist of a water-repellent and a water-attracting part, they enable water and oil to mix; they can form foam and facilitate the detachment of dirt.
The lipid bilayer is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a lipid bilayer, as are the nuclear membrane surrounding the cell nucleus, and membranes of the membrane-bound organelles in the cell. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Lipid bilayers are ideally suited to this role, even though they are only a few nanometers in width, because they are impermeable to most water-soluble (hydrophilic) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and pH by transporting ions across their membranes using proteins called ion pumps.
Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances, and are used for smoothing food textures, emulsifying, homogenizing liquid mixtures, and repelling sticking materials.
Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybeans, from which they are mechanically or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. Dipalmitoylphosphatidylcholine (lecithin) is a major component of the pulmonary surfactant, and is often used in the lecithin–sphingomyelin ratio to calculate fetal lung maturity. While phosphatidylcholines are found in all plant and animal cells, they are absent in the membranes of most bacteria, including Escherichia coli. Purified phosphatidylcholine is produced commercially.
Infant respiratory distress syndrome (IRDS), also known as surfactant deficiency disorder (SDD), and previously called hyaline membrane disease (HMD), is a syndrome in premature infants caused by developmental insufficiency of pulmonary surfactant production and structural immaturity in the lungs. It can also be a consequence of neonatal infection and can result from a genetic problem with the production of surfactant-associated proteins.
Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorbing to the air-water interface of alveoli, with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC), reduces surface tension.
In cell biology, lamellar bodies are secretory organelles found in type II alveolar cells in the lungs, and in keratinocytes in the skin. They are oblong structures, appearing about 300-400 nm in width and 100-150 nm in length in transmission electron microscopy images. Lamellar bodies in the alveoli of the lungs fuse with the cell membrane and release pulmonary surfactant into the extracellular space.
Surfactant protein B is an essential lipid-associated protein found in pulmonary surfactant. Without it, the lung would not be able to inflate after a deep breath out. It rearranges lipid molecules in the fluid lining the lung so that tiny air sacs in the lung, called alveoli, can more easily inflate.
Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion channels.
Surfactant protein A1(SP-A1), also known as Pulmonary surfactant-associated protein A1(PSP-A) is a protein that in humans is encoded by the SFTPA1 gene.
The lecithin–sphingomyelin ratio is a test of fetal amniotic fluid to assess for fetal lung immaturity. Lungs require surfactant, a soap-like substance, to lower the surface tension of the fluid coating the alveolar epithelium in the lungs. This is especially important for premature babies trying to expand their lungs after birth. Surfactant is a mixture of lipids, proteins, and glycoproteins, lecithin and sphingomyelin being two of them. Lecithin makes the surfactant mixture more effective.
One property of a lipid bilayer is the relative mobility (fluidity) of the individual lipid molecules and how this mobility changes with temperature. This response is known as the phase behavior of the bilayer. Broadly, at a given temperature a lipid bilayer can exist in either a liquid or a solid phase. The solid phase is commonly referred to as a “gel” phase. All lipids have a characteristic temperature at which they undergo a transition (melt) from the gel to liquid phase. In both phases the lipid molecules are constrained to the two dimensional plane of the membrane, but in liquid phase bilayers the molecules diffuse freely within this plane. Thus, in a liquid bilayer a given lipid will rapidly exchange locations with its neighbor millions of times a second and will, through the process of a random walk, migrate over long distances.
Poractant alfa is a pulmonary surfactant sold under the brand name Curosurf by Chiesi Farmaceutici. Poractant alfa is an extract of natural porcine lung surfactant. As with other surfactants, marked improvement on oxygenation may occur within minutes of the administration of poractant alfa. The new generic form of surfactant is Varasurf developed in PersisGen Co. and commercialized by ArnaGen Pharmad. It has fully comparable quality profile with Curosurf.
Surfactant metabolism dysfunction is a condition where pulmonary surfactant is insufficient for adequate respiration. Surface tension at the liquid-air interphase in the alveoli makes the air sacs prone to collapsing post expiration. This is due to the fact that water molecules in the liquid-air surface of alveoli are more attracted to one another than they are to molecules in the air. For sphere-like structures like alveoli, water molecules line the inner walls of the air sacs and stick tightly together through hydrogen bonds. These intermolecular forces put great restraint on the inner walls of the air sac, tighten the surface all together, and unyielding to stretch for inhalation. Thus, without something to alleviate this surface tension, alveoli can collapse and cannot be filled up again. Surfactant is essential mixture that is released into the air-facing surface of inner walls of air sacs to lessen the strength of surface tension. This mixture inserts itself among water molecules and breaks up hydrogen bonds that hold the tension. Multiple lung diseases, like ISD or RDS, in newborns and late-onsets cases have been linked to dysfunction of surfactant metabolism.
Beractant, also known by the trade name of Survanta, is a modified bovine pulmonary surfactant containing bovine lung extract, to which synthetic DPPC, tripalmitin and palmitic acid are added. The composition provides 25 mg/mL phospholipids, 0.5 to 1.75 mg/mL triglycerides, 1.4 to 3.5 mg/mL free fatty acids, and <1.0 mg/mL total surfactant proteins. As an intratracheal suspension, it can be used for the prevention and treatment of neonatal respiratory distress syndrome. Survanta is manufactured by Abbvie.
Egg lecithin is a type of lecithin, a group of compounds primarily containing phospholipids, that is derived from eggs.
A unilamellar liposome is a spherical liposome, a vesicle, bounded by a single bilayer of an amphiphilic lipid or a mixture of such lipids, containing aqueous solution inside the chamber. Unilamellar liposomes are used to study biological systems and to mimic cell membranes, and are classified into three groups based on their size: small unilamellar liposomes/vesicles (SUVs) that with a size range of 20–100 nm, large unilamellar liposomes/vesicles (LUVs) with a size range of 100–1000 nm and giant unilamellar liposomes/vesicles (GUVs) with a size range of 1–200 μm. GUVs are mostly used as models for biological membranes in research work. Animal cells are 10–30 μm and plant cells are typically 10–100 μm. Even smaller cell organelles such as mitochondria are typically 1–2 μm. Therefore, a proper model should account for the size of the specimen being studied. In addition, the size of vesicles dictates their membrane curvature which is an important factor in studying fusion proteins. SUVs have a higher membrane curvature and vesicles with high membrane curvature can promote membrane fusion faster than vesicles with lower membrane curvature such as GUVs.
Pulmonary surfactant is used as a medication to treat and prevent respiratory distress syndrome in newborn babies.