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Page 1The walls of the respiratory bronchioles are made up of very thin, flattened squamos cells and a thin layer of connective tissue. They lack the smooth muscle and mucus producing cells of the conducting airways. Alveolar ducts branch from the respiratory bronchioles, and the walls of the alveolar ducts are made up entirely of alveoli. Each alveolar duct ends in a cluster of alveoli, which together are called an alveolar sac. Each alveolar sac opens into about 10 – 16 alveoli. Type I pneumocyte cells are very large, thin, and flat. They cover about 93% of the alveolar surface and allow for the diffusion of gases. Interspersed on the alveolar surface are the Type II pneumocytes. Even though there are twice as many of them, they are very small, comprising only 7% of the alveolar surface. The Type II pneumocytes play a very important role in the lung. The Type II cells manufacture a complex substance called surfactant. Surfactant consists mainly of phospholipids (dipalmitoyl lecithin), neutral lipids, and the surface proteins (SP), SP-A, SP-B, SP-C, and SP-D. The theorized role of each of these proteins is listed below:
Surface proteins B and C (SP-B and SP-C) appear critical to maintain normal surfactant function, while SP-A and SP-D are not.
Surfactant Function
Surfactant is critical in maintaining the condition of the alveolar surface so that gas exchange can occur. Clinically, surfactant performs the following three critical functions:
To understand the importance of surfactant, we must first understand surface tension. The surface of a liquid acts as if there were an elastic skin constantly pulling in, attempting to contract the liquid into the smallest surface area. This force is called surface tension. It is created by uneven forces of attraction of the molecules at the surface of the liquid. The molecules under the surface have equal forces of attraction all around them. The molecules at the surface are in contact with air (this is called the gas-liquid interface); there is no attraction between the surface molecules and air, so the surface molecules are pulled inward and down, creating the force called surface tension. It is this surface tension that makes liquid contract into a small sphere, such as, for example, the water drops that “bead” on a freshly waxed car. Without surface tension, the water drop would spread out into a large puddle. The surface of alveoli also has a layer of fluid, comprised largely of water. The greater the surface tension of the fluid, the smaller the sphere becomes, and in turn, the smaller the sphere becomes, the greater the surface tension gets. By the law of LaPlace, the alveoli will eventually decrease to their critical volume. Below this volume, the force of the surface tension will cause the alveoli to collapse, resulting in atelectasis. Once alveoli collapse, the pressure required to reopen them is much greater than the pressure required to inflate an alveolus that is just above its critical volume. This pressure is called the critical pressure. Surfactant is secreted by the Type II pneumocytes and stored in vesicles called lamellar bodies. The lamellar bodies unravel in the alveoli, and the surfactant forms a thin film called a monolayer on the inner surface of the alveoli. The air-liquid interface is replaced with an air-lipid interface, which has a much lower surface tension. In this way, the alveoli are stabilized above their critical volumes and do not collapse. Lower surface tension allows the alveoli to expand into a larger sphere, which provides a larger surface area, for greater gas diffusion. The lower surface tension also makes it easier to inflate the alveoli, which results in a lower work of breathing. The action of surfactant and its effect on surface tension is a very dynamic process. Surface tension varies with alveolar volume. On inspiration, the alveolar volume increases, spreading the surfactant molecules further apart, and surface tension increases. This helps prevent alveolar overdistension. On exhalation, the surface molecules are tightly packed, decreasing surface tension and preventing collapse. Surfactant has a relatively short half-life and must be continuously replaced at the alveolar surface. During exhalation, old surfactant is squeezed out of the monolayer, and new surfactant is added on inspiration. Under normal circumstances, most of the surfactant (90% to 95%) is taken back up and recycled by the Type II pneumocytes. Since inflation and deflation are important in maintaining a health monolayer and low surface tension in the alveoli, you can see that lung collapse or atelectasis disrupts surfactant production. Hypoxia can also damage the Type II pneumocytes and interrupt surfactant production, and repeated collapse and reopening of alveoli cause a lot of lung damage, inflammation, and leaking of protein-rich fluid into the alveoli. This also disrupts surfactant production.
The Effects of Surfactant on Alveolar Surface Tension
Indications for Surfactant Replacement Therapy The surfactant that is produced naturally in lung tissue is called endogenous surfactant. Exogenous surfactants are those produced outside of the body and administered as a therapy. The major indication for surfactant replacement therapy is to prevent or treat infants with Respiratory Distress Syndrome (RDS). RDS is a disease associated mainly with prematurity and low birth weight. The Type II pneumocytes in these infants are not mature enough to produce surfactant. In other cases, the Type II pneumocytes can be damaged from the hypoxemia that results from perinatal asphyxia. In either case, an inadequate amount of surfactant leads to alveolar collapse, hypoxemia, and increased work of breathing for the infant.
General Techniques of Surfactant Administration Surfactant is administered intratracheally. This requires placement of an endotracheal tube. The tube must be positioned properly above the carina to ensure even distribution to both lungs. The baby should be suctioned to remove any secretions that would interfere with medication delivery. Surfactant can be given immediately after birth, as close to the first breath as possible, to premature infants with very low birth weight. This early administration is called prophylactic (preventative for RDS). Rescue therapy is administered 6 to 8 hours after birth to treat RDS once signs and symptoms have already developed.
Types of Exogenous Surfactants There are two types of exogenous surfactants that are currently available, natural/modified and synthetic. Colfosceril palmitate (Exosurf). Exosurf is a synthetic surfactant. Synthetic surfactants are mixtures of synthetic components that are produced in the laboratory. This means that the drug is free of infection and foreign proteins, which is an advantage, but it may not perform as well as natural surfactant because of the organic chemicals that are substituted for the natural proteins.
Dose and Administration The dose is 5 ml/kg of Exosurf administered intratracheally. Multiple doses can be give 4-6 hours apart if there has not been a good response to a single dose. Two or three doses are usually given if the clinical response of the baby indicates the need for further treatment. Exosurf is supplied in a powder form and must be reconstituted with the liquid supplied by the manufacturer. It needs to be mixed thoroughly but gently so that it does not form bubbles. The reconstituted solution is instilled down the baby’s endotracheal tube through the sideport of a special adapter provided by the manufacturer. The medication can be instilled through the sideport while the infant is attached to the ventilator. After instillation of half of the dose, the baby is turned 45 degrees to the right side for 30 seconds, while ventilation continues. He or she is then returned to the supine position while the second half is instilled. He or she is turned 45 degrees to the left for 30 seconds, then returned to supine, and the catheter is removed. This procedure is to distribute the surfactant as widely as possible throughout the lung.
Beractant (Survanta). Survanta is a natural/modified surfactant comprised of natural bovine (cow) lung extract modified with three other additives. Natural surfactant is obtained from animals or humans by means of alveolar wash or amniotic fluid. The surfactant is then extracted from the liquid by centrifugation or simple filtration. The surfactant is modified by adding or removing certain components to improve its function in the lung, reduce protein contamination, and ensure sterility. This preparation consumes a lot of time, which adds to the cost of the drug. There is also concern over the possibility of viral infection and immunologic reaction to foreign proteins. However, the advantage of natural surfactants is that they contain the phospholipids and proteins (SP-B and SP-C) necessary for absorption and spreading.
Dose and Administration The dose is 4 ml/kg administered by direct tracheal instillation. The dose can be repeated in 6 hours for up to 4 doses if required on the basis of clinical judgment. An endotracheal tube with a sideport can be used, or the baby can be briefly disconnected from the ventilator while a 5 French catheter is placed directly in the endotracheal tube to instill the Survanta. The manufacturer recommends that the baby be placed in four positions: inclined 5-10 degrees, head turned to the right, then head turned to the left, the reclined 5-10 degrees with the head to the right, and finally with the head turned to the left. If the catheter is being placed directly into the endotracheal tube, the catheter is withdrawn and the infant returned to the ventilator after each instillation.
Adverse Reactions A steady improvement in oxygenation is usually seen following surfactant administration, but one must keep in mind that these drugs often produce rapid changes in lung compliance. It is critical to make appropriate adjustments in the ventilator settings. There are several hazards one must be aware of. They can be divided into those that occur during administration and those that occur after administration. During administration:
After administration:
Uncommon side effects include:
The patient should be monitored closely and appropriate ventilator changes made following surfactant administration. As the baby’s ling compliance improves, tidal volumes may increase significantly. Ventilator pressure may need to be decreased to prevent alveolar damage or rupture. Oxygen levels in the baby’s blood may also increase, allowing for the baby’s oxygen concentration to be decreased. Monitoring may include chest X-ray, chest movement or tidal volume changes, arterial blood gases, and oxygen saturation measurements.
Surfactant Replacement Therapy Indications Surfactants have been used anecdotally and successfully to treat several other conditions, including the following:
Surfactant Administration in Adult So far, surfactant has not been proven to be successful in treatment of adults and children with ARDS. Only a few studies of adults with ARDS have been done, and the results have been conflicting. One large trial where Exosurf was nebulized continuously for 5 days showed little improvement and no difference in outcome. The actual dose that was delivered to the lungs in this study is not known. It has been suggested that the delivered dose may not have been sufficient. A smaller study, where Survanta was instilled directly into the lungs of adults, showed a decrease in mortality from 43.8% in the control group to 17.8% in the group who received Survanta. These results suggest that there may be some benefit, but more research is needed. The dose and delivery technique may need to be modified for adults. This could make treatment extremely costly (one estimate was $5000 per dose for adults). Finally, there are differences in the pathophysiology of ARDS. In IRDS, the problem is a primary surfactant production deficiency, while in ARDS, the surfactant deficiency is secondary to lung injury and inflammatory response. This may account for the different response to surfactant replacement therapy. Exosurf, Survanta, Infasurf, and Curosurf are available in the U.S., and there are several others that are available throughout the world. Page 2Radiology of the lungs involves the observation of shadows that are caused by temporary or permanent collapse of portions of the lung. The patterns of atelectasis and of more diffuse lung disease can be better understood by the study of alveolar mechanisms, of which surfactant physiology contributes an important part. Surface tension is the result of unopposed attractive forces between molecules ( or molecular aggregates ) in a fluid at a particular boundary. Because of the fewer inter-molecular attractive forces acting upon molecules at the surface of a fluid, extra work is needed to bring further molecules to the surface when the surface area is increased. Surfactants reduce those surface forces and permit the formation of structures like soap bubbles that otherwise would be extremely unstable.
Consider some air bubbles rising to the surface of a liquid. The reduction in external pressure from reducing depth of fluid will allow contained air to expand any bubble. The bubbles will be unstable, unless the thin boundary layer can move and absorb the pressure variations, thermal and other potentially distractive forces. The risk of rupture is reduced if the rising bubble can increase the surface area of the original fluid-air interface without needing to do much work at the surface layer. The increased volume of the bubble will then nullify the potentially disruptive pressure difference between contents and the surrounding air.
On a smooth surface, the same internal forces will constrain a fluid to form a bead, rather than spreading thinly over the surface. The thickness of the bead depends on the surface tension of the fluid and the density of the fluid. The presence of surfactant or a soap will reduce the mutually attractive force from elements of the fluid at its boundary and the reduction of surface tension will allow water to wet smooth surfaces or allow bubbles to persist.
There is an experiment where soap bubbles of different sizes are connected. By inspection of the forces on a bubble you can deduce that the pressure in bubbles depends on how small is their radius. Assuming that the surface tension is the same in each bubble, of two connected soap bubbles, the smaller will empty into the larger. The alveolus as connected bubbles
The lung is the site of separation of body fluids from air and
contains multiple pouches of varying size that may change with
respiration. If we assume that the lung is at a stable state
after partial inspiration, given that the lung is entire and
potentially all of its cavities communicate on normal
inspiration, each normally distended alveolus should have the
same air pressure difference and a similar distraction force,
originating from negative intrathoracic pressure and moderated
through
elasticity of neighboring tissues. Since the elastic
forces in the wall are equal and the radius variable, the
pressure/radius equation cannot apply without a variation in
surface activity between alveoli of different size or a total
absence of surface tension in both.
Elsewhere the breathing mechanism is discussed, particularly where our blood oxygenation does not change when we take a large or small breath. Although the high affinity of hemoglobin for oxygen allows large variations in ventilation and perfusion in the normal, not all of the pulmonary sub-units are used to the same extent at the same time. The unpredictability of alveolar collapse on expiration is similar to unpredictability of cavity sizes when you squeeze a sponge. To maintain normal blood oxygen saturation, all normally perfused alveoli must retain dimensions to permit air diffusion and exchange. Gill described sequential derecruitment as well as size reduction of alveoli on deflation of lung specimens. The folding of the alveolar walls described in that paper is reasonable given the incompressibility of cellular layers, but has implications for the nature of pulmonary surfactant which will be considered later. Some alveoli must be partially collapsed on quiet breathing. This means that surfactant in the lung is not as simple as a soap bubble.
The easiest way to realize this is to consider the bubble of
vanishingly small dimensions. With little or no radius, the
force required to inflate the bubble gets close to infinity. We
know that in the
collapsed
lung reinflation is possible. The baby's first breath
is another good example. Despite the same pressure gradient at the alveolus, the theoretical considerations of connected bubbles and the necessary normal variation in alveolar size, the alveoli will all inflate with full inspiration. This variation in alveolar ventilation and alveolar size with respiration imply that the properties of the surface film do not remain constant. To look at this, we will need to consider monolayers and particularly the Langmuir-Blodgett method of investigating them.
Compression, Folding and Distorting
Surface tension can be investigated by using a teflon-lined trough with a bar that separates a surface layer on fluid from uncoated fluid, as in the upper of the three images. The force on the bar will reflect the contribution of the surface activity of the added compound. Most biological surfactants and soaps will have a polar ( electrically charged ) and non-polar group. The polar end resembles those compounds that are freely soluble in water, hydrophilic, and the non-polar group might resemble compounds that are soluble in oils, hydrophobic. Over water, the surfactant layer molecules are oriented with their hydrophilic polar ends towards the fluid. Movement of the bar will require greater applied force as the surface layer is compressed. Such compressed surface layers are very important in Materials Science, where pure uniformly oriented molecules and polymers are being used to generate new display technologies or molecular wires, for example. The lower two images show how monolayers on compression can be made to fold and form irregular thickening. The up-down displacement of a graphite plate or added matrix will impose folding or doubling, which can also depend on additional molecules that may influence the appearance or expression of non-homogeneities in the compressed surface layer. Micrographs show that pulmonary surfactant is primarily a monolayer in the alveolus, separating the minimal water phase from the air and lying almost adjacent to the surface of cells. These monolayers become double in the folds of underinflated alveoli. Stabilization or a predisposition to folding can be imparted by the presence of proteins in biological surfactant layers. As the layer is compressed, reorientation of the molecules will change the compressive force needed in the experimental trough. Excess compression can force proteins from a surfactant layer, but the full significance of this mechanism in-vivo remains to be determined. Additional substances may may affect friction forces on movement of the surface layers. The compression of an experimental surface layer of long-chain phosphatidylcholines requires less work, once a pulmonary surfactant protein has been added. Not only the folding of molecules, but also the discussion itself can be convoluted when we generalize. Cell membranes and cytoplasmic reticulum are a special case of surface layers, binary monolayers. The folding of the membrane influences cell-manufactured proteins and proteins influence folding of membranes. This is not just to confuse the reader. The secretion of proteins is affected by the surface chemistry of cells and the surface chemistry is altered by combinations of proteins. The mediating mechanism in the cell-membrane may be shared. Local changes in beta adrenergic activity have been found to stimulate surfactant production via cyclic 3'5'Adenosine Mono Phosphate, that so often mediates cell-membrane reactions to hormones.
Surfactant Physiology The lining cells of the alveolus are, in the main, either thin structures, type I cells, or bulky type II cells with lots of intracellular tools ( mitochondria, granules and lamellar bodies ) for making, storing and secreting things. The type II cells secrete the components of pulmonary surfactant and, after alveolar injury, will divide to form more type I cells. In the lung, the long-chain phosphatidylcholines are combined with originally three, now known to be four proteins, predictably labeled; Pulmonary Surfactant Proteins SP-A, SP-B, SP-C and SP-D. The proteins make roughly 10 percent of the mass and improve surfactant adsorption to the saline-air interface and cells in the alveolus, including type II aveolar cells and macrophages. SP-B and SP-C proteins are particularly hydrophobic, presumably indicating their association with the lipid layer. Their function is to improve flexibility of the layer and they contribute to lowering its surface energy on compression. The heavier molecules, SP-A and SP-D, are glycoproteins. SP-A binds phospholipids, but experimental mice can survive without it. SP-A seems to inhibit surfactant production and can bind to receptors on the type II cells. SP-D is poorly bound to phospholipids and seems to enhance phagocytosis of bacteria. Immunologists call it a collectin, rather than an opsonin. Both SP-A and SP-D are collectins. Recent theory suggests a role for collectins in clearing all the inhaled pollution without generating any feature of inflammation in the normal lung. The immunological role of type II alveolar cells is supported by the observation that they can make proteins that cause neutrophil chemotaxis.
Surfactant has a high rate of turnover and is replaced with a
half life of about 10 hours. The discussion of Pulmonary
Surfactant is readily made complicated, because much remains to
be discovered. From the study of connected bubbles, we know
that, in the normal lung, surface tension must be different ( or
totally absent ) in different sized alveoli. The biology of
surfactant appears to be normal instability with continual
change, alteration and many potential reactions: The proportions of proteins in the surface layer change, once secretion has taken place. Experimental compression of surfactant can 'squeeze out' protein from the surface layer. This and the surface layer folding in alveoli on expiration engenders theories that the act of breathing will consume functional surfactant.
Although demonstrable increase in surfactant production will
follow a single large breath, or hyperventilation, its
biochemical mechanism remains undetermined. The chemical
feedback of secretions upon the type II alveolar cell may be
altered by surface layer folding in alveoli that are
incompletely distended, but the cells themselves are also
distorted by alveolar enlargement. Each alveolus contains an infinitely variable combination of immunoglobulins, cytokines, macrophage migration inhibiting factor and surface proteins that may all affect the surfactant function. It should be no surprise that precise predictions of cellular accumulations in the alveolus and subsequent lung disease are so difficult. Surfactant in the newborn
The description of
respiratory distress includes a premature infant of
28-32 weeks gestation, who breathes initially, but soon develops
breathing problems. The problem is not an absolute lack of
pulmonary surfactant, but insufficient replacement by the
immature type II alveolar cells. At birth, the concentration of
surfactant in the immature affected individual is at ( or above
) normal levels. The adsorption, removal and recycling of
surfactant is reduced in the immature type II alveolar cells,
explaining both its initial excess and subsequent insufficiency. Surfactant in Adult Respiratory Distress syndrome Adults who end up on intensive care are markedly unwell with poor cardiac output, sludging of fibrin and platelets in pulmonary capillaries, poor respiratory function and small areas of pulmonary atelectasis. Poor oxygenation and the proteins in any exudate will adversely affect surfactant activity. Any mechanical disadvantage in ventilation will be magnified, if surfactant function is not normal in alveoli of all sizes. The surfactant response to overinflation is not predictable, but must rely upon lung elasticity in the stretched alveoli and a normal film of surfactant (folding ) in the smaller alveoli. If there is insufficient surfactant to cover the stretched alveoli, presumably the secondary effects on protein accumulation, and immune cells might also be altered.
References: Gill et Al. 'Alveolar volume surface area relation in air and saline-filled lungs, fixed by vascular perfusion'. [ J. of Appl. Physiol. 47:990-1001 ( 1979 ) ]
Papers in: Chander A; Fisher. 'Regulation of lung surfactant secretion'. [ Am. J. Physiol. 258 L:241-253 (June 1990) ] Mason R. Green K. Voelker D. 'Surfactant protein A and surfactant protein D in health and disease'. [ Am. J. Physiol. 275 L:1-11 (July 1998) ] Hartshorn K.L. et Al. 'Pulmonary surfactant proteins A and D enhance neutrophil uptake of bacteria.' [ Am. J. Physiol. 274 L:958-969 (June 1998) ]
There will be some nice review papers in
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