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Radiology 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.
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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.
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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.
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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.
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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 neighbouring 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.
The possibility that unbalanced surface tension forces from the
differing radii would balance wall tension differences in variably
distended alveoli is both unlikely and inherently unstable and so
is left out of this theoretical discussion, for simplicity.
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 haemoglobin 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 realise 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.
[By the way, this has implications for surfactant dynamics in
neonatal Respiratory distress syndrome ].
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.
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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.
Stabilisation 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 generalise. 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.
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:
Radio-isotope studies demonstrate that pulmonary surfactant is
absorbed by macrophages and, to a lesser degree, type II alveolar
cells. The component proteins are adsorbed at different rates onto
the macrophages.
The proteins in the surfactant improve macrophage phagocytosis of
surfactant lipid and improve its adhesion to type II alveolar
cells.
The presence of adsorbed SP-A protein can reduce secretion of new
surfactant.
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.
One place to look for a mechanism is the article on the function of
cell microtubular and microfilament architecture in Scientific American
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.
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.
The use of corticosteroids prior to birth will increase the
maturity of the type II alveolar cells and increase the overall
rate of production of pulmonary surfactant. There is no guarantee
that all alveoli will be mature at exactly the same time. There are
bound to be small differences. The relation between pressure and
radius indicates that overinflation of alveoli with interstitial
emphysema will occur easily at low positive inflation pressures.
Any slight variation in alveolar size and surfactant activity will
be magnified by any excess pressure.
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:
Donald E. Ingber Scientific American: Feature Article: The Architecture
of Life: January 1998.
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:
Müller B. and von Wichert P. (Editors) 'Lung Surfactant:
Basic Research in the Pathogenesis of Lung Disorders' [ Prog.
Resp. Res. 27:69-73 (1994) Basel Karger ]
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
[ Biochim. Biophys. Acta 1408(2-3):100-263 (1998) ],
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Ian Maddison Jan 1999
