Archives of Perinatal Medicine 16(3), 134-139, 2010
ORIGINAL PAPER
Pulmonary surfactant – structure, metabolism
and the role in RDS and ARDS treatment
ANNA DYLIK1, ANDRZEJ MARSZAŁEK1,2
Abstract
Pulmonary surfactant is a complex mixture of lipids and proteins that, by modulating surface tension during
breathing, prevents alveolar collapse at exhalation and overdistention at inspiration. Surfactant is synthesized by
type II pneumocytes, assembled in lamellar bodies and secreted at the air-liquid interface of the alveolus. This
surface-active material is re-uptaken by alveolar type II cells and eliminated by macrophages. Deficiency or dysfunction of pulmonary surfactant contributes to several respiratory pathologies, such as among other respiratory
distress syndrome (RDS) in newborns and acute respiratory distress syndrome (ARDS) in children and adults.
Surfactant replacement therapy in the treatment and prophylaxis of RDS substantially reduces mortality and
morbidity in preterm infants. However, ARDS treatment trials involving adult patients have not brought about
good results. The aim of the paper is to present structure, function and metabolism of pulmonary surfactant as
well as an overview of publications on the use of exogenous surfactants in RDS and ARDS treatment.
Key words: surfactant, RDS, ARDS
Introduction
Pulmonary surfactant is a mixture of lipids and proteins synthesized by the alveolar type II epithelial cells
(pneumocytes). It acts within peripheral part of lower
airways, where it is playing an important role in the lung
environment homeostasis [1-3]. Its lipid component
mainly consists of bipolar phospholipids and it is responsible for lowering surface tension of the thin aqueous
layer lining the respiratory epithelium of lungs [1, 4].
The protein constituent is composed of 4 proteins bearing their names according to the sequence of their discovery, namely: SP-A, SP-B, SP-C and SP-D (surfactant
protein A, B, C, D). These proteins play a key role in surfactant metabolism regulation, leading to a complex and
dynamic cycle of surfactant material at the air-liquid
interface of alveoli [2-4]. Moreover, pulmonary surfactant
proteins take part in local defence mechanisms and immunomodulation within the terminal portion of lungs [5-7].
The main function of surfactant is to stabilize gases
in the alveoli and to increase the lung compliance [8]. Its
deficiency causes respiratory distress syndrome (RDS)
in premature neonates. The multiform defect of surfactant function also leads to the development of acute respiratory distress syndrome (ARDS) in both infants and
adults [9-11].
Several attempts to find a cause of morphological
changes accompanying RDS and ARDS and understanding of their development have encouraged clinicians to
1
2
use exogenous surfactants in treatment. According to
a number of publications, surfactant replacement therapy in newborns with respiratory disorders gave beneficial therapeutic results [12-14]. However, ARDS treatment trials involving adult patients revealed that exogenous surfactant may improve oxygenation but did not
improve mortality. Future studies may potentially discover an approach to use exogenous surfactants in ARDS
[9, 15, 16].
The structure and metabolism of surfactant
The alveolar-capillary barrier (so-called air-blood barrier) is the place in which main gas exchange in the lung
takes place. These are unusually delicate structures
made by the cytoplasm of alveolar type I cells and the capillary endothelium separated by the common basement
membrane (fig. 1) [7, 17]. Pulmonary surfactant seems
to be essential for the proper functioning of air-blood
barriers. This lipid-protein complex constitutes a layer
which separates the gas phase from the aqueous layer
covering the alveoli (hypophase) and reducing surface
tension almost to zero. This protects the alveoli from
collapse during expiration as well as prevents them from
overdistention during inspiration [1-3]. Surfactant mainly
consists of lipids (90 per cent of its mass). The major
fraction is composed by phosphatidylcholine with
saturated and unsaturated fatty acids. The most frequent
substituents among the unsaturated fatty acids are
Department of Clinical Pathomorphology, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz
Department of Clinical Pathomorphology, University of Medical Sciences in Poznań
Pulmonary surfactant
palmitic and oleic acids [1, 3, 18]. The other components
include phosphatidylglycerol, phosphatidylethanolamine,
sphingomyeline, neutral lipids and glycolipids [11].
Fig. 1. Scheme of air-blood barrier
(modification from www.education.vetmed.vt.edu)
Surfactant proteins are divided into 2 groups: large
and water-soluble SP-A and SP-D proteins and small,
hydrofobic SP-B and SP-C proteins. SP-A and SP-D proteins belong to the calcium-dependent type of lectins [5,
19]. They are characterized by ability to bind to bacteria,
viruses and other pathogens as well as to activate alveolar macrophages. Both mechanisms are of great importance to defense mechanisms of the lung [5, 6, 11]. The
basic function of SP-B and SP-C proteins is to increase
the stability of phospholipidic surface film [4].
Surfactant proteins and lipids are synthesized by the
alveolar type II cells, which are also known as granular
pneumocytes. A certain amount of surfactant (except SPC) is also produced in Clara cells [1, 19]. Phospholipids
are synthesized from the precursors like glycerol, fatty
acids and choline in the smooth endoplasmic reticulum
of aforementioned cells. Then they are moved to be converted in the Golgi apparatus in which lamellar bodies,
serving as storages, are finally formed [1, 3]. The lipid
synthesis ensues relatively quickly (approx. 1-2 hrs). The
production and processing of surfactant proteins does
not basically differ from the general pattern of protein
production [1]. Glucocorticoids, prolactin, estrogenes,
thyroid hormones and catecholamine exert stimulating
influence on the surfactant constituents synthesis whereas fetal hyperinsulinism (caused usually by maternal diabetes), hypoxia and acidosis delay its production. Such
conditions result in the frequent development of RDS in
135
neonates [1]. Lamellar bodies are surrounded by a membrane round or oval special organelles where the surfactant material is assembled in series of densely packed
bilayers as seen by electron microscopy [4, 20]. These
structures begin to arise in the alveolar type II cells
in the human fetus arround 17-24 weeks of gestation –
a long time before the alveoli are formed and lung are
prepared for breathing [18].
Surfactant secretion occurs by means of exocytosis,
during which the membrane limiting lamellar bodies
undergoes a fusion with the apical plasma membrane of
the type II pneumocytes. The process involves microtubules and other elements of the cytoskeleton (actin filaments among others) [1, 19]. The surfactant released
from alveolar type II cells undergoes a number of morphological and functional changes ranging from transformation into tubular myelin to conversion into a lipid
monolayer at the air-liquid interface (fig. 2). It is worth
to notice that the above mentioned changes are mainly
dependent on the interaction between lipids and proteins [4, 19].
Fig. 2. Surfactant structure (modification from
www.ucm.es/info/respira/dip/Membranas-negro.jpg)
Tubular myelin formation process needs the presence of calcium ions, phospholipids and SP-A, SP-B proteins [4, 15]. The research by Walski and co-workers
showed that posttranslational blocking of protein synthesis with puromycine leads to irregularities in lamellar
bodies as well as it contributes to the underdevelopment
of myelin-like structures. At a longer period of puromycine treatment any tubular myelin structures were observed [21, 22].
Tubular myelin is the immediate precursor of a monomolecular surfactant form, which as an ultrathin film
lines the surface of the alveolus [20]. The main constituent of the monolayer is dipalmitoylphosphatidylcholine
(DPPC), which is a bipolar lipid (it has a hydrophilic
‘head’ and a lipophilic ‘tail’). A drop of this substance
‘spills around’ on the surface of water due to the polar
group attraction by water molecules [17]. DPPC determi-
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A. Dylik, A. Marszałek
nes the stability of the surfactant monolayer irrespective
of the changeable pressure parameters. SP-B and SP-C
proteins seem to be essential to the transformation of
tubular myelin into its monomolecular form [4, 23]. An
electron microscope examination indicated that hydrophobic proteins show an ability to bound, aggregate and
cut the phospholipid complexes. SP-A protein can play
a role in monolayer formation as well, however it is
much less effective [20].
Surfactant secretion may be stimulated or inhibited
by physicochemical factors and by stimulating corresponding receptors. For instance, hyperventilation, temperature growth or calcium ions concentration have
been proposed as possible inducers of surfactant secretion. A similar effect may be produced by stimulating
cholinergic, beta-adrenergic, purine and vasopressin receptors [1, 18, 24]. Atelectasis cause a reduction of surfactant in atelectatic areas due to exhaustion abilities on
its synthesis [1]. Also, its secretion seems to be inhibited by SP-A reabsorption in the alveolus [25].
Pulmonary surfactant is in a state of continuous change. There is a dynamical balance between the monomolecular film which lines the alveoli and the part of surfactant in the type II pneumocytes [1]. Surfactant is constantly removed from the alveoli surface through reuptake
by the type II pneumocytes, where it can be recycled or
degraded and reused to synthesize new amount of surfactant. Yet another phenomenon is its clearance by alveolar macrophages [5]. Clara cells do not engage in recirculation [6]. It is highly probable that lipid disintegration
may also occur in the monolayer of surfactant [1].
The whole process of surfactant lipids exchange
lasts from 5 to 10 hours. The rate of recirculation depends on fraction and a morphological form of surfactant. The uptake of extracellular surfactant is stimulated
by SP-A, SP-B, SP-C proteins and phosphatidylglycerol.
The amount of recycled surfactant components is dependent on the lung aeration (after birth 90 percent of surfactant undergoes recirculation) [1].
SP-A protein is essential for regulating the recycling
of surfactant. According to its C-type lectin activity SP-A
can bind to the carbohydrate groups on the type II pneumocytes. It facilitates the uptake of phospholipids by
both type II pneumocytes and alveolar macrophages and
protects surfactant lipids from degradation in type II
cells [5, 25]. It is worth mentioning that SP-A is uptaken
by the alveolar type II cells and incorporated into lamellar bodies independently [1, 25].
A small amount of surfactant is permanently removed
from the lung through airways and circulatory system.
The clearance may take place in alveolar macrophages
and is connected with their migration from lung tissue.
Moreover, surfactant may be removed as a result of ciliary
movement, which causes the part of material to be moved
into trachea and then into the esophagus [1, 26].
The use of surfactant in RDS and ARDS treatment
Exogenuous surfactant treatment was introduced
into clinical practice by Fujiwara and co-workers, who
administered it to neonates suffering from breathing
disturbances [12]. Since then, a number of published clinical reports have proven the effectiveness of surfactant
replacement therapy [9, 13] The use of surfactants combined with mechanical ventilation has made it possible
for premature babies weighting merely 750 g to survive
[1]. There were ahead published research involved a range of different preparations, including so-called synthetic
surfactants as well as semi-natural preparations. Synthetic surfactants being chemically-synthesized substances
contained a mixture of lipids, which were supposed to
approximately match the basic composition of alveolar
surfactant. Semi-natural preparations were derived from
animals and contained not only lipids but also some
naturally-found proteins [3, 10]. At present, production
of natural surfactants preparation from amniotic fluid collected during cesarean sections in full-term pregnancy,
have become a history. Although they contain all the essential phospholipids and proteins, for single therapeutic
dose it is needed up to 1.6 l of amniotic fluid [10, 14, 27].
Over the last years various methods for surfactant
administration into trachea have been developed [3].
The most frequent one is to deliver surfactant in a bolus
through the endotracheal intubation during artificial
ventilation or soon after the respirator has been removed. In case the ventilator is not used simultaneously,
an Ambu bag has to be used to assure an even distribution of surfactant [3, 28]. It seems essential to adjust
surfactant administration to a given breathing cycle phase so as to avoid reverse flows into the trachea [1].
Usually, one dose of surfactant is recommended to be
administered. However, if the patient is kept under controlled respiration in addition to being given oxygen, it
may be necessary to administer another dose after 12
hours. The OSIRIS Collaborative Group studies have indicated that there is no need to continue surfactant
administration to infants who show RDS symptoms after
two standard doses have been applied [13].
At the beginning of the “surfactant era” the preparation was given only to neonates with RDS confirmed
by both chest radiography and biochemical tests for the
Pulmonary surfactant
maturity of lung tissue. At present surfactant is more
and more often used prophylactic in neonates at risk of
severe RDS, it means born before 28 and after 28 week
of gestation with a confirmed immaturity of lungs [28].
As prophylactic treatment we describe instillation of the
drug within 5 to 30 minutes after birth, very often in the
delivery room. The infant must be intubated and stabilized so that surfactant can be administered. As it was
published earlier neonates with a 5-minute Apgar score
under 3 are not suitable for preventive treatment [28].
Clinical trials have shown that prophylactic surfactant
therapy brings a number of benefits. For instance there
are a decrease in the requirement for ventilatory support in the first days of life as well as a reduction in the
incidence of air leak syndrome [13, 28]. However, intratracheal surfactant administration to newborns induces
a number of technical problems. There were cases described of administering preparation to not a fully-stabilized patient, without radiographic verification of endotracheal tube placement. Another disadvantage of the
method is an impossibility to verify acid-base equilibrium
before administration [28]. Amniotic puncture are routinely carried out for estimation of fetal lung maturity so
the procedure seems to be safe for the mother and her
baby. The trials to administer surfactant prenatally directly into amniotic fluid as a new RDS preventive treatment are made. The results from animal and observational human studies have seemed promising, however there is no current evidence from randomized controlled
trials to guide the use of intraamniotic instillation of surfactant for women at risk of preterm birth [3, 29, 30].
The optimistic results of surfactant treatment in
neonates have encouraged clinicians to employ a similar
therapy for children and adults with ARDS. ARDS is
a respiratory failure caused by various factors that directly and indirectly damage the lung (table 1). Inflammatory
process in lungs causes pulmonary surfactant dysfunction, which finally leads to alveolar flooding and atelectasis [31, 32].
Trials involving the use of synthetic surfactant (Exosurf) in ARDS, conducted by Anzueto and co-workers,
did not produce expected results [33]. In the studied
group, neither mortality rate decrease nor peripheral
blood oxygenation improvement were found. The reason
for failure of such therapy may have been the use of protein-free surfactant. The presence of proteins, as it was
mentioned above, is essential for proper surfactant
spreading on the alveoli surface. Undoubtedly, the method of surfactant delivery used by Anzueto and coworkers was meaningful for results of therapy [1, 33].
137
Table 1. Disorders associated with the development
of the acute respiratory distress syndrome (ARDS)
(modification from [31])
Extrapulmonary
causes of ARDS
Sepsis
Disseminated intravascular
coagulation
Severe trauma with shock
Multiple transfusion
Acute pancreatitis
Drug overdose
Malaria
Severe burns
Intracranial hypertension
Extracorporeal circulation
Pulmonary
causes of ARDS
Pneumonia (bacterial, viral,
by fungi, parasitical)
Aspiration of gastric content
Fat emboli
Lung contusion
Near-drowning
Inhalational injury
(toxic gases)
Reperfusion pulmonary
edema
Mountain sickness
Thorax irradiation
The exogenous preparation was administered in the
form of aerosol and as researches estimated less than 5%
of the dose reached the lungs [33]. The effects produced
in Walmarth’ trials show that better results may be
achieved by instilling surfactant with a bronchoscope
directly into segmental bronchi [34].
Meta-analysis conducted by Davidson and co-workers
reveal that exogenous surfactant may improve oxygenation but did not improve mortality of ARDS patients.
One potential explanation for the lack of effectiveness of
surfactant therapy is that ARDS often develops in association with many serious medical disorders, which dramatically influences the prognosis [16]. The most frequent cause of mortality among patients with ARDS is
not the respiratory failure itself, but a primary disease.
It seems that surfactant replacement therapy may play
an important role in treatment of ARDS caused by factors that directly damage the lung [16, 32, 35].
Besides, we should take into consideration that the
pathophysiology of ARDS is complex, involving a variety
of insult leading to neutrophil infiltration, pulmonary
fibrosis and increased alveolocapillary permeability [36].
Several in vitro-studies show that neutrophil elastase can
damage surfactant proteins and impaired the function of
surfactant [37]. This finding has important implication
for surfactant therapy in ARDS. Advanced cases might
require bronchoscopic focal lavage to remove plasma
proteins and inflammatory mediators prior to surfactant
instillation to areas of the great needs [11, 36].
Another important issue is proper dosage of exogenous preparation. In ARDS patients, as mentioned above, the triggering of pro-inflammatory cascades leads to
a markedly reduction of surfactant activity by different
mechanism, for example degradation of lipids and proteins by lipases and proteases. Supplementation with
138
A. Dylik, A. Marszałek
exogenous surfactant in ARDS requires enough amount
of preparation to reduce inactivation [9]. On the other
hand, the trials on animals by Wąsowicz and co-workers
indicated that an excessive amount of surfactant per surface unit may lead to air-blood barrier damage and activation of the inflammatory process [17]. In addition numerous of studies demonstrated that synthetic preparations induce more adverse effects in lungs compared
with semi-natural surfactant preparations [17, 23].
Recent intensive clinical research has led to the development of new surfactants, which can enhance the therapeutic potential of treatment patients with ARDS. These
new generation of preparations are made of synthetic
peptides that mimic the function of hydrophobic proteins
SP-B and SP-C combined to phospholipids [9, 38]. The
results of two randomized control trials with use of recombinant SP-B analog called KL4 seem promising [39].
Moreover phospholipase-resistant phospholipid analogues
have been designed, synthesized, and tested as potential
components in new preparation [9]. It is likely that proteins containing synthetic surfactants with highly reproducible composition, produced in large amount at a low
cost, will become available in the near future [9, 38].
Conclusion
The major function of surfactant is to lower surface
tension at the air-liquid interface in alveoli and terminal
conducting airways, which prevents alveolar collapse at
exhalation and overdistention at inspiration.
Administration of surfactant to newborns with RDS
has been established as appropriate preventive and treatment therapy. However ARDS treatment trials involving
adult patients have not brought about expected results.
New preparation, dosage and methods of administration
are among the issue that may improve the efficiency of
surfactant treatment. New well planned laboratory studies as well as clinical trials are expected.
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J
Andrzej Marszałek
Chair and Department of Clinical Pathomorphology
Nicolaus Copernicus University in Toruń
Collegium Medicum in Bydgoszcz
M. Skłodowskiej-Curie 9, 85-094 Bydgoszcz, Poland
e-mail: [email protected]