(The FASEB Journal. 2001;15:59-69.)
© 2001 FASEB
Surfactant protein A (SP-A): the alveolus and beyond
KAVITA R. KHUBCHANDANI and
JEANNE M. SNYDER1
Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA
1Correspondence: Department of Anatomy and Cell Biology, 1–550 Bowen Science Bldg., University of Iowa College of Medicine, Iowa City, IA 52242, USA. E-mail: jeanne-snyder{at}uiowa.edu
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ABSTRACT
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Surfactant protein A (SP-A) is the major protein component of pulmonary
surfactant, a material secreted by the alveolar type II cell that
reduces surface tension at the alveolar air–liquid interface. The
function of SP-A in the alveolus is to facilitate the surface
tension-lowering properties of surfactant phospholipids, regulate
surfactant phospholipid synthesis, secretion, and recycling, and
counteract the inhibitory effects of plasma proteins released during
lung injury on surfactant function. It has also been shown that SP-A
modulates host response to microbes and particulates at the level of
the alveolus. More recently, several investigators have reported that
pulmonary surfactant phospholipids and SP-A are present in nonalveolar
pulmonary sites as well as in other organs of the body. We describe the
structure and possible functions of alveolar SP-A as well as the sites
of extra-alveolar SP-A expression and the possible functions of SP-A in
these sites.—Khubchandani, K. R., Snyder, J. M. Surfactant
protein A (SP-A): the alveolus and beyond.
Key Words: lectins • cystic fibrosis • extra-alveolar sites • innate immunity
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PULMONARY SURFACTANT AND SP-A
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PULMONARY SURFACTANT IS a lipoprotein synthesized and
secreted by alveolar type II cells that reduces the surface tension at
the lung alveolar air–liquid interface (1)
. Pulmonary
surfactant is composed of phospholipids (
80%), cholesterol
(10%), and proteins (10%). Four surfactant-associated proteins
(SP) have been identified and can be divided into two groups: the
hydrophilic proteins, SP-A and SP-D; and the hydrophobic proteins, SP-B
and SP-C (1)
. SP-B and SP-C greatly increase the
adsorption of surfactant lipids onto the surface film that lines the
alveolus (1)
. SP-A is a 34–36 kDa protein that
facilitates the surface tension-lowering properties of surfactant
phospholipids in the alveolus, regulates surfactant phospholipid
synthesis, secretion, and recycling, and counteracts the inhibitory
effects of plasma proteins released during lung injury on surfactant
function (2)
. SP-D is a 43 kDa protein that has sequence
homology to SP-A (3)
. Recent studies suggest that both
SP-A and SP-D are involved in innate immune responses in the lung via
their ability to bind various pathogens including viruses, bacteria,
fungi, and particulates such as pollen grains and mite allergens
(4)
.
The most abundant of the surfactant proteins is SP-A (2)
.
Human SP-A protein is encoded by two genes, SP-A1 and SP-A2, which are
94% identical in nucleotide sequence and 96% identical in amino acid
sequence (5
6
7)
. Each human SP-A gene gives rise to
multiple mRNA transcripts. The primary structure of SP-A protein
consists of four domains: an amino-terminal domain, a collagenous
domain, a neck domain, and a carbohydrate recognition domain (CRD). In
the lung alveolus, human SP-A forms trimers that are thought to be
composed of two SP-A1 molecules and one SP-A2 molecules
(8)
. As depicted in Fig. 1
, the native SP-A protein is made up of six SP-A trimers that form a
‘flower bouquet’ structure (8)
. The amino-terminal of
the SP-A molecule is a short peptide of 7 amino acids, with a cysteine
residue at position 6 that aids in the formation of interchain
disulfide bonds between SP-A molecules. The collagenous domain of SP-A
consists of 23 glycine-X-Y tripeptide repeats, with the Y most often
being a hydroxyproline (5)
. Cysteine residues involved in
SP-A trimer formation are also found in this region. An interruption
occurs after the 13th glycine-X-Y tripeptide repeat in SP-A, with a
proline residue inserted that introduces a flexible kink in the
collagen region. This kink causes the trimers to bend outward in
different directions, giving the mature SP-A octadecamer a flower
bouquet appearance (8)
. The neck region of SP-A consists
of a short sequence of hydrophobic residues and an amphipathic helix,
whereas the CRD contains a calcium-dependent, carbohydrate binding site
(9)
. Post-translational modifications of SP-A include
cleavage of a signal peptide, hydroxylation of proline residues,
sulfation, acetylation, and glycosylation with N-linked
oligosaccharides (2)
.
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Figure 1. Structural models of SP-A protein. Left: The SP-A
trimer. The collagen-like regions of three SP-A monomers form a triple
helix rod-like region whereas the globular head of the trimer is formed
by the lectin domains of the three SP-A monomers. It has been proposed
that the human SP-A trimer is a heterotrimer consisting of two SP-A1
molecules (black) and one SP-A2 molecule (red). Right:
The SP-A octadecamer. Six SP-A trimers associate to form a flower
bouquet-like structure.
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SP-A is a member of the collectin family of C-type lectins, which
includes mannose binding protein, the C1q component of complement, the
bovine protein conglutinin, and surfactant protein D. The human SP-A
genes, along with the genes for the other collectins, are found
together on chromosome 10 (5)
. Collectins are
characterized by a collagen-like domain and the ability to bind
carbohydrates. They bind to specific carbohydrates on the surface of
bacterial and viral pathogens and act as an opsonin (4)
.
They also mimic C1q in the activation of the classical complement
pathway and can activate macrophages and other phagocytic cells
(4)
. Mutations in one of the collectins, mannose binding
protein, have been associated with increased susceptibility to
infectious disease (10)
. To date, no diseases have been
associated with genetic mutations in human SP-A, although certain SP-A
alleles may be associated with an increased risk of developing
respiratory distress syndrome (RDS) (11)
. Transgenic mice
with SP-A gene deletion have no major abnormalities in lung respiratory
function but are more susceptible to infection with group B
Streptococcus, Pseudomonas aeruginosa,
respiratory syncytial virus, and Mycoplasma pulmonis
(12
13
14
15)
. Recently, Harrod and colleagues observed that
exogenous human SP-A enhanced viral clearance and inhibited
inflammation in SP-A gene-deleted mice infected with recombinant
adenovirus (16)
.
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SP-A RECEPTORS
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SP-A acts as an opsonin by recognizing and binding to
carbohydrates on the surface of microorganisms. SP-A isolated from rat,
dog, or human binds to macrophages, stimulates their oxidative
activity, and promotes lymphocyte proliferation (17
, 18)
.
Human SP-A increases the production of proinflammatory cytokines
(TNF-
, interleukins) in rat alveolar macrophages and peripheral
blood mononuclear cells (19)
. These effects as well as the
increase in the expression of cell surface proteins—CD14, CD54, and
CD11b—have been observed in a human monocytic/macrophage cell line,
THP-1 cells (20)
.
Several proteins have been suggested as a candidate for the cellular
SP-A receptor. A 126 kDa protein named C1qRp (i.e., C1q receptor that
mediates phagocytosis) has been described that binds C1q, mannose
binding lectin, and SP-A (21)
. Another SP-A receptor,
identified by affinity chromatography, is a 210 kDa protein present in
rat lung and the U937 cell line (22)
. Binding of SP-A to
this receptor is calcium dependent and based on protein–protein
interactions, not carbohydrate recognition, since the binding of SP-A
to this protein is not inhibited by mannan or other sugars. Polyclonal
antibodies against this SP-A receptor block the inhibitory effects of
SP-A on phospholipid secretion by alveolar type II cells and block
SP-A-mediated uptake of bacillus Calmette-Guerin by rat macrophages
(23)
. A third SP-A receptor identified on rat alveolar
type II cells is a >200 kDa protein that may be responsible for
SP-A-mediated uptake of phosphatidylcholine by alveolar type II cells
(24)
.
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REGULATION OF SP-A
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SP-A is undetectable in human fetal lung tissue during the early
part of the second trimester, i.e., prior to the differentiation of the
alveolar epithelium (25)
. Differentiated type II cells
that contain lamellar bodies are observed in human fetal lung by 22
wk of gestation, and active surfactant secretion into amniotic fluid
occurs after 30 wk of gestation. Immunoreactive SP-A can be detected
in amniotic fluid at 30 to 32 wk of gestation (26)
. Khoor
et al. have detected immunoreactive SP-A in prealveolar-type II cells
at 20 wk gestation (27)
.
SP-A gene expression is regulated by several growth factors, hormones,
and regulatory agents (2)
. SP-A levels are increased by
treatment with cAMP analogs (28
, 29)
, epidermal growth
factor (30)
, interferon gamma (31)
,
prostaglandins (32)
, oxygen (33
, 34)
,
endotoxin (35
, 36)
, and ß-adrenergic agonists
(37)
. SP-A is decreased by insulin (38)
,
transforming growth factor (TGF-ß) (30)
, tumor necrosis
factor (TNF-) (39)
, and
12-O-tetradecanoyl-phorbol-13-acetate (40)
.
Both inhibitory and stimulatory effects of glucocorticoids on SP-A
expression have been reported, with the inhibitory effect observed at
higher hormone concentrations (41
, 42)
.
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FUNCTIONS OF SP-A
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Surface tension
Once lamellar bodies are secreted from the alveolar type II cell,
they assume a geometric lattice-like morphology known as tubular myelin
(1)
. Tubular myelin is thought to retain surfactant
phospholipids in the alveolus until they spread into the monolayer that
lines the alveolus. SP-A is localized in the corners of this lattice
structure and is required for the formation of tubular myelin
(43)
. Infants suffering from RDS have a deficiency of both
tubular myelin and SP-A (44)
, consistent with a role for
SP-A in the formation of tubular myelin. In agreement with these
observations, tubular myelin is reduced in SP-A gene-deleted mice
(45)
. SP-A enhances the rate of formation of a
phospholipid surface film at an air–liquid interface in
vitro (46)
, probably by binding to
dipalmitoylphosphatidylcholine, the most abundant phospholipid in
surfactant (47)
. SP-A binds to a receptor on type II cells
and enhances the uptake of surfactant phospholipids for recycling.
Surfactant clearance is also carried out by macrophages and this
function is likewise enhanced by SP-A (48)
. SP-A has also
been shown to inhibit the secretion of surfactant phospholipids by rat
alveolar type II cells in vitro, data suggestive that SP-A
is involved in a negative feedback loop that regulates surfactant
homeostasis in the alveolus (49)
. Surprisingly, pulmonary
function is not altered in SP-A gene-deleted mice (45)
.
However, it is still possible that SP-A may play a role in surfactant
function when surfactant phospholipid levels are low—for example,
early in development.
SP-A prevents inhibition of surfactant activity by blood proteins
Leakage of blood components into the alveolar space as a result of
lung injury has been implicated in the pathology of respiratory
distress syndrome (50)
. Plasma proteins have been shown to
inhibit surfactant activity both in vitro and in
vivo (50
, 51)
. Bovine SP-A reduces the inhibition of
surfactant activity mediated by plasma proteins (52)
. This
is specific to SP-A since the addition of bovine serum albumin to
surfactant did not produce the same effect. The inhibition of
surfactant activity is abolished only when SP-A is added to the
surfactant preparation before the addition of the inhibitory plasma
proteins. The addition of lysophosphatidylcholine (lyso-PC) to the
surfactant preparations also inhibits surfactant activity; however, the
addition of SP-A has no effect on the lyso-PC-mediated inhibition
(52)
, suggesting that the effect of SP-A in inhibiting the
surface tension reduction is specific to plasma proteins. Consistent
with these observations, surfactant from SP-A knockout mice is more
sensitive to inhibition by plasma proteins than is surfactant obtained
from wild-type mice (53)
.
SP-A binds LPS
Lipopolysaccharide (LPS), or endotoxin, is a major component in
the cell walls of gram-negative bacteria. LPS consists of lipid A,
which is its biologically active component, a core carbohydrate region,
and a terminal polysaccharide of variable length and composition, i.e.,
the O-antigen domain (54)
. Lipid A and the core region
make up rough LPS, whereas smooth LPS consists of the core region and
the O-antigen domain. Human SP-A binds rough LPS via lipid A, and this
binding is not inhibited by either the addition of carbohydrates or the
removal of N-linked sugars (54)
. SP-A does not
bind smooth LPS. LPS participates in many events associated with the
inflammatory response at the alveolar level, and has been shown to
increase the production of colony-stimulating factor (CSF) by cultured
alveolar type II cells and macrophages (55)
. Human and rat
SP-A, when added alone, also cause an increase in CSF secretion by
cultured rat alveolar type II cells and macrophages (55)
.
However, this increase is reversed when the SP-A and LPS are added
together (55)
. Human SP-A enhances the binding of LPS to
alveolar macrophages, but inhibits the binding of LPS to neutrophils
(56)
. Human SP-A binds to gram-negative bacteria via LPS
and facilitates their aggregation, phagocytosis, and killing by rat
macrophages (57)
. The interactions of SP-A and LPS suggest
that SP-A may influence the pathogenicity of gram-negative bacteria in
the pulmonary alveolus.
Activation of macrophages
The killing of microorganisms by macrophage phagocytosis can be
initiated by a variety of mechanisms, including the secretion of
proteolytic enzymes and the production of toxic oxygen metabolites,
which together constitute the respiratory burst. Rat, canine, and human
SP-A can cause the respiratory burst in rat and human macrophages and
also enhance the chemotaxis of activated macrophages (58
, 59)
. Tenner (60)
showed that immobilized human SP-A
binds to human monocytes and up-regulates complement receptor and
immunoglobulin receptor-mediated phagocytosis. Human SP-A also
up-regulates the human macrophage mannose receptor and enhances
phagocytosis (61
, 62)
. Aggregation of SP-A may also lead
to the activation of macrophages and the stimulation of phagocytosis
(57)
. Rat, canine, and human SP-A stimulates the
generation of oxidative activity (17)
and promotes
lymphocyte proliferation in rat macrophages (18)
. Human
SP-A also promotes the production of proinflammatory cytokines such as
TNF- and interleukins in the THP-1 cell line, a monocytic cell line
that can be stimulated in vitro to differentiate into
macrophages (63)
. Human and rat SP-A have also been shown
to increase nitric oxide production in rat alveolar macrophages
(64)
. Human SP-A activates macrophages via a
phosphoinositide/calcium signaling pathway (65)
.
Surfactant lipids inhibit some macrophage functions, including several
that are stimulated by SP-A (18
, 20)
.
Human SP-A has been shown to increase neutrophil uptake and killing of
lung pathogens (66)
. In response to airway infection,
cytokines and other mediators of inflammation released by phagocytes
and by the airway epithelium can lead to a chronic inflammatory
response in the airways (18
, 67)
. SP-A suppresses these
inflammatory responses (68)
. In agreement with this
concept, it has been reported that the concentrations of
proinflammatory cytokines are greater in SP-A gene-deleted mice
infected with P. aeruginosa than in wild-type mice
(13)
. Other investigators have reported that a heightened
immune response is associated with a decrease in the ratio of SP-A to
surfactant phospholipid in cystic fibrosis patients (69)
.
SP-A acts as an opsonin for pathogens
SP-A is thought to bind to lung pathogens via its CRD, and in this
way promote binding and phagocytosis of pathogens by macrophages
(70)
. The efficiency of interaction between SP-A and
microorganisms may depend on the oligomeric state of the SP-A protein,
which may vary in different disease states. There appears to be a shift
toward increased abundance of lower oligomeric forms of SP-A in several
disease states (71)
. Table 1
summarizes the microorganisms that have been shown to bind SP-A and
whether SP-A enhances their phagocytosis by macrophages.
Human SP-A binds to Aspergillus fumigatus
(72)
, a fungus that causes pulmonary
aspergillosis, and Candida albicans (73)
, and
increases their uptake by human macrophages. Other fungi that human
SP-A interacts with include acapsular Cryptococci neoformans
(74)
and Pneumocystis carinii
(73)
.
SP-A binds to and stimulates the phagocytosis of both gram-positive and
gram-negative bacteria. Human SP-A stimulates the macrophage uptake of
gram-positive bacteria such as Staphylococcus aureus, S.
pneumoniae, and group A Streptococcus (58
, 70
, 75
). All these organisms have been shown to cause airway
infections. Human SP-A increases the phagocytosis and killing of
certain strains of gram-negative bacteria such as Esherichia
coli that express rough LPS (54
, 57)
, as well as
Haemophilus influenzae type A (70)
and
Klebsiella pneumoniae (76)
. Binding of SP-A to
P. aeruginosa is controversial; however, human SP-A has been
shown to enhance its phagocytosis by rat alveolar macrophages
(62)
. Human SP-A binds to M. pulmonis, a
pathogen that causes pneumonia in mice, and increases the phagocytosis
of this pathogen by human alveolar macrophages (15)
.
SP-A isolated from human alveolar proteinosis lavage and recombinant
rat SP-A have both been shown to enhance the binding and phagocytosis
of Mycobacterium tuberculosis by human macrophages
(61)
and to increase the binding and phagocytosis of
bacillus Calmette-Guerin by rat macrophages and human monocytes via the
210 kDa SP-A receptor (23)
. Human SP-A also binds the
herpes simplex and influenza A viruses via its carbohydrate moiety and
enhances their phagocytosis by human and rat macrophages (77
, 78)
.
Other mechanisms of SP-A action in local defense may exist. For
example, human SP-A has been shown to cause aggregation of pathogens,
thus facilitating their clearance by the mucociliary escalator
(66)
. Alternatively, the binding of human SP-A to some
pathogens may inhibit their binding to the airway epithelium
(79)
.
SP-A levels in disease
Abnormalities in SP-A levels have been detected in several disease
states. For example, SP-A levels are decreased in the amniotic fluid of
diabetic pregnant mothers (80
, 81)
. Pregnancies
characterized by low levels of amniotic fluid SP-A before delivery are
associated with an increased risk of the infant being born with RDS
(82)
. In agreement with this observation, SP-A levels are
low in tracheal aspirates obtained from infants with RDS
(44)
. Respiratory dysfunction in animal models of lung
injury is correlated with decreased amounts of large surfactant
aggregates, forms of surfactant that are enriched in SP-A
(83)
. A decrease in SP-A levels has also been observed in
the bronchoalveolar lavage (BAL) of adult patients with acute RDS
(ARDS) (84)
.
BAL SP-A levels in patients with cystic fibrosis (CF) and lower airway
infections are higher than in CF patients without infection
(85)
. This increase may occur in response to infection.
However, a decrease in BAL SP-A levels was observed in patients with
bacterial and viral pneumonia (86
, 87)
. Decreased BAL SP-A
levels have also been reported in bronchopulmonary dysplasia with
infection in baboons (88)
and in interstitial pneumonia
with collagen vascular disease (84)
. On the other hand,
BAL SP-A and serum SP-A levels in patients with AIDS-related pneumonia
are increased when compared to normal healthy subjects
(89)
. This increase is not pathogen specific and is seen
in infections with P. carinii and non-P. carinii
infections. Whether the increase in SP-A in AIDS-related pneumonia is a
cause or an effect of infection is unclear. Decreased SP-A levels are
observed in lavage of patients with idiopathic pulmonary fibrosis (IPF)
(84
, 90)
. However, another report showed no difference in
SP-A levels in BAL of IPF patients when compared to controls. SP-A
levels are increased in BAL of patients with pulmonary alveolar
proteinosis (PAP), sarcoidosis, and hypersensitivity pneumonitis
(91
92
93)
. PAP is frequently associated with mycobacterial
infections, a finding that supports the concept that SP-A may
facilitate the binding and entry of bacteria into cells lining the
respiratory tract.
Since it is known that blood proteins may leak into the alveolar spaces
as a result of lung injury, it is reasonable to assume that surfactant
proteins may leak into the vascular spaces in disease. Serum SP-A
levels may be useful as an indicator of lung function and
alveolar-capillary membrane injury due to disease. Kuroki et al.
(94)
reported an increase in serum SP-A levels in patients
with idiopathic pulmonary fibrosis, pulmonary alveolar proteinosis,
tuberculosis, bacterial pneumonia, and chronic pulmonary emphysema
(84)
. They observed no difference in serum SP-A levels in
patients with bronchial asthma and sarcoidosis when compared to healthy
individuals (84)
. Serum levels of SP-A are also increased
in patients with acute cardiogenic pulmonary edema and in ARDS
(94)
.
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SUMMARY OF SP-A FUNCTION IN THE ALVEOLUS
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Surfactant protein A has been shown to regulate the homeostasis of
surfactant phospholipids and facilitate the lowering of surface tension
in the alveolus. SP-A also prevents the inhibition of surfactant
function by plasma proteins that have leaked into the injured alveolus.
Recent studies using SP-A knockout mice have revealed that no major
abnormalities in normal lung function exist in these animals. However,
the SP-A gene-deleted mice are more susceptible to infection with group
B Streptococcus pneumonia, P. aeruginosa, M.
pulmonalis, and respiratory syncytial virus. In addition,
surfactant function is inhibited by plasma proteins in SP-A
gene-deleted mice to a greater degree than in wild-type mice. Several
in vivo and in vitro studies have shown that SP-A
binds to bacteria and/or macrophages and also enhances the phagocytosis
and killing of lung pathogens. Thus, the major role of SP-A in the
alveolus may be related to local host defense mechanisms.
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SP-A IN NONALVEOLAR SITES IN THE RESPIRATORY SYSTEM
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SP-A in the conducting airways
Tracheal surfactant from porcine lungs has the same phospholipid
composition as BAL surfactant, which suggests an alveolar origin for
this surfactant (95)
. However, SP-A mRNA and protein have
been detected in human fetal tracheal and bronchial epithelium and
submucosal glands (27
, 96
, 97)
. Our laboratory (97
, 98)
and that of Saitoh et al. (99)
have
demonstrated that only the SP-A2 gene is expressed in human fetal and
adult trachea and bronchi. SP-A2 is also the predominant SP-A protein
present in the adult human trachea (98
, 99)
. We have
localized SP-A2 mRNA to the serous cells of submucosal glands of the
adult human conducting airways by in situ hybridization
(Fig. 2
; 98
). The SP-A2 protein present in the fetal and adult
tracheal submucosal glands has the same molecular weight and
post-translational modifications as that of distal lung heterotrimeric
SP-A protein (Fig. 3
; 98
). No studies to evaluate the regulation or function of
the conducting airway form of SP-A protein have been performed to date.
We hypothesize that this novel SP-A protein functions in combination
with other submucosal gland serous cell secretions in local
anti-microbial host defense mechanisms in the airways. There is no gene
deletion model available for studying the airway SP-A protein, because
the mouse does not have submucosal glands in its conducting airways and
has only a few glands located at the top of the trachea.
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Figure 2. In situ hybridization of SP-A mRNA in adult human lung
bronchi. A, C, E) Bright field images; B, D,
F) corresponding dark field images. SP-A mRNA was not detected
in the surface epithelium (asterisks) or in the ciliated duct (CD)
portion of the submucosal glands. The lumen of the airway is indicated
by an ‘L’. SP-A mRNA was present in some tubules of the submucosal
glands (arrows) but absent in others (T). The bar at the lower right
corner indicates 100 µm (from Khubchandani et al., ref
98
).
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Figure 3. Immunoblot analysis of SP-A protein in adult human tracheal submucosal
tissue. Total protein homogenates were separated by polyacrylamide gel
electrophoresis and transferred to a membrane, then probed using
anti-human SP-A antibodies and enhanced chemiluminescence (ECL).
A) Human SP-A purified from alveolar proteinosis
material was used as a positive control (lane 1: lower arrow depicts
the 35 kDa SP-A monomer; upper arrow depicts the 65 kDa SP-A
dimer). A 35 kDa SP-A immunoreactive band was detected in cultured
human fetal lung explants (lane 2), as well as in adult human tracheal
submucosal tissues (lanes 3–6). The higher molecular weight band in
lanes 3–6 may represent an unglycosylated dimer of SP-A. The amount of
SP-A protein present in the tracheal samples varied considerably.
B) Peptide-N glycosidase F (PNGF) digestion of the SP-A
protein in adult human tracheal submucosal tissues to remove
N-linked carbohydrates. SP-A isolated from human
alveolar proteinosis material and protein homogenates from adult human
tracheal submucosal tissues were digested with PNGF and analyzed by
immunoblotting. Intact SP-A immunoreactive bands (35 kDa monomer,
65 kDa dimer, long arrows) were detected in the undigested purified
SP-A (lane 1) and in undigested adult human tracheal submucosal tissues
(lanes 3, 5, 7). After digestion with PNGF, lower molecular mass bands
(31 kDa monomer, 50 kDa dimer, short arrows) were detected in the
purified human SP-A (lane 2) and in the adult human tracheal submucosal
tissues (lanes 4, 6, 8) (from Khubchandani et al., ref
98
)
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SP-A in the Eustachian tube, middle ear, and paranasal sinuses
Immunoreactive SP-A has been detected in the cells
lining the Eustachian tube in the human. The presence of a surface
tension-lowering substance in the Eustachian tube had previously been
postulated when it was demonstrated that the opening of guinea pig
Eustachian tubes became more difficult after the tubes were irrigated
with saline, presumably because the washing removed the ‘surfactant’
(100)
. In another study, natural surfactant from guinea
pig lungs, saline, or a mixture of phospholipids was injected into the
middle ears of rats (101)
. The pressure required to open
the Eustachian tube decreased significantly in the surfactant and
phospholipid-treated animals, and natural surfactant also reduced the
pressure more than the phospholipid mixture (101)
. Western
blot analysis of middle ear effusion fluid revealed an 80 kDa
immunoreactive protein that was recognized by monoclonal antibodies
directed against human SP-A (102)
. In another study,
Yamanaka et al. (103)
detected SP-A immunoreactivity in
middle ear effusions obtained from patients with otitis media with
effusion. Our laboratory has demonstrated the presence of SP-A mRNA and
protein in the middle ear epithelium and in submucosal glands in the
paranasal sinuses of adult rabbits (ref 104
; Fig. 4
and Fig. 5
). We also observed higher levels of SP-A mRNA in infected rabbits when
compared to pathogen-free rabbits. Recently, Paananen and co-workers
detected the presence of SP-A in porcine Eustachian tube epithelium
(105)
. There are no reports as yet concerning the function
of SP-A in the middle ear or paranasal sinuses sites. Surfactant
phospholipids may function in reducing the surface tension in the
Eustachian tube and in this manner prevent its collapse. Collapse of
the Eustachian tube may hinder ventilation of the middle ear and
increase the risk of infection (106)
. We and others have
also speculated that SP-A may contribute to local immunity in the
middle ear, Eustachian tube and paranasal sinuses.
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Figure 4. SP-A mRNA in rabbit middle ear and sinus tissues. Total RNA was
isolated, separated by gel electrophoresis, transferred to a membrane,
and probed with a radiolabeled rabbit SP-A cDNA. A)
Northern blot analysis of SP-A mRNA (arrow) in adult rabbit lung (lane
A), trachea (lane B), and maxillary sinus (lane C). B)
Northern blot analysis of SP-A mRNA (arrow) in rabbit lung (lane A),
and middle ear (lane B) (from Dutton et al., ref 104
)
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Figure 5. SP-A immunolocalization in lung, middle ear, and maxillary sinus
tissues. A) SP-A was present in alveolar type II cells
(arrows) of adult rabbit lung tissue. B) SP-A was
localized in the surface epithelium (arrows) of the rabbit middle ear
tissues. C) SP-A was localized in submucosal glands
(arrows) of maxillary sinus tissues. D) No staining was
observed in maxillary sinus tissues when PBS was used instead of
primary antibody. Arrows denote brown staining for SP-A. SM indicates
submucosal tissue, L indicates lumen. The bar at the lower right corner
indicates 100 µm. (from Dutton et al., ref
104
)
|
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SP-A IN NONRESPIRATORY TRACT SITES
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SP-A in the gastrointestinal tract
Hills et al. detected a pulmonary surfactant-like material in the
gastrointestinal mucosa as early as 1983 (107)
. A
hydrophobic layer of surface-active phospholipids was detected between
the apical border of epithelial cells of the gastrointestinal tract and
the lumenal contents, and was designated gastrointestinal surfactant
(107
, 108)
. In the stomach, surfactant phospholipids were
detected in multilamellar structures on the mucosal surface
(109)
. Epithelial cells in the intestine of the rat have
been shown to produce SP-A mRNA and protein (109)
. The
SP-A protein made in the intestine has the same charge and molecular
weight heterogeneity as the SP-A protein found in the lungs
(109)
. Moreover, the intestinal SP-A protein was found
only in epithelial cells of the jejunal and colonic mucosa, and was not
present in the gastric mucosa (108)
. Lu (110)
detected no SP-A mRNA in human small intestine and colon by Northern
blot analysis. More recently, however, Eliakim and co-workers have
reported the presence of surfactant-like particles and SP-A in both rat
and human colon (111)
. The lamellar bodies in these sites
contain saturated phosphatidylcholine and are able to lower surface
tension. It has been proposed that gastrointestinal surfactant may be
involved in lubrication within the gastrointestinal tract and in
reducing surface tension in the intestine, where peristalsis may be
benefited. Surfactant may also act as a barrier against ulcer-causing
agents. The specific function of SP-A in the gastrointestinal tract has
not been determined, but several authors have speculated that it may be
involved in regulating surfactant phospholipid uptake and secretion by
the gastrointestinal tract epithelium. SP-A in these sites may also aid
in host defense functions via presentation of pathogens to macrophages
and/or by prevention of attachment of pathogens to the epithelium.
SP-A in the prostate gland
Northern blot analysis revealed the presence of SP-A mRNA in the
human prostate (110)
. Our laboratory has detected SP-A
mRNA in human prostate by Northern blot analysis using a human SP-A
cDNA probe (Fig. 6
). We also detected an 35 kDa SP-A immunoreactive protein in human
seminal fluid (Fig. 6)
. To our knowledge, these are the only reports
concerning the presence of SP-A mRNA or protein in prostate. Since
there are no published reports concerning the presence of a
surfactant-like material in the prostate, we can only speculate that
the SP-A present in the prostate and prostatic secretions may be
involved in host defense mechanisms in the male and perhaps also in the
female reproductive system. These organs communicate with the outside
environment and are susceptible to pathogen exposure and subsequent
infection. SP-A in these sites may act along with proteins such as
seminal plasmin, an anti-microbial protein present in bovine seminal
plasma that prevents invasion of infectious pathogens
(112)
.
View larger version (45K):
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|
Figure 6. Presence of SP-A mRNA and protein in human prostate (A,
lane 2) and human seminal fluid (B, lane 2),
respectively. A) Northern blot analysis of SP-A mRNA. 2
µg of mRNA from human lung tissue and 2 µg of mRNA from human
prostate was separated by gel electrophoresis, transferred to a
membrane, and probed with a radiolabeled human SP-A cDNA. SP-A mRNA was
detected in human lung tissue (lane 1) and human prostate (lane 2).
B) Immunoblot analysis revealed the presence of SP-A
protein in purified human alveolar proteinosis material (50 ng, lane 1)
and in human seminal fluid (100 µg, lane 2).
|
|
SP-A in the thymus and spleen
Alcorn et al. created transgenic mice with fusion genes
composed of the 5' flanking regions of the rabbit SP-A gene linked to a
human growth hormone (hGH) reporter gene (113)
. In
addition to detecting high levels of hGH mRNA in the lung, reporter
gene expression was also frequently detected in the thymus and spleen.
One other investigator has described low levels of SP-A mRNA in the
human thymus (110)
. The role of SP-A in the spleen and
thymus is unlikely related to surface tension but may be related to
host defense function.
SP-A in mesothelium and synovium
A study conducted by Dobbie reported that SP-A immunoreactivity is
present in the synovial intima and mesothelial cells of the pleura,
pericardium, and peritoneum (114)
. Lamellar organelles
similar to the lamellar bodies present in alveolar type II cells have
been observed in the synovial intima cell cytoplasm and on the surface
of peritoneal, pericardial, and pleural mesothelial cells, as well as
in the synovial membrane or synovium (114
115
116)
. Maximal
SP-A immunoreactivity was detected in synovium of rheumatoid arthritis
patients. The function of surfactant and lamellar bodies in these sites
may be to aid in lubrication, reduce surface tension, and prevent the
development of adhesions such as those that occur after surgery or
occur in joints with rheumatoid arthritis. These investigators also
suggest that surfactant on these surfaces may also bind disease-causing
antigens and present them to macrophages. In another study, it was
reported that immunoreactive SP-A proteins of 35 kDa and 65 kDa
were detected by immunoblot analysis in synovial, pericardial, and
peritoneal fluids (114)
. These investigators also describe
the detection of immunoreactive SP-A in the ductal epithelium of
lacrimal and salivary glands. If SP-A is present in tears and saliva,
it may function as part of the first line of a host defense mechanism
against pathogens in the eye and mouth.
|
SUMMARY
|
|---|
Surfactant protein A has been shown to regulate the homeostasis of
surfactant phospholipids, facilitate the lowering of surface tension in
the alveolus, and prevent the inhibition of surfactant function by
plasma proteins. SP-A gene-deleted mice have normal lung function, but
are more susceptible to infection. Several in vivo and
in vitro studies have shown that SP-A binds to bacteria
and/or macrophages and also enhances the phagocytosis and killing of
lung pathogens. The detection of low levels of SP-A in nonalveolar
sites is a recent observation. SP-A mRNA and/or protein have been
detected in the conducting airways, middle ear and paranasal sinuses,
gastrointestinal tract, reproductive tract, spleen, thymus,
mesothelium, and synovium. We hypothesize that the SP-A present in
these sites may contribute to host defense function, although a role in
surface tension lowering may also be possible. Further investigation
will be required to characterize the function of SP-A in extra-alveolar
sites and to determine whether the human SP-A protein in extra-alveolar
sites is a product of the SP-A1 or SP-A2 gene, or both.
|
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TOP
ABSTRACT
PULMONARY SURFACTANT AND SP-A
