Am J Physiol Lung Cell Mol Physiol 291: L847L850, 2006;

doi:10.1152/ajplung.00261.2006.

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The wisdom of lung surfactant: balancing host defense and surface

tension-reducing functions

Address for reprint requests and other correspondence: J. R. Wright, Box

3709, Dept. of Cell Biology, Duke Univ. Medical Center, Durham, NC 27710
(j.wright@cellbio.duke.edu).
This lecture was presented as part of the American Physiological Society
Award Physiology in Perspective: The Walter B. Cannon Award Lecture at
Experimental Biology Meeting, San Francisco, CA, 2006.
http://www.ajplung.org

matory response (recently reviewed in Ref. 13). In addition

to enhancing phagocytosis, SP-A and SP-D also regulate
cytokine and free radical production and the uptake of
apoptotic cells and have direct bactericidal activity (Fig. 2).
Both SP-A and SP-D have been shown to bind to a variety
of allergens, such as house dust mite and Aspergillus fumigatus, and intranasal administration of SP-A and SP-D to
mice reduces the eosinophilia and specific antibody levels in
mouse models of allergic bronchopulmonary aspergillosisand house dust mite-induced allergy (16).
In addition to mediating innate immune responses, SP-A
and SP-D have more recently been implicated in modulation
of the adaptive immune response (reviewed in Ref. 23).
Both SP-A and SP-D bind to dendritic cells in a calciumdependent manner; SP-D enhances dendritic cell antigen
presentation (3), whereas SP-A inhibits dendritic cell maturation (2). Both SP-A and SP-D also inhibit T cell proliferation, in part by inhibiting calcium signaling (1). Recent
studies suggest that transforming growth factor (TGF)-
present in SP-A preparations may account for at least some
of the inhibition of T cell proliferation by SP-A (14).
Whether or not SP-D inhibits T cell proliferation via TGF-independent mechanisms is not known. A role for SP-D in
regulating T cell responses in vivo is supported by studies
showing that lungs of SP-D null mice contain activated
lymphocytes as evidenced by an increased percentage of
both CD4 and CD8 T cells expressing CD69 and CD25
(8). Furthermore, SP-D null mice had elevated CD4 cells
and increases in IL-13 and chemokine levels following
allergic sensitization (10). In aggregate, the studies briefly
summarized above, and many others that cannot be included
here due to space limitations, suggest that SP-A and SP-D
mediate multiple and varied functions of many different
types of immune cells, and, in some cases, elicit both proand anti-inflammatory responses.
An important and somewhat daunting task has been the
identification of specific receptors for SP-A and SP-D. Both
proteins in a promiscuous manner to a plethora of different
ligands, and, perhaps not surprisingly, a number of potential
receptors have been identified and include surfactant protein
receptor 210 (SP-R210), glycoprotein-340 (GP-340), signalinhibitory regulatory peptide (SIRP-), Toll-like receptors,
receptors for C1q, and the complex of CD91 and calreticulin
(reviewed in Ref. 13). Gardai and coworkers (9) intriguing
study provided data consistent with the possibility that the
ability of SP-A and SP-D to modulate both pro- and antiinflammatory responses may be a consequence of whether or
not the SP is attached to a pathogen or apoptotic cell. Their
data suggest that when the CRD of SP-A or SP-D is bound
to a pathogen or apoptotic cell, the unobligated collagen
domain interacts with CD91/calreticulin to activate NF-B
and the inflammatory signaling cascade. In contrast, in the
normal uninfected lung, the CRD of SP-A or SP-D is free to
bind SIRP- and thereby suppress the inflammatory signal-

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THE MIXTURE OF LIPIDS AND PROTEINS that comprises pulmonary

surfactant is both complex and multifunctional. Although
surfactant was originally identified as a lipoprotein complex
that reduces surface tension at the air-liquid interface of the
lung (4, 20), both in vitro and in vivo studies support a
second important role for surfactant in modulating lung host
defense (reviewed in Refs. 12, 13, 23). The surfactant
lipoprotein complex consists predominately of lipids and
four proteins known as surfactant protein (SP) -A, -B, -C,
and -D; all these components are synthesized and secreted
by alveolar epithelial type II cells in response to a variety of
stimuli, including a deep breath and exercise. Upon secretion into the liquid hypophase that covers the alveolar
surface, surfactant lipids form a monolayer at the air-liquid
interface and thereby reduce surface tension and the work of
breathing. SP-B and SP-C are small, hydrophobic proteins
that function in conjunction with lipids to reduce surface
tension (reviewed in Ref. 19). A deficiency of surfactant,
frequently observed in babies born prematurely, results in
impaired lung function and gas exchange that is known as
infant respiratory distress syndrome (4). Abnormalities in
protein expression due to mutations in the genes for the
hydrophobic proteins have been associated with fatal neonatal lung disease for SP-B and chronic lung disease for
SP-C (reviewed in Ref. 19).
The concept that surfactant may be involved in pulmonary
host defense was generated, at least in part, by the finding of
Voss and coworkers (22) that SP-A is structurally homologous with C1q, a protein of the complement system that has
multifunctional roles in host defense. A second key observation made by Drickamer and colleagues (7) was that SP-A
and SP-D are members of a family of mammalian C-type
lectins that have in common an NH2-terminal collagen-like
region and a COOH-terminal lectin or carbohydrate recognition domain (CRD) (Fig. 1). This family of collagen-like
lectins is known as the collectin family and includes the
mannose binding lectin (6). The collectins are pattern
recognition molecules that bind via their CRDs to oligosaccharides found on the surface of microorganisms. Numerous in vitro studies have shown that both SP-A and
SP-D opsonize and frequently aggregate bacteria and viruses and enhance their uptake by immune cells such as
alveolar macrophages and neutrophils (reviewed in Refs. 13
and 23). In vivo studies have provided concordant data
showing that SP-A and SP-D null mice are more susceptible
to bacterial and viral infections and, in general, that they
have higher viral and bacterial loads and a greater inflam-

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ing cascade via SRC homology 2 (SH2)-domain-containing

protein tyrosine phosphatase 1-mediated inhibition of P38
(Fig. 3). These intriguing studies shed some light onto how
both pro- and anti-inflammatory responses may be mediated

by SP-A and SP-D; future important studies are required to

define the mechanisms by which receptor expression is
regulated and to determine whether specific cell types express different receptors under basal conditions and whether

Fig. 2. SP-A and SP-D have multifunctional roles in host defense. SP-A and SP-D both bind to, and in many cases aggregate, pathogens and apoptotic cells and
enhance their uptake and removal by immune cells such as alveolar macrophages and neutrophils. The lung collectins also have direct antimicrobial activity. Both
SP-A and SP-D also regulate a variety of immune cell functions, such as production of cytokines and free radicals. [From Wright (23).] Reproduced with
permission from Nature Reviews Immunology, 5: 58 68 (2005), Macmillan Magazines Limited.

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Fig. 1. Structure of lung collectins and mannose binding lectin (MBL). Collectins have in common an NH2-terminal collagen-like region and a COOH-terminal
carbohydrate recognition domain (CRD). Collectin trimers are assembled into oligomers of varying size. Drawing is not to scale. SP, surfactant protein. [From
Wright (23).] Reproduced with permission from Nature Reviews Immunology, 5: 58 68 (2005), Macmillan Magazines Limited.

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receptor expression changes during an inflammatory or

infectious episode.
Although SP-A and SP-D are known as SPs, both are
found in many extrapulmonary sites (reviewed in Ref. 13).
For example, SP-D mRNA has been detected in several
organs, including mouse stomach and kidney; salivary,
sweat, and lachrymal glands; and throughout the female
reproductive tract albeit at levels lower than found in the
lung. A recent intriguing study by Condon and coworkers
(5) suggests that SP-A plays a role in the initiation of
parturition in mice. Increases in amniotic fluid levels of
SP-A paralleled increases in expression of IL-1 and NF-B
in intrauterine macrophages. Furthermore, intrauterine injection of SP-A caused premature labor. A role for SP-A in
mediating host defense against Pseudomonas aeruginosa
infections in the cornea was also recently reported (18). It
seems likely that many future studies will help clarify the
extrapulmonary functions of SP-A and SP-D, and, at some
point in time, the appropriateness of their names may be
questioned.
Although substantial progress has been made in understanding the role of the surfactant collectins in host defense
in the lung and more recently in other organs, many important and unanswered questions remain. Studies in mice
suggest that exogenously administered SP-A and SP-D may
be effective therapy for treating allergic and bacterial inflammation and infection. To date, there have been no
clinical trials in humans investigating the efficacy of surfactant preparations containing SP-A or SP-D for treatment
of acute lung injury or infections, although surfactant replacement therapy with preparations containing lipids
AJP-Lung Cell Mol Physiol VOL

and/or SP-B and SP-C have been tested for treatment of

acute lung injury with limited success (17). Also, a growing
number of recent studies have provided evidence that associations exist between genetic polymorphisms of the human
gene and lung disease (e.g., Refs. 15 and 21), but our
investigations in this area must be expanded. In addition, a
clear understanding of the regulation of SP-A and SP-D
synthesis, secretion, and catabolism in diseased lungs or
other organs is not well understood. Many studies have
provided evidence that levels of all of the SPs and lipids are
altered in a variety of lung diseases (reviewed in Ref. 11). In
many cases, the alterations in levels are different for the
different components, suggesting that the changes are not
due to nonspecific suppression of surfactant production due
to damage to the alveolar epithelium. Clearly, the lung of
the healthy host requires adequate amounts of functional
surfactant to both reduce surface tension and defend the
lung against infection and inflammation. Exciting future
investigations both in basic research and clinical studies will
be required to fully understand how the wisdom of the lung
is manifest in maintaining appropriate levels of the multifunctional and complex substance known as surfactant.
ACKNOWLEDGMENTS
Since this short article is a follow-up to the Physiology in Perspective: The
Walter B. Cannon Award Lecture, I would like to thank all of my students and
trainees, including those who participated in the work summarized here.
Working with students, postdocs, and fellows has been the greatest joy of my
scientific career. I also thank my formal mentors, Drs. Phil Miles and John
Clements, for support and guidance; I learned so very much from them, and
they have been an inspiration to me when trying to mentor my own students.

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Fig. 3. SP-A and SP-D bind to a variety of potential cell surface receptors. Binding to specific receptors results in activation or suppression of different signaling
pathways. PKC, protein kinase C; TLR, Toll-like receptor. [From Wright (23).] Reproduced with permission from Nature Reviews Immunology, 5: 58 68 (2005),
Macmillan Magazines Limited.

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I also thank the National Heart, Lung, and Blood Institute, American Lung
Association, Parker B. Francis Foundation, and American Heart Association
for support over the years, including recent awards HL-30923, HL-51134, and
HL-68072.
REFERENCES

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Jo Rae Wright
Department of Cell Biology
Duke University Medical Center
Durham, North Carolina
November 2006, Volume 291 (35)

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