PERSPECTIVE
Surfactant Protein A
Regulation of Innate and Adaptive Immune Responses in Lung Inflammation

Jo Rae Wright, Paul Borron, Karen G. Brinker, and Rodney J. Folz

Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina

The concept that surfactant may have a connection with bone marrow transplant may be startling to many. In fact, the paper by Yang and colleagues (1) provides evidence for such a connection by demonstrating that surfactant protein (SP)-A suppresses the T-cell dependent lung inflammatory response that often occurs in patients (and mice) following allogeneic bone marrow transplant. How is it that surfactant, most widely recognized for its ability to reduce surface tension at the air-liquid interface of the lung, could mediate such a function?

	Surfactant Proteins Participate in the Innate Immune Response

Both in vitro and in vivo studies carried out over the past 15 years or so have provided compelling evidence that surfactant functions in pulmonary host defense (reviewed in (2, 3)). Although surfactant lipids have been shown to modulate immune cell function, much more is known about the immunomodulatory roles of two of the surfactant proteins, surfactant protein (SP)-A and SP-D, which are members of a family of proteins known as collectins (reviewed in (4)). Members of the collectin family of proteins share in common an N-terminal collagen-like domain and a C-terminal lectin domain that binds carbohydrates in a calcium-dependent manner. The collectin family includes SP-A and SP-D, the liver-derived serum mannose binding lectin (MBL), and two proteins found in bovine serum, CL-43 and conglutinin.

The collectins fall into a broader category of proteins known as "pattern recognition molecules" that function in innate immunity (5). The innate immune system is generally considered to be a first line of host defense carried out by phagocytes and germ-line encoded proteins that provide a rapid response prior to induction of antibody-mediated adaptive immunity. By virtue of their ability to recognize molecular patterns that are present on the surfaces of various types of microbes, pattern recognition molecules bind to pathogens and target them for clearance by cells of the innate immune system. For example, both SP-A and SP-D bind to a variety of such non-self molecular structures including lipopolysaccharide of gram negative bacteria and other components of bacteria and viral surfaces (reviewed in (6)). This binding, in many cases, enhances the uptake of pathogens by phagocytes of the innate immune system such as alveolar macrophages and neutrophils. SP-A and SP-D also regulate the production of cytokines and free radicals by innate immune cells (Table 1) (3). Definitive proof of a role for these proteins in pulmonary host defense has been provided by studies with SP-A and SP-D knock-out mice. These mice are more susceptible to bacterial (7) and viral infections (10, 11) and to LPS-induced lung inflammation (12, 13). Thus, both in vivo and in vitro studies demonstrate an important role for surfactant proteins in regulating functions of immune cells of the innate immune system.

	Surfactant Also Regulates Cells of the Adaptive Immune System

That surfactant also regulates functions of cells of the adaptive immune response has been a subject of recent studies. The cells of the adaptive immune system include B and T lymphocytes, each of which express a receptor for a distinct antigen (for a recent review, see (14)). An adaptive (e.g., antibody-mediated) immune response is initiated when antigen presenting cells present antigen to T-lymphocytes, which respond by proliferating and producing effector cytokines that stimulate B lymphocyte division and differentiation into antibody secreting plasma cells. The adaptive immune response is much slower to mature than the innate response, but once mature, can result in a more rapid and effective response against subsequent infections.

Ansfield and coworkers (15) reported over two decades ago that lymphocytes in the alveolar compartment are hyporesponsive with respect to their ability to proliferate when stimulated with mitogen in vitro compared with lymphocytes from circulating blood. An important recent study by Seitzman and colleagues confirmed that lung lymphocytes proliferate minimally in vivo in response to an antigen challenge (16). Since lymphocyte proliferation is a key factor in propagation and expansion of the adaptive immune response (17), it has been proposed that suppression of lymphocyte proliferation in the alveolar space protects the host from tissue damage and inflammation that would occur if the T-cells were constantly activated (18). In fact, excessive T-cells responses have been associated with a variety of lung diseases, including asthma and sarcoidosis (19, 20), and the severity of idiopathic pneumonia syndrome is dependent on the presence of allogeneic T cells (21).

Because alveolar lymphocytes share the airspace with surfactant, Ansfield and coworkers speculated that surfactant may contribute to their hyporesponsiveness (22). Their investigations and subsequent studies showed that both surfactant lipids and proteins affect lymphocyte function although part of the hyporesponsiveness of lavage-derived T-lymphocytes is mediated by secretory products of alveolar macrophages (such as prostaglandin E₂, superoxide, and vitamin D metabolites (23, 24) and nitric oxide metabolites (25)) and unidentified secretory products of type II cells (26), all of which inhibit lymphocyte proliferation. Ansfield and coworkers showed that "whole surfactant" purified from lavage fluid (22) as well as individual surfactant lipids such as phosphatidylglycerol and phosphatidylcholine (27) inhibited mitogen-induced lymphocyte proliferation. The binding of mitogen to the cells was not inhibited by surfactant and it was concluded that some "early metabolic process" is inhibited (28). Borron and coworkers extended these studies two decades later to investigate the hypothesis that surfactant proteins also inhibit lymphocyte proliferation. Purified preparations of SP-A were shown to inhibit proliferation of human peripheral blood and tonsillar mononuclear cells stimulated with either phytohemagglutinin or anti-CD-3 (29). SP-D also inhibited lymphocyte proliferation (30) and both SP-A and SP-D inhibited the production of the potent T-cell mitogen, interleukin (IL)-2. The functional domain of SP-A was mapped to a six amino acid Arg-Gly-Asp (RGD) motif-containing span of the collagen-like domain (31). An important recent study by Wang and colleagues (32) showed that SP-A and SP-D inhibit proliferation of lymphocytes induced by phytohemagglutinin and inhibit histamine release stimulated by mite allergen Dermatophagoides pteronyssinus. Inhibition occurred with cells from stable asthmatic children, but SP-A and SP-D exhibited only mildly suppressive effects on cells derived from children who were having acute asthmatic attacks. This study shows that both SP-A and SP-D inhibit two essential steps in the development of asthmatic symptoms: an early phase of histamine release in response to allergen provocation and a late phase of lymphocyte proliferation. This study raises the intriguing possibility that surfactant proteins may be important mediators of airway reactivity.

	Surfactant Participates in Cross-talk between Innate and Adaptive Immunity and Attenuates Lung Inflammation

Although innate and adaptive immunity have long been regarded as two separate and distinct host defense systems, several lines of evidence show that there is cross-talk between the two systems (33, 34). Indirect evidence for this cross-talk has been in the literature for years but remained largely ignored until it was highlighted in a 1989 Cold Spring Harbor Symposium talk that was delivered by Janeway (33), in which he noted that antibody production is greatly augmented by the use of adjuvants, which are in fact mixtures of oils, killed bacteria, and bacterial products that should have no direct effect on the interaction of antigen and antigen receptors. Janeway suggested that adjuvants activate the innate immune system, which recognize the adjuvant as microbial and that the antigen is "guilty by association" with the adjuvant. In fact, several aspects of the innate immune system are known to affect adaptive immunity (reviewed recently in (35)). Of relevance to this discussion is that pattern recognition molecules such as the collectins (34) and Toll-like receptors (36, 37) participate in recognition of microbial patterns and consequently regulate the production of cytokines.

Although little is known about the cross-talk between innate and adaptive immunity in the lung specifically, we speculate that the lung collectins may participate in this cross-talk via several mechanisms (Figure 1). For example, SP-A and SP-D affect the ability of innate immune cells such as macrophages to produce cytokines, which may in turn influence lymphocytes. Several studies discussed in detail above show that the pulmonary collectins directly regulate the functions of T-lymphocytes. In addition, the investigation by Yang and colleagues (1) suggests that SP-A may regulate production of mediators by lung lymphocytes of the adaptive immune system which can then influence alveolar macrophages of the innate pulmonary immune system.

View larger version (18K): [in this window] [in a new window]   Figure 1.   SP-A and SP-D act directly on innate immune cells to regulate production of cytokines and reactive species, which may in turn regulate lymphocyte function. SP-A and SP-D also directly regulate the functions of lymphocytes including inhibiting lymphocyte proliferation. Both collectins may also directly regulate the production of cytokines such as interferon , which in turn may regulate the activities of innate immune cells, such as the production of nitric oxide synthase by alveolar macrophages. Thus, both SP-A and SP-D may directly regulate innate and adaptive immune cells as well as provide mediators that regulate cross-talk between the two systems.

The study by Yang and colleagues (1) investigates the role of SP-A in mediating lung inflammation in a mouse model of idiopathic pneumonia syndrome (IPS). IPS is a noninfectious form of severe diffuse lung injury that has been estimated to occur in 10-20% of all patients following allogeneic or autologous bone marrow, peripheral stem cell, or cord blood transplant (38). The National Marrow Donor Program estimates that 1,455 unrelated donor marrow transplants were performed in 1999. While the majority of these transplants are for various forms of leukemia (75%), there are now almost 100 different diseases for which transplants have been conducted. The development of IPS can be an ominous sign, as it is associated with a mortality rate as high as 50%. Clinically, IPS most often occurs in a delayed fashion with a median onset after marrow transplant of approximately seven weeks. Histopathology of the IPS lung consistently shows diffuse alveolar damage and interstitial pneumonitis (39), as well as interstitial fibrosis (42). However, little is known about the pathogenesis of IPS, although it is believed that inflammatory mediators play early key roles. For example, Bhalla and coworkers have shown elevated IL-6 and IL-8 levels in the lavage of breast cancer patients who were undergoing autologous BMT, suggesting that these patients are primed for developing lung disease (43). Clark and coworkers reported that patients with IPS have increased levels of IL-1, IL-2, IL-6, and TNF- in BALF (39). The initial insult that drives this inflammatory reaction is not clear, but may be related to direct lung cytotoxic effects of chemotherapy, oxidative/nitrosative stress, and/or radiation lung injury (40).

Dissecting out additional pathogenic mechanisms has been difficult due to the lack of animal models of this disease. Only recently have mouse models of IPS been developed. Blazar and colleagues at the University of Minnesota have characterized the mouse model of IPS utilized by Yang and coworkers (1). Lung injury in this model requires exposure to allogeneic T cells, cytoxan, and total body irradiation and may be mediated, in part, by peroxynitrate (44, 45). Cooke and coworkers at the Dana Farber Cancer Institute have proposed that lipopolysaccharide plays a key role in their mouse allogeneic bone marrow transplant model of lung injury (46), a mediator that appears to have some relevance to the pathogenesis of human IPS (39). Shenkar and coworkers have characterized a milder form of murine IPS and demonstrated a critical initial involvement and infiltration of CD8+ T-cells into the lung followed by a prominent accumulation of CD4+ T-cells (47, 48). While these allogeneic models of murine IPS have given us new insights into its pathogenesis, the actual mechanisms important in human IPS are likely even more complicated since these proposed immunologic mechanisms are unlikely to contribute to IPS seen following autologous bone marrow transplant where alloantigens stimulated T-cell inflammation and graft versus host disease presumably does not take place. Surfactant dysfunction, specifically SP-A dysfunction, could be one common factor in the development of human IPS that occurs following both autologous and allogeneic BMT regimens.

The current study of Yang and colleagues (1) provides important insights into the mechanisms by which SP-A modulates the lung inflammatory response. SP-A isolated by butanol extraction of lavage fluid of patients who have alveolar proteinosis was shown to inhibit activation of macrophages in this model of lung injury, as measured by production of TNF- and nitric oxide. In addition, SP-A inhibits the production of interferon (IFN)- by T-lymphocytes. As a consequence, lung injury, as assessed by macrophage cytotoxicity and permeability edema, is more severe in the absence of SP-A than in the presence of SP-A. It remains unclear whether SP-A is acting directly on both of these cell types in this model. However, in vitro studies have demonstrated that SP-A directly inhibits production of TNF- by macrophages stimulated with LPS (49) or Candida albicans (50) and by U937 cells stimulated with smooth, but not rough, serotypes of LPS (51). In addition, SP-A deficient mice challenged with LPS (12) or with Pseudomonas aeruginosa (8) or respiratory syncytial virus have higher levels of TNF- (10) than do wild-type mice. Thus, there is reason to believe that SP-A may act directly on macrophages to inhibit production of proinflammatory cytokines. SP-A may also indirectly inhibit macrophage production of nitric oxide by down-regulating T-cell production of IFN-, a potent stimulus for macrophage production of inducible nitric oxide synthase (25). The in vitro effects of SP-A on production of IFN- by T-cells have not been reported to the best of our knowledge; however, SP-A has been shown to inhibit the production of other cytokines by T-cells, such as IL-2, a process that is at least partly dependent on the SP-A receptor, SPR-210 (31). Therefore, a precedent exists for regulation of T-lymphocyte function by SP-A. It will be important in future studies to elucidate basic signaling mechanisms involved in these processes.

Thus, the studies by Yang and coworkers, as well as other in vitro and in vivo studies, demonstrate that SP-A inhibits the production of proinflammatory mediators. However, SP-A has been reported to enhance the production of proinflammatory cytokines and free radicals under some experimental conditions. For example, SP-A enhances production of TNF- by U937 cells stimulated with a rough serotype of LPS (51), by macrophages incubated with bacillus Calmette-Guerin (52) and by peripheral blood mononuclear cells and U937 cells in the presence of respiratory syncytial virus (53). In addition, SP-A directly simulates TNF- production by the monocytic cell line, THP-1 (54). Studies by Hickman-Davis and coworkers showed that upregulation of nitric oxide by SP-A appears to be one mechanism by which SP-A mediates killing of Mycoplasma pulmonis both in vitro and in vivo (55). Weikert and coworkers (52) recently showed that SP-A increased the production of nitric oxide induced by bacillus Calmette-Guerin organisms and that SP-A enhanced killing of bacillus Calmette-Guerin was mediated by nitric oxide dependent pathways.

How can we reconcile these disparate findings that SP-A both inhibits and augments production of inflammatory mediators such as TNF- and nitric oxide? Some possible explanations are that the effects of SP-A vary with the type of effector cell, the state of activation of the cell, or the type of pathogen or insult. In support of this hypothesis are the studies cited above in which different cells have been found to respond differently to SP-A. Further support is provided by studies showing that SP-A enhances LPS-induced production of nitric oxide by macrophages activated with IFN- but inhibits nitric oxide by the same cell type that has not been activated with IFN- (56). The possibility that specific pathogens elicit distinct responses in the presence of SP-A is supported by data showing that SP-A enhances production of nitric oxide by macrophages activated with IFN- and challenged with M. pulmonis (55), whereas SP-A inhibits production of nitric oxide by macrophages challenged with Mycobacterium tuberculosis (57). In addition, since endotoxin contamination will affect SP-A function, the purified protein should be analyzed and treated to remove endotoxin, if necessary (58). The method of isolation of SP-A can also affect its function (59), as illustrated by the current study (1). Finally, as proposed by Yang and coworkers (1), the discrepancy in SP-A mediated functions may be due to the immune status of the lung. Thus, SP-A may act in the innate immune response to initiate a first line of host defense, including enhancing phagocytosis and killing of pathogens by innate immune cells such as macrophages and neutrophils. However, if this first line of defense is inadequate and if the potent adaptive immune system becomes activated, SP-A may act to protect the delicate pulmonary tissues from the damage that could occur if T-cells become activated in the alveolar space by either directly suppressing production of inflammatory mediators by alveolar macrophages or indirectly by regulating functions of T-lymphocytes.

	Summary

Although the bulk of available studies demonstrate a role for SP-A and SP-D in pulmonary innate immunity, a growing body of literature supports the possibility that the lung collectins directly mediate functions of cells of the adaptive immune response. The report by Yang and coworkers (1) lends credence to the hypothesis that SP-A and SP-D may mediate cross-talk between innate and adaptive immunity in the lungs, a prospect that requires further investigation. The current study also raises the provocative possibility that SP-A containing surfactant preparations may be important for treatment of idiopathic pneumonitits syndrome and other pulmonary inflammatory diseases. Currently, neither SP-A nor SP-D are components of the surfactant replacement therapies that are routinely used to treat infant respiratory distress syndrome or in the surfactant preparations that have been tested as therapies for acute respiratory distress syndrome, an inflammatory disease associated with deficiencies in SP-A and SP-D (60) as well as other surfactant components (61). Although there are still many unanswered questions about the functions of these proteins, the rationale is building for considering these proteins as therapies for lung inflammation.

	Footnotes

Address correspondence to: Jo Rae Wright, Ph.D., Box 3709, 438 Nanaline Duke, Dept. Cell Biology, Duke University Medical Center, Durham, NC 27710. E-mail: j.wright{at}cellbio.duke.edu

(Received in original form March 23, 2001).

Acknowledgments: Supported in part by HL-30923 (J.R.W.), HL-51134 (J.R.W.), the Parker B. Francis Fellowship Program (P.B.), and HL-55166 (R.J.F.).

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