American Journal of Respiratory Cell and Molecular Biology

Surfactant proteins (SP)-A and SP-D (SP-A/-D) play important roles in numerous eosinophil-dominated diseases, including asthma, allergic bronchopulmonary aspergillosis, and allergic rhinitis. In these settings, SP-A/-D have been shown to modulate eosinophil chemotaxis, inhibit eosinophil mediator release, and mediate macrophage clearance of apoptotic eosinophils. Dysregulation of SP-A/-D function in eosinophil-dominated diseases is also not uncommon. Alterations in serum SP-A/-D levels are associated with disease severity in allergic rhinitis and chronic obstructive pulmonary disease. Furthermore, oligimerization of SP-A/-D, necessary for their proper function, can be perturbed by reactive nitrogen species, which are increased in eosinophilic disease. In this review, we highlight the associations of eosinophilic lung diseases with SP-A and SP-D levels and functions.

This review summarizes the functions of surfactant proteins A and D (SP-A/-D) in the lung and proposes several mechanisms by which SP-A/-D may regulate eosinophil activity and function in inflammatory airway diseases. Understanding how SP-A/-D regulate airway inflammation will help us to develop novel strategies to treat lung diseases in which eosinophils play an important role in disease pathogenesis.

Surfactant proteins (SP-A, SP-B, SP-C, and SP-D) make up 5 to 10% of all pulmonary surfactant. They differ from one another in their synthesis, oligomerization, and function. Whereas SP-B and SP-C are hydrophobic and function to prevent alveolar collapse by reducing surface tension in the distal lung, SP-A and SP-D are hydrophilic and play unique and important roles in lung host defense. In this review we focus on SP-A and SP-D. SP-A and SP-D belong to the collectin (collagen-like lectins) family of proteins. Collectins have four unique regions: an N-terminal segment with one to three cysteine residues, a collagen-like region, an α-coiled neck region, and a C-terminal carbohydrate recognition domain (CRD). SP-A and SP-D monomers can undergo trimerization by disulfide crosslinking of their N-terminal domains and additional noncovalent hydrogen bonding. In addition, the neck region of SP-D, which is an α-helical coiled-coil with a centrally place tyrosine ring, can mediate oligomerization of its three CRDs into a trimeric assembly (1). Upon complete oligomerization, SP-D forms a cruciform-like structure composed of four-trimeric subunits (dodecamer), which can participate in higher orders of multimerization to form astral bodies (2), and SP-A assembles into a bouquet-like structure of six-trimeric subunits (octadecamer). Unlike SP-A, the collagen-like tails of SP-D are buried under normal conditions.

The CRDs of SP-A and SP-D mediate binding to a variety of ligands that exhibit glycosylation motifs, including pathogens, lipids, cells, and receptors. Despite the similarities and some shared functions of SP-A and SP-D, they have distinct characteristics and roles as well (3). For decades, the most notable immune function of SP-A and SP-D was attributed to their opsonic activity to bind and aggregate pathogens via their CRDs and to aid in pathogen uptake by immune cells, such as macrophages and neutrophils. More recently, SP-A/-D have been shown to act as direct mediators of cellular signal transduction. Altered SP-A/-D levels are commonly observed as markers of airway and lung diseases. However, the clinical associations with disease are ambiguous as to whether SP-A/-D dysregulation/dysfunction is important for disease pathology or rather a byproduct of the diseased lung environment (4). In this review we highlight the association of altered surfactant protein levels in eosinophil-dominated lung diseases and speculate on possible mechanisms by which SP-A/-D may regulate or be regulated by eosinophil functions, thus highlighting a lesser-appreciated area of SP-A/-D immunobiology.

Numerous studies have examined the roles of SP-A and SP-D as opsonins and their participation in pathogen phagocytosis (515). Most often, increased phagocytosis of opsonized pathogens is beneficial to the host as a mode of clearance. However, in some instances, pathogens are able to subvert the normal phagocyte clearance machinery and utilize the protective environment of the phagocyte. In these rare cases, enhanced SP-A/-D binding may be a risk factor contributing to worsening of disease and increased pathogen burden (1619). As an example, SP-D–deficient mice infected with the fungus Cryptococcus neoformans (CN) have decreased pulmonary eosinophils and lower IL-5 levels in lung lavage fluid compared with control wild-type (WT) mice. Moreover, CN-infected SP-D mice have decreased fungal burden and improved survival compared with the WT controls (20). These findings support the concept that SP-D is a virulence factor for CN and facilitates its infection in mice. This is of clinical interest in the HIV-seropositive population, who are disproportionately infected by this fungus. Studies examining SP-D levels in lung fluid have found significantly higher levels of SP-D in HIV-seropositive/AIDs subjects with low CD4 T cell counts (< 200 cells/μl) as compared with those with high CD4 T cell counts (> 200 cells/μl) (21). Additionally, IL-5 is often reported to be elevated in HIV-seropositive individuals (22), further suggesting a link between SP-D regulation of IL-5 and risk for CN infection in HIV-seropositive individuals (22).

In addition to aiding in clearance of bacteria and viruses via opsonization, surfactant proteins bind to other biological/abiotic particles and to various cell populations and participate in their clearance from the pulmonary environment. SP-A has been shown to enhance phagocytosis of IgG-opsonized particles (23) and complement-coated particles (24) and to preferentially bind apoptotic neutrophils, which aides in their removal from the inflamed lung (25, 26). SP-D is known to aggregate and aid in the removal of pollen starch granules (27, 28), to bind and enhance clearance of genomic DNA and apoptotic cells (29), and to aggregate and remove nanoparticles (30).

Apart from the more traditional role of phagocytosis, neutrophils can extrude neutrophil extracellular traps (NETs) as a last mode of defense to directly combat microbes (31). NETs are composed of decondensed chromatin fibers coated with antimicrobial histones and granular proteins and can be released upon stimulation by a variety of agents (e.g., protozoa, fungi, viruses, bacteria, and endotoxin) (reviewed in Reference 32). Recent studies have demonstrated that SP-D can bind to NET-DNA and to bacteria simultaneously, thereby promoting bacterial trapping by the NETs (33). SP-D–NET binding is also thought to promote NET clearance by macrophages. Extracellular DNA traps can also be generated from eosinophils (eosinophil extracellular traps [EETs]) (34) and have been found in several eosinophil-associated diseases, including bronchial asthma, contact dermatitis, spirochetosis, and scabies (reviewed in Reference 35). Thus far, the function of SP-A/-D in mediating EETs has not been defined. However, SP-A/-D bind eosinophils, and, during allergic inflammation when functional SP-A/-D levels are decreased, the association with and regulation of eosinophils may be diminished. In the absence of functional SP-A/-D, we speculate that EETs will then be stimulated more readily by factors commonly elevated in the allergic lung environment, such as IL-5, thymic stromal lymphopoietin, eotaxin, and C5a (reviewed in Reference 35). Additionally, if either SP-A or SP-D aides in EET-DNA removal by macrophages, lack of functional SP-A/-D may lead to prolonged presence of EETs, which could contribute to worsened symptoms due to extracellular localization of cytotoxic granular agents.

Although the globular head domain of SP-A/-D binds to pathogens and pathogen-associated molecular patterns, their collagen-like tails are left exposed to initiate phagocytosis by interactions with phagocytes. However, the interaction of the SP-A/-D tail region is also capable of initiating cellular signaling cascades by specific receptor interactions. Gardai and colleagues (36) showed that SP-A and SP-D bind SIRP-α through the globular head region to initiate a signaling pathway that attenuates proinflammatory cytokine production. In contrast, the collagenous tail, by interacting with CD91/calreticulin, stimulates proinflammatory mediator production.

As shown by Nguyen and colleagues (37), SP-A and surfactant lipids up-regulate IRAK-M, a negative regulator of Toll-like receptor (TLR)-mediated inflammation, and inhibit LPS-induced cytokine production in human macrophages. More recently, SP-A has been shown to mediate LPS–TLR-4 signaling by interactions with β-arrestin 2 (38). By enhancing the colocalization of TLR-4 with the post-Golgi compartment in alveolar macrophages, SP-A significantly reduces the LPS-induced colocalization of TLR-4 with the early endosome antigen, leading to attenuation of the proinflammatory response. SP-A is unable to exert this affect in β-arrestin 2−/− mice, which demonstrates that SP-A modulates LPS-induced TLR-4 trafficking by interacting with β-arrestin 2.

Increases in exhaled nitric oxide (NO) are associated with eosinophilic inflammation and correlate with other indices of inflammation in asthma. Under these conditions, posttranslational modifications of SP-D appear to modulate the inflammatory properties of SP-D. For example, NO can modify key cysteine residues in the tail domain of SP-D, which leads to a dissociation of SP-D multimers into trimers, thus exposing the S-nitrosylated N-termini (see discussion below). This exposed S-nitrosylated tail domain can then bind to the calreticulin/CD91 receptor complex and potentiate this proinflammatory pathway, which occurs via phosphorylation of p38 and NF-κB activation (39).

The majority of SP-A is synthesized by alveolar type (AT)II cells in the distal airways. Newly synthesized SP-A is packaged into lamellar bodies by the ATII cells for storage and ensuing secretion via regulated exocytosis (40). Upon release of SP-A into the extracellular milieu, it begins to form tubular myelin (lipid transport system unique to the lungs) in conjunction with lipids (4143). SP-A is not only synthesized and secreted from the ATII cells; it is also predominantly recycled by them (44, 45). Although SP-D is synthesized and secreted constitutively by ATII cells, it is also produced by nonciliated Clara cells in the upper airways (46). Similar to SP-A, SP-D release is regulated by granule exocytosis (47, 48). Although the majority of surfactant phospholipid and protein are removed from the alveolus by ATII cell uptake (4951), evidence suggests that alveolar macrophages are also important participants in the uptake and degradation of exhausted surfactant protein (5254). Uptake by macrophages and ATII cells is mediated predominantly by endocytosis via clathin-coated pits (55, 56).

Accumulating evidence suggests that dysregulated SP-A/-D metabolism and signaling play key roles in the pathobiology of lung diseases. Indeed, changes in SP-A/-D levels in serum (57) and bronchoalveolar lavage (BAL) are seen in a variety of lung diseases (Table 1). Below, we focus on eosinophilic diseases in which aberrant SP-A/-D levels or function have recently been implicated.

Table 1. Bronchoalveolar Lavage Surfactant Proteins in Human Lung Disease

Lung DiseasesChange in SP-A/-DNumber of SubjectsReference
Lung diseases with increased SP-A/-D  
 Asthma*↑↑SP-A asthma (6.1 ± 0.8 μg/ml);versus healthy control subjects (4.4 ± 0.5 μg/ml); andn = 10 patients with asthma; n = 11 healthy control subjects139
 ↑↑SP-D asthma (0.62 ± 0.04 μg/ml) versus healthy control subjects (0.42 ± 0.06 μg/ml)n = 10 patients with asthma; n = 11 healthy control subjects139
 Asthma (segmental challenge)*↑↑SP-Dn = 23 patients with asthma; n = 10 healthy control subjects140
 AEP*↑↑SP-A AEP (3.461 μg/ml ± 2.449) versus healthy control subjects (1.209 ± 28 μg/ml)n = 5 patients with AEP; n = 7 healthy control subjects72
 ↑↑SP-D AEP (1.693 μg/ml ± 2.233) versus healthy control subjects (0.196 ± 0.0024 μg/ml)n = 5 patients with AEP; n = 7 healthy control subjects72
 Pulmonary Langerhans cell histiocytosis*↑↑SP-A versus healthy control subjects or COPDn = 1 each141
 HP*↑↑SP-A (8 ± 0.7 μg/ml) HP versus healthy control subjects (4 ± 0.3 μg/ml)n = 10 patients with HP; n = 21 healthy control subjects91
 PAP↑↑SP-A PAP (39.3 ± 12.5 μg/l) versus healthy control subjects (3.5 ± 1.1 μg/ml)n = 6 patients with PAP; n = 13 healthy control subjects142
Lung diseases with decreased SP-A/-D   
 Asbestos exposure↑↑SP-D PAP (19.3 ± 9.3 μg/ml) versus healthy control subjects (0.88 ± 0.13 μg/ml)n = 9 patients with PAP; n = 28 healthy control subjects143
 ARDS↓↓SP-A ARDS (29.88 ± 6.18 μg/ml) versus healthy control subjects (123.64 ± 118.04 μg/ml)n = 67 patients with ARDS; n = 29 healthy control subjects144
 COPD/smoker↓↓SP-D never-smoker (0.558 ± 309 μg/ml) versus smoker/COPD (0.235 ± 0.203 μg/ml)n = 65 never-smokers; n = 22 COPD/smokers99
 IPCD≈SP-D IPCD (0.62 ± 0.16 μg/ml) versus healthy control subjects (0.88 ± 0.13 μg/ml)n = 7 patients with IPCD; n = 28 healthy control subjects143
 IPF*≈SP-D IPF (0.58 ± 0.06 μg/ml) versus healthy control subjects (0.88 ± 0.13 μg/ml)n = 33 patients with IPF; n = 28 healthy control subjects143
 ↓↓SP-A IPF (1.13 ± 0.252 μg/ml) versus healthy control subjects (1.53 ± 0.136 μg/ml)n = 34 patients with IPF; n = 25 healthy control subjects93
 Sarcoidosis≈SP-D sarcoidosis (0.97 ± 0.08 μg/ml) versus healthy control subjects (0.88 ± 0.13 μg/ml)n = 60 patients with sarcoidosis; n = 28 healthy control subjects143
 ↑↑SP-A sarcoidosis (9.0 ± 1.7 μg/ml) versus healthy control subjects (4.0 ± 0.3 μg/ml)n = 35 patients with sarcoidosis; n = 21 healthy control subjects91
 Smokers↓↓SP-A smoker (1.8 ± 0.4 μg/ml) versus nonsmoker (3.1 ± 0.4 μg/ml)n = 10 nonsmokers; n = 8 smokers100
 ↓↓SP-D smoker (0.5 ± 0.1 μg/ml) versus nonsmoker (1.3 ± 0.2 μg/ml)n = 12 nonsmokers; n = 7 smokers100
 ↓↓SP-D never-smoker (0.558 ± 309 μg/ml) versus smoker (0.287 ± 0.204 μg/ml)n = 65 never-smokers; n = 23 smokers99

Definition of abbreviations: AEP, acute eosinophilic pneumonia; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; HP, hypersensitivity pneumonitis; IPCD, interstitial pneumonia with collagen disease; IPF, idiopathic pulmonary fibrosis; PAP, pulmonary alveolar proteinosis; SP-A/-D, surfactant proteins A and D.

*Eosinophilic disease.


Asthma is a common chronic disease of the airways characterized by inflammation and reversible airflow obstruction caused by a combination of genetic and environmental factors. Based on studies in murine models of allergic inflammation and in studies of patients with asthma, it has become increasingly evident that SP-A and SP-D play important regulatory roles in allergic airways diseases. Mice challenged with OVA, house dust mite (HDM), or fungi have alterations in SP-A/-D levels at the height of eosinophilia (5860). An increase in SP-A/-D during eosinophilic inflammation is likely a key defense mechanism for eosinophil regulation: SP-D inhibits eosinophil chemotaxis, SP-A and SP-D bind eosinophils and attenuate degranulation, and SP-A suppresses IL-8 production from eosinophils (6163). In support of these findings, when mice lacking SP-A or SP-D are challenged with allergen, they develop severely enhanced eosinophilia compared with WT control mice and display worsened symptoms of allergic airways inflammation tied to Th2-dominant disease (64, 65).

In studies of segmental antigen challenge in atopic and individuals with asthma, the ability of total surfactant (lipoproteins and proteins) extracted from the antigen-challenged lobe was found to be dysfunctional in its ability to maintain airway patency as compared with surfactant from a control (saline challenged) lobe (66, 67). Normal activity could be achieved by removing water-soluble inhibitors from the extracted surfactant, which was attributed to leakage of plasma proteins into the lumen during inflammation. Studies have demonstrated that plasma proteins, albumin, and fibrinogen impair surfactant function at physiological concentrations (68). Additionally, a product released from activated eosinophils, eosinophil cationic protein, had a profound effect on the arrangement of phospholipids within the surfactant biofilm due to what appeared to be unwinding of the lamellar bodies (68). Normally, SP-A will partially protect from this surfactant-inhibiting effect. However, in chronic inflammatory lung conditions such as asthma, functional SP-A levels may be decreased and unable to adequately regulate this interaction. Indeed, SP-A isolated from subjects with asthma has been shown to be less effective at inhibiting Muc5AC and IL-8 production by stimulated epithelial cells versus SP-A isolated from normal healthy control subjects (69). Although the mechanisms for asthma-derived SP-A dysfunction are unclear, the increased eosinophilia and eosinophil-derived factors (eosinophil peroxidase, eosinophil cationic protein, eosinophil associated RNase, and major basic protein) associated with Th2-predominant asthma may alter SP-A oligomerization and render SP-A incapable of carrying out normal host protective functions.

Acute Eosinophilic Pneumonia

Acute eosinophilic pneumonia (AEP) is a rare disease of unknown etiology characterized by acute respiratory failure, bilateral infiltrates, hypoxemia (PaO2 < 60 mm Hg), and eosinophilic infiltration of the lung (70). Unfortunately, no animal models for AEP exist. Although the pathophysiology of AEP is unknown, eosinophils are believed to play a role because they comprise greater than 25% of BAL cells and because IL-5 and IL-1rα are detected at increased levels in the BAL of affected patients (71). Levels of SP-A and SP-D in BAL and serum are reported to be significantly elevated in patients with AEP compared with healthy control subjects (72). It is not clear what the implications of these observations are for the pathobiology of AEP. One may speculate that, during AEP, the increase in eosinophilia would lead to SP-A/-D breakdown and dysfunction, and therefore, as a compensatory mechanism, more SP-A/-D would be produced and secreted in an attempt to regulate eosinophil activities.

Allergic Bronchopulmonary Aspergillosis

The ability of SP-A and SP-D to interact with the glycosylated antigens and allergens of the fungal pathogen Aspergilous fumigatus (AFU) to inhibit specific IgE binding to these allergens makes them an attractive therapeutic target for AFU-associated diseases (7375). Murine models of pulmonary hypersensitivity induced by AFU immunologically resemble the human disease allergic bronchopulmonary aspergillosis (ABPA) a condition characterized by serum and pulmonary eosinophilia, hypersensitivity to AFU, and increased total IgE. These models have successfully established a protective role for SP-A and SP-D in the treatment of ABPA. Expression of SP-D is increased in BAL in AFU-sensitized mice (76) and in serum of humans with ABPA (77). Ablation of SP-A and SP-D leads to enhanced eosinophilia and increases total IgE in AFU-sensitized mice (65, 78). Additionally, evidence is accumulating that genetic polymorphisms of SP-A1 and SP-A2 are associated with increased susceptibility to ABPA (79, 80). Moreover, treatment of AFU-sensitized WT and SP-A– and SP-D–deficient mice with “rescue” SP-A and SP-D, respectively, has been shown to suppress IgE levels, eosinophilia, cellular inflammation in the lung, and shift the pathogenic TH2 cytokine profile to a protective TH1 profile (75, 81).

Allergic Rhinitis

Allergic rhinitis (AR) is an IgE-mediated chronic inflammatory disease characterized by the recruitment of eosinophils, basophils, and T cells expressing TH2 cytokines to the nasal mucosa (82). In a murine model of AR, treatment with exogenous SP-A decreased eosinophil number in nasal epithelium, corrected the TH1/TH2 imbalance, and blocked ovalbumin (OVA)-specific IgE (83); these findings strongly suggest a protective role for SP-A in AR.

In humans, SP-A, -B, -C, and -D are components of healthy nasal mucosa and have been shown to increase with inflammation, with the exception of SP-C (84). Expression of SP-A is much higher in patients with AR and nasal polyps than in control subjects, and the level of SP-A positively correlates with eosinophil number within the basement membrane of epithelium (85). Because these findings are somewhat in contrast to studies in mice showing that a decrease in eosinophilia results when exogenous SP-A is given, one may speculate that the increased level of SP-A detected in the patients with AR is compensating for defective SP-A, which is unable to adequately regulate eosinophil functions. This potentially defective SP-A may be a direct product of the inflammatory milieu associated with activated eosinophils and their proteolytic mediators that can alter the oligomeric structure of SP-A. A lack of protective SP-A would likely lead to localized enhanced production of SP-A in an attempt to compensate for the decreased immune function.

To date, only SP-A expression in nasal mucosa has been shown to correlate with severity of disease as measured by the Rhinitis Symptom Utility Index in patients with AR (86), suggesting that it plays a key role in the inflammatory process regulating AR and nasal polyp formation in these patients. Indeed, early studies using liposomes, which consist of phospholipids that make up 75% of the nasal surfactant layer, have been found to be comparable to cromoglycolate therapy in the treatment of patients with AR (87). In patients with chronic rhinosinusitis associated with cystic fibrosis, expression of SP-A, SP-B, and SP-D is also increased (88, 89).

Idiopathic Lung Disease

Interstitial lung diseases are a heterogeneous group of lung diseases resulting from damage to lung parenchyma by varying patterns of inflammation and fibrosis. These diseases involve not only the interstitium of the lung but also the vessels and airways and are frequently associated with increased BAL eosinophils and peripheral blood eosinophilia (90). Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is an immune mediated interstitial lung disease induced by inhalation of antigens to which a person is already sensitized. The clinical presentation and radiographic imaging findings of HP overlap broadly with other interstitial lung diseases, making it difficult to diagnosis, especially because identification of the antigen exposure is often challenging. Elevated serum SP-A levels have been reported in patients diagnosed with HP and idiopathic pulmonary fibrosis (IPF), an interstitial lung disease of unknown etiology (9193); however, SP-A levels are not consistently elevated in the BAL of these patients (93). Findings in IPF show a significant negative correlation between BAL SP-A levels and the presence of BAL eosinophils. Low levels of BAL SP-A in subjects with enhanced eosinophilia associated with IPF suggest that SP-A may be involved in the regulation of eosinophil recruitment, survival, or resolution in the lung in response to environmental stresses (94). An alternative explanation could be that in patients with IPF with associated eosinophilia, degradation of SP-A occurs, lowering the detectable levels of SP-A.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is generally considered to be a neutrophilic disease. However, there is increasing evidence to suggest that a subgroup of patients with stable COPD exists that have chronic airway eosinophilia and steroid responsive disease (95, 96).

Cigarette smoke is the major risk factor for COPD and is known to adversely affect surfactant (97, 98). Decreased levels of BAL SP-A and SP-D have been detected in healthy smokers compared with nonsmoking control subjects. The decreased concentration of SP-A and SP-D in lung lavage in smokers (99, 100) is speculated to impair the host defense functions of surfactant in the peripheral airways and may contribute to the development of chronic obstructive lung disease.

In patients with COPD, sputum SP-A/-D (101) and serum SP-D levels associate with lung function and with health status (102) and increase significantly during COPD exacerbations (103), suggesting that SP-D may be a biomarker of disease severity for COPD. In a recent candidate gene association study by Kim and colleagues, SP-D was identified as one of two risk loci for COPD from among circulating COPD biomarkers measured in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study (104). These findings support the relevance of SP-D in the pathogenesis of COPD. There is no direct evidence linking changes in SP-A/-D expression/function and eosinophil activity in COPD. However, cigarette smoke has been shown to lead to disruption of the quaternary structure of SP-D (105), which supports the “translocation hypothesis” that dissociation of pulmonary SP-D into smaller subunits can lead to rapid increases in serum SP-D. Because SP-D has been shown to inhibit eosinophil chemotaxis (62), a loss of pulmonary-associated SP-D may facilitate subsequent recruitment of eosinophils into the airspace and induced sputum, as observed in smokers with COPD (106).

SP-A and SP-D come into contact with a wide range of inhaled allergens. Binding of SP to these foreign allergens leads to a competitive interaction for cell-sequestered IgE, resulting in an attenuation of mast cell degranulation. HDM allergens, a major cause of allergic asthma in developed countries, have cysteine protease activity that leads to degradation of SP-A and SP-D under physiological conditions (107). More generally, SP-A and SP-D can be degraded by a range of host- and pathogen-derived proteases, including Pseudomonas aeruginosa and human neutrophil elastases (108, 109), cathepsin-S (110), and matrix metalloproteinase-9 (111), and it is therefore plausible that increased proteolytic activity might serve to inactivate SP-A in eosinophil-dominated diseases.

SP-D and SP-A oligomeric structures can be altered by HDM protease, and SP-D is altered by many of the neutrophil derived proteinases (elastase, proteinase-3, and cathepsin-G) (107, 112). These altered oligomers limit the SP ability to bind carbohydrates and agglutinate bacteria. In addition, reactive oxygen and nitrogen species may also affect posttranslational modifications of SP-D that alter its structure and function at sites of inflammation (39, 113). For example, NO, produced locally by airway epithelial cells and increased in asthma (114), has been shown to S-nitrosylate two free Cys thiols in the N-terminus of dodecameric SP-D (Cys-15 and Cys-20) and to affect dissociation into SP-D trimers (115). Consequences of this structural perturbation include the activation of SP-D proinflammatory chemoattractant function and the loss of control TLR4 blockade (39). Tyrosine nitration of SP-A and SP-D and Tyr-Tyr crosslinking of SP-D have been also found in protein exposed in vitro to peroxynitrite (116119) and in inflammatory lung diseases (120). Nitration of SP-A has been detected at Tyr164, Tyr166, and Tyr220 (116), and these modifications decrease lectin activity (117, 121). Reactive nitrogen species cause nitration of SP-D at Tyr341 and crosslinking of Tyr228 (119). In addition to increases in FeNO, increased tyrosine nitration has been demonstrated in allergic asthma (122), which may be a specific activity of eosinophils and eosinophil peroxidase (123125). Thus, although the effects associated with posttranslational modification of Tyr have not been link to a particular oligomeric state, these data nonetheless suggest an additional mechanism for modulation of SP-D activity under conditions of eosinophilic inflammation.

Modification of SP-D oligimerization and Tyr crosslinking have been investigated in the context of allergic asthma (126). SP-D in BAL fluid collected from subjects with asthma before and after allergen challenge or the combination of allergen and LPS challenge had increases in both monomeric and in tyrosine-crosslinked SP-D. These effects, which were correlated with high levels of BAL eosinophils, NO, SNO–SP-D, and Th2-dominant cytokines, were not observed after challenge of nonasthmatics or with LPS alone. These data suggest, for the first time, a correlation between regulatory posttranslational modifications of SP-D and allergic airway inflammation.

In addition to posttranslational modification, surfactant levels are altered after subsegmental allergen challenge in asthma (67). Also, purified eosinophil cationic protein has been shown to alter surfactant structure and function (68, 127), although these in vitro studies used Alveofact (Boehringer Ingelheim, Ingelheim, Germany), a natural bovine surfactant devoid of SP-A (128). Leakage of plasma and serum proteins in the airway space, which is more likely during lung inflammation, can accelerate the conversion of functional surfactant large aggregates into poorly functional small aggregates (129). This conversion is typically regulated by SP-A and is consistent with dysfunctional SP-A in asthma.

Although surfactant therapy in preterm neonates had dramatically changed their long-term outcome, the current formulation is devoid of SP-A and SP-D. Additionally, preterm neonates often suffer from respiratory distress syndrome and have a higher risk for development of infection and bronchopulmonary dysplasia. Given our current knowledge of the protective roles of SP-A and SP-D in these areas, clinicians using new surfactant therapies may consider the addition of SP in the treatment of these patients.

Much of what we know about the potential use of SP-A/-D therapy has arisen from studies using SP-A– or SP-D–deficient mice that are given exogenous SP as a “rescue” treatment. Although the oligomeric structure of SP-A and SP-D is thought to be essential for some SP function, several research publications have also found specific regions and fragments with activity. An animal model using AFU-allergen in SP-D–deficient mice shows that exogenous SP-D treatment given to the mice can rescue their allergic phenotype (75, 130). Additional studies have determined that SP-D given as a full-sized dodecamer oligomer or as a shorter fragment containing the trimeric subunit and CRD are capable of alleviating allergic inflammation in an OVA mouse model (131). Likewise, SP-D fragments were capable of reducing early airway responses to AFU allergen and led to significantly decreased airway hyperresponsiveness, eosinophilia, and histamine levels as compared with placebo (132). In fact, studies examining the mechanisms behind the difference in allergic airways phenotype between Balb/c and C57Bl/6 mice revealed that SP-D levels were significantly elevated in the C57BL/6 mice as compared with Balb/c mice, which could account for the attenuation of response (133).

Fewer studies have examined the consequence of SP-A rescue therapy in allergic airways. Although SP-D is commonly synthesized recombinantly from cell lines, SP-A is typically extracted from the lavage of patients with alveolar proteinosis. Several studies have given SP-A from APP as a rescue in other murine models, including the bleomycin model of pulmonary fibrosis and in LPS-driven inflammation. In both cases, exogenous given SP-A led to “rescue” of the innate and adaptive immune phenotypes observed in SP-A–deficient mice (134137). More recently, Awasthi and colleagues has found that a specific fragment of SP-A (20-mer) has the ability to inhibit LPS-induced cytokine production and lung inflammation by interaction with TLR-4 (138). This finding suggests the possibility of other SP-A fragments that may be active against a specific receptor target for which SP-A is known to associate, such as TLR-2, SIRP-α, and CD91. Because SP-A and SP-D are known to bind the FCgRII/III (CD16/32) complex, this receptor should also be examined in SP-A/-D–mediated eosinophil activities, including cytokine regulation, degranulation, apoptosis, and chemotaxis.

Pulmonary surfactant proteins are critical in mediating a variety of immune and physiological responses during health and disease. Many lung diseases associated with eosinophilia also have dysregulated SP-A/-D metabolism, as detected by altered levels in serum, BAL, or both. Although the etiology of altered levels of SP-A/-D is unclear in each of the diseases mentioned, SP-A and SP-D bind eosinophils and regulate their degranulation. Additionally, SP-D inhibits eosinophil chemotaxis, and SP-A binds apoptotic eosinophils and aides in their engulfment by macrophages. A proposed model (Figure 1) suggests that a common underlying mechanism for dealing with enhanced eosinophilia may be to up-regulate SP-A/-D production. Alternatively, eosinophil-derived proteases, environmental irritants, or NO produced in the inflamed lung milieu may alter the oligomeric structures and render SP-A/-D dysfunctional.

Although rescue treatments that give exogenous full-length or peptides of SP-A or SP-D have shown promising results in allergic animal models, to the best of our knowledge, no studies have examined the therapeutic potential of purified SP-A/-D or targeted SP-A/-D peptides in human lung diseases in which eosinophils are thought to play an important role in pathogenesis.

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Correspondence and requests for reprints should be addressed to Loretta G. Que, M.D., Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care, Duke University medical Center, 203 Research Drive, CB #2641, Durham, NC. E-mail:

This work was supported by National Institutes of Health grants HL111151, AI81672, and HL107590.

Author Contributions: Conception and design: J.G.L., L.G.Q. Drafting and interpretation: J.G.L., K.J.A., M.W.F., L.G.Q. Final approval of edited version: J.G.L., K.J.A., M.W.F., L.G.Q.

Originally Published in Press as DOI: 10.1165/rcmb.2014-0095TR on June 24, 2014

Author disclosures are available with the text of this article at


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