SP-A) And D Research Articles

Could SP-A and SP-D Serum Levels Predict COVID-19 Severity?

Given the various clinical manifestations that characterize Coronavirus Disease 2019 (COVID-19), the scientific community is constantly searching for biomarkers with prognostic value. Surfactant proteins A (SP-A) and D (SP-D) are collectins that play a crucial role in ensuring proper alveolar function and an alteration of their serum levels was reported in several pulmonary diseases characterized by Acute Respiratory Distress Syndrome (ARDS) and pulmonary fibrosis. Considering that such clinical manifestations can also occur during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we wondered if these collectins could act as prognostic markers. In this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n = 51) at admission (T0) and after seven days (T1) and compared with healthy donors (n = 11). SP-D increased in COVID-19 patients compared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. In light of these results, SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia, and the early detection of SP-D serum levels could be crucial for preventive clinical management.

Nebulized inhalation of nintedanib-loaded biomimetic nano-liposomes attenuated bleomycin-induced interstitial lung fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial lung disease with a poor prognosis. However, there are currently few drugs available for its treatment. Nintedanib is clinically effective but is associated with gastrointestinal adverse effects and weight loss. Due to drug intolerance, the overall outcomes of nintedanib therapy are substantially compromised in quite a few patients. In the present study, we synthesized nintedanib-loaded biomimetic liposomes (Nin-lipo) to improve the antifibrotic efficacy and drug tolerance of nintedanib. It was observed that nebulized inhalation of small doses of Nin-lipo (2 mg/kg) resulted in greater delivery efficiency and higher drug concentrations in lung tissue than conventional oral doses of nintedanib (60 mg/kg). Furthermore, Nin-lipo significantly inhibited bleomycin (BLM)-induced pulmonary fibrosis and improved lung function in mice. The possible molecular mechanism of anti-fibrosis by Nin-lipo was investigated. Nin-lipo was found to act mechanistically on alveolar macrophages via alveolar surfactant proteins A and D (SP-A/D) by simulating pulmonary surfactants and inhibiting the polarization of M2 macrophages. These effects thereby reduced the secretion of transforming growth factor 1 (TGF-β1) in macrophages. Moreover, Nin-lipo demonstrated significant efficacy against weight loss and liver function abnormalities in a mouse model caused by nintedanib. Therefore, nebulized Nin-lipo could greatly improve the antifibrotic efficacy of nintedanib while maintaining an excellent safety profile. Nin-lipo could potentially be developed as a new therapy for IPF.

Structural insights into ACE2 interactions and immune activation of SARS-CoV-2 and its variants: an in-silico study

The initial interaction between COVID-19 and the human body involves the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor. Likewise, the spike protein can engage with immune-related proteins, such as toll-like receptors (TLRs) and pulmonary surfactant proteins A (SP-A) and D (SP-D), thereby triggering immune responses. In this study, we utilize computational methods to investigate the interactions between the spike protein and TLRs (specifically TLR2 and TLR4), as well as (SP-A) and (SP-D). The study is conducted on four variants of concern (VOC) to differentiate and identify common virus behaviours. An assessment of the structural stability of various variants indicates slight changes attributed to mutations, yet overall structural integrity remains preserved. Our findings reveal the spike protein’s ability to bind with TLR4 and TLR2, prompting immune activation. In addition, our in-silico results reveal almost similar docking scores and therefore affinity for both ACE2-spike and TLR4-spike complexes. We demonstrate that even minor changes due to mutations in all variants, surfactant A and D proteins can function as inhibitors against the spike in all variants, hindering the ACE2-RBD interaction. Communicated by Ramaswamy H. Sarma

Surfactant proteins and innate immunity of otitis media.

Otitis media (OM) is the most common disease among young children and one of the most frequent reasons to visit the pediatrician. Development of OM requires nasopharyngeal colonization by a pathogen which must gain access to the tympanic cavity through the eustachian tube (ET) along with being able to overcome the defense mechanisms of the immune system and middle ear mucosa. OM can be caused by viral or bacterial infection. The three main bacterial pathogens are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Innate immunity is important in OM resolution as the disease occurs in very young children before the development of specific immunity. Elements of innate immunity include natural barriers and pattern recognition receptors such as Toll like receptors (TLRs), and Nod like receptors (NLRs). Surfactant proteins A (SP-A) and D (SP-D) act as pattern recognition receptors and are found in the lung and many other tissues including the ET and the middle ear where they probably function in host defense. Surfactant has a potential for use in the treatment of OM due to surface tension lowering function in the ET, and the possible immune functions of SP-D and SP-A in the middle ear and ET.

Complex Evaluation of Surfactant Protein A and D as Biomarkers for the Severity of COPD

PurposePulmonary surfactant proteins A (SP-A) and D (SP-D) are lectins, involved in host defense and regulation of pulmonary inflammatory response. However, studies on the assessment of COPD progress are limited.Patients and MethodsPulmonary surfactant proteins were obtained from the COPD mouse model induced by cigarette and lipopolysaccharide, and the specimens of peripheral blood and bronchoalveolar lavage (BALF) in COPD populations. H&E staining and RT-PCR were performed to demonstrate the successfully established of the mouse model. The expression of SP-A and SP-D in mice was detected by Western Blot and immunohistochemistry, while the proteins in human samples were measured by ELISA. Pulmonary function test, inflammatory factors (CRP, WBC, NLR, PCT, EOS, PLT), dyspnea index score (mMRC and CAT), length of hospital stay, incidence of complications and ventilator use were collected to assess airway remodeling and progression of COPD.ResultsCOPD model mice with emphysema and airway wall thickening were more prone to have decreased SP-A, SP-D and increased TNF-α, TGF-β, and NF-kb in lung tissue. In humans, SP-A and SP-D decreased in BALF, but increased in serum. The serum SP-A and SP-D were negatively correlated with FVC, FEV1, FEV1/FVC, and positively correlated with CRP, WBC, NLR, mMRC and CAT scores (P < 0.05, respectively). The lower the SP-A and SP-D in BALF, the worse the lung function and the increased probability of complications and ventilator use. Moreover, the same trend emerged in COPD patients grouped according to GOLD severity grade (Gold 1–2 group vs Gold 3–4 group). The worse the patient’s condition, the more pronounced the change.ConclusionThis study suggests that SP-A and SP-D may be related to the progression and prognostic evaluation of COPD in terms of airway remodeling, inflammatory response and clinical symptoms, and emphasizes the necessity of future studies of surfactant protein markers in COPD.

Diagnosis of Chronic Obstructive Pulmonary Disease and Regulatory Mechanism of miR-149-3p on Alveolar Inflammatory Factors and Expression of Surfactant Proteins A (SP-A) and D (SP-D) on Lung Surface Mediated by Wnt Pathway.

Objective To study the mechanism of chronic obstructive pulmonary disease (COPD) in diagnosing alveolar factors and analyze the effect of miR-149-3p on alveolar inflammatory factors and the expression of surfactant protein D (SP-D) and SP-A on the lung surface mediated by Wnt pathway. Methods Patients with stable COPD were taken as the research subjects, and healthy volunteers as the control group. Cardiac color Doppler ultrasound was adopted to measure the ventricular structure of patients. The ultrasound simulation method was introduced in the ultrasound imaging. The ultrasound image was processed based on the intelligent ultrasound simulation algorithm. The changes in the structure of the left and right ventricles were analyzed and compared in the two groups. The expression changes of miR-149-3p, Wnt1, β-catenin, RhoA, and Wnt5a in lung tissues of mice in three groups were detected, as well as the content of tumor necrosis factor- (TNF-) α, IL-1β, interleukin (IL-6), nuclear factor kB (NF-kB), and other inflammatory factors in bronchoalveolar tissues of mice in three groups. Results The position where the attenuation ratio was less than 0.92 in the experiment under the ultrasonic simulation algorithm had a gray value of 50. Compared with the control group, the right ventricular mass index of patients with stable COPD was statistically considerable (P < 0.05). In patients with stable COPD, the overall right ventricular longitudinal strain, right ventricular diastolic longitudinal strain rate (RV DLSR), right ventricular diastolic circumferential strain rate, and right ventricular longitudinal displacement were significantly impaired (P < 0.05). The content of miR-149-3p in the lung tissue of the model group was dramatically inferior to that of the control group and the interference group (P < 0.05). The contents of Wnt1, β-catenin, RhoA, and Wnt5a in the lung tissue of the model group were dramatically superior to those of the control group (P < 0.05). In addition, the expressions of TNF-α, IL-1β, IL-6, and NF-kB in the alveolar lavage fluid of the model group were statistically different from those of control group (P < 0.05). The expression levels of SP-D and surfactant protein A (SP-A) in the COPD group were also statistically different from those of control group (P < 0.05). Conclusion miR-149-3p regulated the expression of Wnt1, β-catenin, RhoA, and Wnt5a, which also affected the signal transmission of the Wnt pathway, causing changes in the expression of alveolar inflammatory factors. Eventually, it affected the development of COPD.

A study of pneumoproteins in crystalline silica exposed rock drillers

Objective: The objective was to assess serum concentrations of club cell protein 16 (CC-16) and the surfactant proteins A (SPs-A) and D (SP-D) in male rock drillers (N = 123) exposed to crystalline silica and in 48 occupationally non-exposed. Methods: The arithmetic mean (AM) duration of exposure was 10.7 years. The geometric mean (GM) crystalline silica exposure was 36 µg/m3 at the time of the study. The GM cumulative exposure was 239 µg/m3. Results: The concentrations of SP-D (GM 12.7 vs. 8.8 µg/L, p < 0.001) and SP-A (AM 1847 vs. 1378 ng/L, p = 0.051) were higher among rock drillers than among occupationally non-exposed. A positive significant association was observed between cumulative crystalline silica exposure and the SP-D concentrations (β = 0.07; p < 0.05). Rock drillers with small airway obstruction with maximal mid-expiratory flow % (MMEF%) <70% (N = 29) had higher SP-D concentrations than rock drillers with MMEF% ≥ 70% (N = 91) (GM 17.3 vs. 11.4 µg/L, p = 0.001). Rock drillers with MMEF% ≥70% (N = 91) had higher concentrations of SP-A (1957 vs. 1287 ng/L, p = 0.01) and SP-D (11.4 vs. 9.0 µg/L, p = 0.007) than non-exposed with MMEF% ≥70% (N = 39). Rock drillers with airway obstruction (FEV1/FVC < 0.70, N = 11) had significantly lower CC-16 concentrations than rock drillers with FEV1/FVC ≥0.70 (N = 109) after adjusting for relevant potential confounders (p = 0.02). Conclusion: The results indicate that pulmonary surfactant is a target for crystalline silica toxicity. The alterations appear to be driven by pulmonary alterations in the small airways and by exposure itself. Further studies on pneumoproteins and pulmonary function in other groups of workers exposed to crystalline silica are needed.

SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties.

Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.

Targeting of the surfactant protein A receptor SP-R210L variant by influenza A virus in macrophages. (INM8P.440)

Abstract Alveolar macrophages (AM) are critical for controlling IAV infection by limiting virus release and by initiating innate and adaptive immunity. Surfactant proteins A (SP-A) and D (SP-D) are a primary line of defense against IAV. Previous studies demonstrated that the SP-A receptor SP-R210 mediates clearance of SP-A-opsonized pathogens. Macrophages express two variants, SP-R210L and SP-R210S, though SP-R210L is predominant on AMs. Here, we studied the role of SP-R210 in IAV infection. We show that disruption of SP-R210L in vitro blocked IAV infection with H3N2 and H1N1 IAV strains. Flow cytometry and microscopy experiments showed that SP-R210L is required for endocytic trafficking of IAV to the nucleus. Furthermore, SP-R210L-mediated infection of macrophages was coupled to the production of TNFα. Interestingly, SP-R210L-deficient macrophages were hyper-responsive to the TLR7 ligand imiquimod. Accordingly, IAV inhibited SP-R210L expression in a time-dependent manner. To address these results in vivo, we studied transgenic mice with conditional disruption of SP-R210 in macrophages; SP-R210-deficient mice were significantly more susceptible to IAV infection as indicated by increased morbidity, decreased survival, and severe lung histopathology compared to WT littermates. Taken together, these findings support the model that by co-opting SP-R210L in AMs, IAV causes a functional ‘knock-down’, reducing the beneficial function of SP-R210L and leading to excessive lung inflammation.

Mechanisms of Interaction Between Lung Collectins and Influenza a Virus Hemagglutinin

The unpredictability and rapid appearance of new influenza A virus (IAV) strains pose major challenges for global health. Highly virulent strains can evolve quickly through genetic reassortment from animal IAV strains and spread rapidly through populations lacking immunity. Some pandemic IAV strains can kill patients rapidly, before the acquired immune system can respond, underscoring the importance of the innate response. The innate activity of pulmonary surfactant proteins A (SP-A) and D (SP-D) forms a front line defense against inhaled pathogens. SP-D targets IAV through lectin-based recognition of high-mannose glycans attached to specific glycosylation sites on viral hemagglutinin (HA) and neuraminidase (NA). This recognition drives HA binding, NA inhibition, and viral aggregation and neutralization. SP-A and glycosylated SP-D variants utilize different mechanisms involving sialic acid recognition by HA. Our studies aim to determine the molecular basis of these mechanisms. Since growing crystals of large complexes that are heterogeneously glycosylated like the HA/SP-D or HA/SP-A complexes is difficult, we have undertaken computational studies to model the interactions. Crystal structures of HA, SP-A, and SP-D with small saccharide ligands offer starting points for modeling full length complex type or high-mannose glycosylation using low energy sugar chain conformations derived from solution studies. Further computational approaches are used to obtain an ensemble of potential complex structures. Analysis of these structures can give insights into the mechanisms of inhibition of SP-D and SP-A variants, as well as the specificity of SP-D and SP-A for certain glycoforms of HA. Measurement of the differences in glycosylation site occupation and the glycans residing on HA and SP-A or SP-D is an important adjunct to the molecular modeling. A complete strategy based on liquid chromatography/tandem mass spectrometry analysis is underway to investigate the different glycosite and glycoforms present.

Surface-bound myeloperoxidase is a ligand for recognition of late apoptotic neutrophils by human lung surfactant proteins A and D

Surfactant proteins A (SP-A) and D (SP-D), both members of the collectin family, play a well established role in apoptotic cell recognition and clearance. Recent in vitro data show that SP-A and SP-D interact with apoptotic neutrophils in a distinct manner. SP-A and SP-D bind in a Ca(2+)-dependent manner to viable and early apoptotic neutrophils whereas the much greater interaction with late apoptotic neutrophils is Ca(2+)-independent. Cell surface molecules on the apoptotic target cells responsible for these interactions had not been identified and this study was done to find candidate target molecules. Myeloperoxidase (MPO), a specific intracellular defense molecule of neutrophils that becomes exposed on the outside of the cell upon apoptosis, was identified by affinity purification, mass-spectrometry and western blotting as a novel binding molecule for SP-A and SP-D. To confirm its role in recognition, it was shown that purified immobilised MPO binds SP-A and SP-D, and that MPO is surface-exposed on late apoptotic neutrophils. SP-A and SP-D inhibit binding of an anti-MPO monoclonal Ab to late apoptotic cells. Fluorescence microscopy confirmed that anti-MPO mAb and SP-A/SP-D colocalise on late apoptotic neutrophils. Desmoplakin was identified as a further potential ligand for SP-A, and neutrophil defensin as a target for both proteins.

Review: Gp-340/DMBT1 in mucosal innate immunity

Deleted in Malignant Brain Tumour 1 (DMBT1) is a gene that encodes alternatively spliced proteins involved in mucosal innate immunity. It also encodes a glycoprotein with a molecular mass of 340 kDa, and is referred to as gp-340 (DMBT1(gp340)) and salivary agglutinin (DMBT1(SAG)). DMBT1(gp340) is secreted into broncho-alveolar surface lining fluid whereas DMBT(SAG) is present in the saliva. The two molecules were shown to be identical and both interact with and agglutinate several Gram-negative and Gram-positive bacteria including Streptococcus mutans, a bacterium responsible for caries in the oral cavity. DMBT1(gp340) interacts with surfactant proteins A and D (SP-D). DMBT1(gp340) and SP-D can individually and together interact and agglutinate influenza A virus. DMBT1(gp340) also binds to HIV-1 and facilitates transcytosis of the virus into epithelial cells. DMBT1 binds to a variety of other host proteins, including serum and secretory IgA, C1q, lactoferrin, MUC5B and trefoil factor 2 (TFF2), all molecules with involvement in innate immunity and/or wound-healing processes. Recent generation of Dmbt1-deficient mice has provided the research field of DMBT1 with a model that allows research to progress from in vitro studies to in vivo functional studies of the multifunctional proteins encoded by the DMBT1 gene.

Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth

Pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D), play important roles in innate immunity of the lung. Legionella pneumophila is a bacterial respiratory pathogen that can replicate within macrophages and causes opportunistic infections. L. pneumophila possesses cytolytic activity, resulting from insertion of pores in the macrophage membrane upon contact. We examined whether pulmonary collectins play protective roles against L. pneumophila infection. SP-A and SP-D bound to L. pneumophila and its lipopolysaccharide (LPS) and inhibited the bacterial growth in a Ca(2+)-dependent manner. The addition of LPS in the culture blocked the inhibitory effects on L. pneumophila growth by the collectins, indicating the importance of LPS-collectin interaction. When differentiated THP-1 cells were infected with L. pneumophila in the presence of SP-A and SP-D, the number of permeable cells was significantly decreased, indicating that pulmonary collectins inhibit pore-forming activity of L. pneumophila. The number of live bacteria within the macrophages on days 1-4 after infection was significantly decreased when infection was performed in the presence of pulmonary collectins. The phagocytosis experiments with the pH-sensitive dye-labeled bacteria revealed that pulmonary collectins promoted bacterial localization to an acidic compartment. In addition, SP-A and SP-D significantly increased the number of L. pneumophila co-localized with LAMP-1. These results indicate that pulmonary collectins protect macrophages against contact-dependent cytolytic activity of L. pneumophila and suppress intracellular growth of the phagocytosed bacteria. The promotion of lysosomal fusion with Legionella-containing phagosomes constitutes a likely mechanism of L. pneumophila growth suppression by the collectins.

The human lung surfactant proteins A (SP-A) and D (SP-D) interact with apoptotic target cells by different binding mechanisms

The role of the lung surfactant proteins SP-A and SP-D in immune defence is well established. They bind to foreign organisms that invade the lungs and target them for phagocytic clearance by resident alveolar macrophages. SP-A and SP-D also bind to various apoptotic cells and facilitate their phagocytic uptake. To date, the molecular mechanisms by which the lung surfactant proteins interact with apoptotic cells and phagocytes are poorly understood. The aims of this study were to investigate further the interactions between SP-A and SP-D and apoptotic cells using human neutrophils and Jurkat cells as model systems. Specifically the binding behaviour of SP-A and SP-D with viable, early apoptotic and late apoptotic cells was investigated and compared. SP-A and SP-D show very distinct binding to the various cell types. SP-A bound to viable and early apoptotic cells in a predominantly Ca 2+-dependent manner but the interaction with late apoptotic cells was Ca 2+-independent, suggesting involvement of other than the lectin- or Ca 2+-binding sites. This was consistent for neutrophils and Jurkat cells. SP-D in contrast, did not interact with viable and early apoptotic Jurkat cells but strongly and in a Ca 2+-independent manner with late apoptotic Jurkat cells. SP-D-binding to viable and early apoptotic neutrophils was inhibited by maltose and ethylene-diamin-tetra-acetate (EDTA), suggesting lectin-binding site involvement whereas the binding to late apoptotic neutrophils was predominantly Ca 2+-independent. These results represent a detailed study of the binding behaviour of SP-A and SP-D with different cell types and stages of viability. The mechanisms of these interactions appear to involve preferential recognition of different ligands on the apoptotic cell surface, which may include nucleic acid, phospholipid, protein and glycan structures.

The Alveolar Epithelium and Pulmonary Fibrosis

Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse pulmonary parenchymal diseases that are comprised of seven distinct clinical and pathological entities. Idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP) represent two of the most prevalent members of the disease group with major differences in their pathogenesis, clinical course and prognosis. IPF is a refractory and lethal IIP characterized by fibroblast prolifera- tion, deposition of extracellular matrix (ECM) and progressive lung scarring. The incidence of IPF is estimated at 15 to 40 cases per 100,000 per year, and the mean survival from the time of diagnosis is 3 to 5 years regardless of treatment. While its pathogenesis is incompletely understood, the currently accepted paradigm proposes that injury of the alveolar epithe- lium is followed by a burst of pro-inflammatory and fibroproliferative mediators that invoke responses associated with dysregulated repair of the damaged alveolar epithelium. Recently, there have been studies suggesting that the activation of the alveolar epithelial cells (AECs) may play an active role in the pathogenesis of pulmonary fibrosis. Here, we review the advances in recent studies on the role of the alveolar epithelium in pulmonary fibrosis. AECS: A BRIEF OVERVIEW OF STRUCTURE AND PHYSIOLOGICAL FUNCTIONS Two types of AECs populate the alveolar epithelium in normal adult lungs, alveolar epithelial type I (AT I) and al- veolar epithelial type II (AT II) cells. AT I pneumocytes comprise 40% of the AECs and cover 90% of the internal surface area of the lung. AT I cells are highly attenuated and form an interface with pulmonary capillaries that are inti- mately involved in gas exchange. These cells also take part in peptide and amino acid transportation across the lung by pinocytosis and transporter-mediated transport (1). Recently, AT I cells have been shown to be also important in the trans- portation of water and sodium across the lung (2, 3). AT II cells, on the other hand, AT II cells make up 16% of the parenchymal cells in the lung and account for only 5% of the alveolar surface. These cells are cuboidal cells that are situated between AT I cells and they contain characteristic lamellar bodies and apical microvilli. AT II cells synthesize, store and secrete the pulmonary surfactant (PS), which con- sists of lipids and their associated proteins and whose func- tion is to reduce the surface tension of the lung alveolus and prevent it from collapse or overdistension with respiration. AT II cells also regulate alveolar fluid balance in normal lungs and during the resolution of pulmonary edema (4) and the pathogenesis of acute lung injury with pulmonary edema is associated with an insufficient number of AT II cells and transportation of water into the lung alveolus. Recently, AT II cells have been shown to synthesize and secrete immuno- modulatory proteins important for host defense, including surfactant proteins A (SP-A) and D (SP-D) (5). SP-A can combine with lipid A in the lipopolysaccharide on the sur- face of bacterium and it also regulates the activities of

Surfactant proteins A and D in human spermatozoa

Surfactant proteins A (SP-A) and D (SP-D) belong to the collectin family and play pivotal roles in the innate immunity of the lung. Pulmonary collectins directly bind with broad specificities to a variety of microorganism and possess anti-microbial effects. Today, both SP-A and SP-D are increasingly recognized as molecules involved in the host defense system of several organs, and their expression has been detected with RT-PCR in many mucosal surfaces in human tissues, including kidney, brain and testis.

Surfactant protein A and surfactant protein D variation in pulmonary disease

Surfactant proteins A (SP-A) and D (SP-D) have been implicated in pulmonary innate immunity. The proteins are host defense lectins, belonging to the collectin family which also includes mannan-binding lectin (MBL). SP-A and SP-D are pattern-recognition molecules with the lectin domains binding preferentially to sugars on a broad spectrum of pathogen surfaces and thereby facilitating immune functions including viral neutralization, clearance of bacteria, fungi and apoptotic and necrotic cells, modulation of allergic reactions, and resolution of inflammation. SP-A and SP-D can interact with receptor molecules present on immune cells leading to enhanced microbial clearance and modulation of inflammation. SP-A and SP-D also modulate the functions of cells of the adaptive immune system including dendritic cells and T cells.Studies on SP-A and SP-D polymorphisms and protein levels in bronchoalveolar lavage and blood have indicated associations with a multitude of pulmonary inflammatory diseases. In addition, accumulating evidence in mouse models of infection and inflammation indicates that recombinant forms of the surfactant proteins are biologically active in vivo and may have therapeutic potential in controlling pulmonary inflammatory disease. The presence of the surfactant collectins, especially SP-D, in non-pulmonary tissues, such as the gastrointestinal tract and genital organs, suggest additional actions located to other mucosal surfaces. The aim of this review is to summarize studies on genetic polymorphisms, structural variants, and serum levels of human SP-A and SP-D and their associations with human pulmonary disease.

In defense of the lung: surfactant protein A and surfactant protein D

The lung is repeatedly exposed to inhaled particles and pathogens that are cleared by the actions of a multi-component innate host defense system. The pulmonary collectins--surfactant proteins A (SP-A) and D (SP-D)--play important roles in innate host defense by binding and clearing invading microbes from the lung. SP-A and SP-D also influence surfactant homeostasis, contributing to the physical structures of lipids in the alveoli and to the regulation of surfactant function and metabolism. In addition to binding and opsonizing infectious pathogens, SP-A and SP-D bind to the surfaces of host defense cells, promoting or inhibiting immune cell activity through multiple cellular pathways. As a consequence of their physiologic functions, SP-A- and SP-D-dependent pathways are targets for clinical therapies designed to limit the proliferation of microoorgansims and to ameliorate inflammation following pulmonary infection.

Ontogeny of protein expression of CD208, surfactant protein A and D, thyroid transcription factor‐1 (TTF‐1), and cell proliferation antigen (Ki‐67) in lung epithelia of pre‐ and full‐term lambs

Children born preterm have an increased susceptibility to respiratory syncytial virus (RSV) compared to those born full-term. RSV initially infects and damages epithelial cells, which are important for adaptive and innate immune responses such as expression of surfactant proteins A (SP-A) and D (SP-D) which are known to protect against RSV infection. However, the extent of expression preterm, as well as the effect of cell proliferation and differentiation has on the production of these proteins have not been determined. SP-A and D protein production as well as the extent of cell proliferation (Ki67 expression) and differentiation (CD208 antigen cells) and Thyroid Transcription Factor-1 (TTF-1; a SP transcription factor) were determined by immunohistochemistry in lung from preterm (80% gestation), full-term, and post-term (15 days of age) lambs. Cell differentiation (CD208+ cells) increased significantly with age; however, no significant changes were seen with proliferation (Ki67 antigen), SP-AD, or TTF-1. SP-AD expression was present in bronchial and bronchiolar epithelial cells, and occasional alveolar epithelial cells in all age groups, TTF-1 was present in non-ciliated airway cells and type II cells as described previously. This work suggests that cell differentiation increases with gestation and that SP-A and D production is present in bronchioles and alveoli in late gestation and at birth. Supported NIH NIAID Awards 5R01AI062787-02 and 5K08AI055499-03, USDA/CSREES/NRI-CGP 2003-35204-13492, and the JG Salsbury Endowment.

Pulmonary Surfactant Proteins A and D: Innate Immune Functions and Biomarkers for Lung Diseases

Pulmonary surfactant, a complex of lipids and proteins, functions to keep alveoli from collapsing at expiration. Surfactant proteins A (SP-A) and D (SP-D) belong to the collectin family and play pivotal roles in the innate immunity of the lung. Pulmonary collectins directly bind with broad specificities to a variety of microorganism and possess anti-microbial effects. These proteins also exhibit both inflammatory and anti-inflammatory functions, which occur through interactions with pattern recognition receptors including Toll-like receptor and CD14, signal inhibitory regulatory protein alpha and a receptor complex of calreticulin and CD91. The collectins enhance phagocytosis of microbes by macrophages through opsonic and/or non-opsonic activities. The proteins stimulate cell surface expression of phagocytic receptors including scavenger receptor A and mannose receptor. Since the expression of SP-A and SP-D is abundant and restricted within the lung, the proteins are now clinically used as biomarkers for lung diseases. The levels of SP-A and SP-D in bronchoalveolar lavage fluids, amniotic fluids, tracheal aspirates and pleural effusions reflect alterations in alveolar compartments and epithelium, and lung maturity. The determination of SP-A and SP-D in sera is a non-invasive and useful tool for understanding some pathological changes of the lung in the diseases, including pulmonary fibrosis, collagen vascular diseases complicated with interstitial lung disease, pulmonary alveolar proteinosis, acute respiratory distress syndrome and radiation pneumonitis.