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Surfactant protein D (SP-D) is a collectin protein synthesized by alveolar type II cells in the lungs. SP-D participates in the innate immune defense of the lungs by helping to clear infectious pathogens and modulating the immune response. SP-D has shown an anti-inflammatory role by down-regulating the release of pro-inflammatory mediators in different signaling pathways such as the TLR4, decreasing the recruitment of inflammatory cells to the lung, and modulating the oxidative metabolism in the lungs. Recombinant human SP-D (rhSP-D) has been successfully produced mimicking the structure and functions of native SP-D. Several in vitro and in vivo experiments using different animal models have shown that treatment with rhSP-D reduces the lung inflammation originated by different insults, and that rhSP-D could be a potential treatment for bronchopulmonary dysplasia (BPD), a rare disease for which there is no effective therapy up to date. BPD is a complex disease in preterm infants whose incidence increases with decreasing gestational age at birth. Lung inflammation, which is caused by different prenatal and postnatal factors like infections, lung hyperoxia and mechanical ventilation, among others, is the key player in BPD. Exacerbated inflammation causes lung tissue injury that results in a deficient gas exchange in the lungs of preterm infants and frequently leads to long-term chronic lung dysfunction during childhood and adulthood. In addition, low SP-D levels and activity in the first days of life in preterm infants have been correlated with a worse pulmonary outcome in BPD. Thus, SP-D mediated functions in the innate immune response could be critical aspects of the pathogenesis in BPD and SP-D could inhibit lung tissue injury in this preterm population. Therefore, administration of rhSP-D has been proposed as promising therapy that could prevent BPD.

Abstract Background Asthma in horses is associated with nonspecific respiratory clinical signs and may be manifested only as exercise intolerance. Its diagnosis relies on bronchoalveolar lavage fluid (BALF) cytology in the presence of compatible clinical signs. The identification of blood biomarkers for this condition would facilitate diagnosis in the field, because there are regional areas where BAL is not routinely performed in clinical practice. Objective Identification of blood biomarkers for the diagnosis of asthma in horses. Animals Fourteen horses with asthma with increased neutrophil numbers in BALF (neutrophilic asthma), 9 healthy control horses, and 10 horses with other pathologic conditions (pathologic controls). Methods Physical examination, clinical score, hematology, and BALF cytology (in a subset of horses) were performed. Serum concentrations of surfactant protein D (SP-D), haptoglobin, and secretoglobin (SCGB) were measured using commercial ELISA assays. Results Serum concentration of SP-D > 43 ng/mL, serum concentration of haptoglobin >5730 ng/mL, and serum concentration of SCGB <19 ng/mL allowed differentiation of horses with neutrophilic asthma from horses of the control groups (healthy and pathologic) with sensitivity of 55, 95, and 75%, and specificity of 67, 28, and 60%, respectively. Specificity of 100% and sensitivity of 45% were obtained with the combination of SP-D, haptoglobin, and SCGB at the serum concentrations indicated above. Specificity of 95% and sensitivity of 45% were obtained with the combination of SP-D and SCGB serum concentrations. Conclusions and Clinical Importance Haptoglobin, SCGB, and SP-D may be diagnostic aids in horses with clinical signs of lower airway disease and neutrophilic pulmonary inflammation.

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.

Deoxynivalenol (DON) is a highly abundant mycotoxin that exerts many adverse effects on humans and animals. Much effort has been made to control DON in the past, and bio-transformation has emerged as the most promising method. However, useful and effective application of bacterial bio-transformation for the purpose of inhibiting DON remains urgently needed. The current study isolated a novel DON detoxifying bacterium, Slackia sp. D-G6 (D-G6), from chicken intestines. D-G6 is a Gram-positive, non-sporulating bacterium, which ranges in size from 0.2–0.4 μm × 0.6–1.0 μm. D-G6 de-epoxidizes DON into a non-toxic form called DOM-1. Optimum conditions required for degradation of DON are 37–47 °C and a pH of 6–10 in WCA medium containing 50% chicken intestinal extract. Besides DON detoxification, D-G6 also produces equol (EQL) from daidzein (DZN), which shows high estrogenic activity, and prevents estrogen-dependent and age-related diseases effectively. Furthermore, the genome of D-G6 was sequenced and characterized. Thirteen genes that show potential for DON de-epoxidation were identified via comparative genomics. In conclusion, a novel bacterium that exhibits the dual function of detoxifying DON and producing the beneficial natural estrogen analogue, EQL, was identified.

SARS-CoV-2 infection of host cells is driven by binding of the SARS-CoV-2 spike-(S)-protein to lung type II pneumocytes, followed by virus replication. Surfactant protein SP-D, member of the front-line immune defense of the lungs, binds glycosylated structures on invading pathogens such as viruses to induce their clearance from the lungs. The objective of this study is to measure the pulmonary SP-D levels in COVID-19 patients and demonstrate the activity of SP-D against SARS-CoV-2, opening the possibility of using SP-D as potential therapy for COVID-19 patients. Pulmonary SP-D concentrations were measured in bronchoalveolar lavage samples from patients with corona virus disease 2019 (COVID-19) by anti-SP-D ELISA. Binding assays were performed by ELISAs. Protein bridge and aggregation assays were performed by gel electrophoresis followed by silver staining and band densitometry. Viral replication was evaluated in vitro using epithelial Caco-2 cells. Results indicate that COVID-19 patients (n = 12) show decreased pulmonary levels of SP-D (median = 68.9 ng/mL) when compared to levels reported for healthy controls in literature. Binding assays demonstrate that SP-D binds the SARS-CoV-2 glycosylated spike-(S)-protein of different emerging clinical variants. Binding induces the formation of protein bridges, the critical step of viral aggregation to facilitate its clearance. SP-D inhibits SARS-CoV-2 replication in Caco-2 cells (EC90 = 3.7 μg/mL). Therefore, SP-D recognizes and binds to the spike-(S)-protein of SARS-CoV-2 in vitro, initiates the aggregation, and inhibits viral replication in cells. Combined with the low levels of SP-D observed in COVID-19 patients, these results suggest that SP-D is important in the immune response to SARS-CoV-2 and that rhSP-D supplementation has the potential to be a novel class of anti-viral that will target SARS-CoV-2 infection.

Neutrophil extracellular traps (NETs) are beneficial antimicrobial defense structures that can help fight against invading pathogens in the host. However, recent studies reveal that NETs exert adverse effects in a number of diseases including those of the lung. Many inflammatory lung diseases are characterized with a massive influx of neutrophils into the airways. Neutrophils contribute to the pathology of these diseases. To date, NETs have been identified in the lungs of cystic fibrosis (CF), acute lung injury (ALI), allergic asthma, and lungs infected with bacteria, virus, or fungi. These microbes and several host factors can stimulate NET formation, or NETosis. Different forms of NETosis have been identified and are dependent on varying types of stimuli. All of these pathways however appear to result in the formation of NETs that contain DNA, modified extracellular histones, proteases, and cytotoxic enzymes. Some of the NET components are immunogenic and damaging to host tissue. Innate immune collectins, such as pulmonary surfactant protein D (SP-D), bind NETs, and enhance the clearance of dying cells and DNA by alveolar macrophages. In many inflammatory lung diseases, bronchoalveolar SP-D levels are altered and its deficiency results in the accumulation of DNA in the lungs. Some of the other therapeutic molecules under consideration for treating NET-related diseases include DNases, antiproteases, myeloperoxidase (MPO) inhibitors, peptidylarginine deiminase-4 inhibitors, and anti-histone antibodies. NETs could provide important biological advantage for the host to fight against certain microbial infections. However, too much of a good thing can be a bad thing. Maintaining the right balance of NET formation and reducing the amount of NETs that accumulate in tissues are essential for harnessing the power of NETs with minimal damage to the hosts.

Surfactant protein D (SP-D) is a C-type lectin that was originally discovered as a lung surfactant associated phospholipid recognising protein. It was originally shown to be of great importance in surfactant turnover and homeostasis in conjunction with another hydrophilic surfactant protein i.e. SP-A. In addition, it was found to agglutinate bacteria in suspension and likely a key defence molecule in the lungs. Since its early days of characterization in 1990s, SP-D has turned out to be a central player in the mucosal immunity as pulmonary as well as extrapulmonary innate immune molecule. The most exciting development has been characterization of its C-type lectin or carbohydrate recognition domain (CRDs) that exists in a homotrimeric form in native as well as recombinant versions. SP-D has a range of strategies to recognise pathogen-associated molecular patterns (PAMPs) and thus act as a soluble PAMP-recognizing receptor (PRR), and subsequent destruction of the pathogens directly, or indirectly via phagocytic cells. SP-D also recognizes a range of allergens, competes out with specific IgE antibodies, and downregulates histamine release by basophils and mast cells. These anti-microbial and anti-allergic properties of SP-D have been validated by in vivo murine models of infection and allergy. The SP-D gene deficient mice exhibit remarkable phenotypes where lungs are leaky, showing features of fibrosis and emphysema. One of the seminal discoveries in the field has been the observation that activated eosinophils (and other immune cells) can be induced into apoptotic pathways by SP-D. This raised the possibility that SP-D can be an innate immune surveillance molecule. Studies have revealed the ability of a recombinant fragment of human SP-D containing homotrimeric neck and CRD region to induce apoptosis via intrinsic as well as extrinsic pathways; in addition, it also seems capable of interfering with epithelial-to-mesenchymal transition. These studies have opened up enormous possibilities for setting up pre-clinical and clinical trials.

This study evaluates the usefulness of serum KL-6, SP-D and TGF-β1 levels in assessing lung impairment and predicting interstitial lung disease (ILD) short-term progression in patients with interstitial pneumonia with autoimmune features (IPAF). A total of 24 patients with IPAF, 21 with connective tissue disease-associated ILD (CTD-ILD) and 23 with CTD without ILD were followed for 1 year. Serum levels of KL-6, SP-D and TGF-β1 were measured and their associations with disease severity and progression were analysed. KL-6, SP-D and TGF-β1 levels were significantly higher in IPAF and CTD-ILD patients compared to CTD without ILD (p < 0.0001, p = 0.0005 and p = 0.0001, respectively). KL-6 (r = 0.45, p = 0.002) and SP-D (r = 0.35, p = 0.02) levels correlated with lung involvement in HRCT in the ILD group. In IPAF, KL-6 levels correlated with pulmonary function tests (FVC%, TLCO%, and 6MWD) and SpO2, while SP-D correlated with 6MWD and SpO2. In CTD-ILD, KL-6 and SP-D levels were positively correlated with BAL cell count (KL-6: r = 0.58, p = 0.04; SP-D: r = 0.63, and p = 0.02). KL-6 also showed a negative correlation with the time since symptom onset (r = −0.51, p = 0.02). No significant associations were found between the baseline biomarker levels and ILD progression risk. KL-6 and SP-D may serve as potential biomarkers for assessing lung impairment in IPAF, though their predictive value for short-term prognosis remains uncertain.

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.

Background This case–control study aimed to compare lead (Pb), cadmium (Cd), and arsenic (As) levels in neonates with respiratory distress syndrome (NRDS) with those levels in normal neonates and tested their associations with the severity of NRDS indicated by the levels of serum surfactant protein D (SP-D) and cord blood cardiac troponin I (CTnI), and high-sensitive C-reactive protein (hs-CRP). Methods The study included two groups: G1 (60 healthy neonates) and G2 (100 cases with NRDS). Cord blood Pb, erythrocytic Cd (E-Cd), neonatal scalp hair As (N-As), maternal urinary Cd (U-Cd), and arsenic (U-As) were measured by a Thermo Scientific iCAP 6200, while CTnI, hs-CRP, and SP-D by their corresponding ELISA kits. Results The levels of cord blood Pb, E-Cd, N-As, U-Cd, U-As, SP-D, CTnI, and hs-CRP were significantly higher in G2 than G1 ( p  = 0.019, 0.040, 0.003, 0.010, 0.011, < 0.001, 0.004, < 0.001, respectively). While the birth weight, and APGAR score at 1, 5 and 10 min were significantly lower in G2 than G1 ( p  = 0.002, < 0.001, < 0.001, < 0.001, respectively). The levels of the studied heavy metals correlated positively with the levels of SP-D, CTnI, and hs-CRP. Conclusion Heavy metals toxicity may be accused to be one of the causes of NRDS especially if other apparent causes are not there. Measuring and follow-up of heavy metal levels should be considered during pregnancy.