A Comprehensive Consolidation of Data on the Relationship Between Surfactant Protein-B (SFTPB) Polymorphisms and Susceptibility to Bronchopulmonary Dysplasia.

BACKGROUND: This meta-analysis aims to evaluate the potential link between common variations in the Surfactant Protein-B (SFTPB) gene and the risk of bronchopulmonary dysplasia (BPD) in preterm neonates. METHODS: All pertinent articles published prior to February 1, 2024, in PubMed, Web of Science, EMBASE, CNKI, and Scopus databases were reviewed. RESULTS: Nineteen case-control studies involving 1149 BPD cases and 1845 non-BPD controls, were analyzed. Combined data indicated a significant link between SFTPB -18 A > C and Intron 4 VNTR polymorphisms with increased BPD susceptibility, while the 1580 C > T polymorphism provides a protective impact on BPD initiation. CONCLUSIONS: Pooled data indicated a significant association between SFTPB -18 A > C and Intron 4 VNTR polymorphisms with increased BPD risk, whereas the 1580 C > T polymorphism confers protection. These findings suggest a genetic susceptibility to BPD, underscoring the complex interplay of different genetic elements in its development.

Association of SNP-SNP interactions of surfactant protein genes with severity of respiratory syncytial virus infection in children.

The severity of respiratory syncytial virus (RSV) may be linked to host genetic susceptibility. Surfactant protein (SP) genetic variants have been associated with RSV severity, but the impact of SNP-SNP (single nucleotide polymorphism) interactions remains unexplored. Therefore, we employed a novel statistical model to investigate the association of SNP-SNP interactions of SFTP genes with RSV severity in two and three-interaction models. We analyzed available genotype and clinical data from prospectively enrolled 405 children diagnosed with RSV, categorizing them into moderate or severe RSV groups. Using Wang's statistical model, we studied significant associations of SNP-SNP interactions with RSV severity in a case-control design. We observed, 1) association of three interactions with increased risk of severe RSV in a two-SNP model. One intragenic interaction was between SNPs of SFTPA2, and the other two were intergenic, involving SNPs of hydrophilic and hydrophobic SPs alone. 2) association of 22 interactions with RSV severity in a three-SNP model. Among these, 20 were unique, with 12 and 10 interactions associated with increased or decreased risk of RSV severity, respectively, and included at least one SNP of either SFTPA1 or SFTPA2. All interactions were intergenic, except one among SNPs of SFTPA1. The remaining interactions were either among SNPs of hydrophilic SPs alone (n=8) or among SNPs of both hydrophilic or hydrophobic SPs (n=11). Our findings indicate that SNPs of all SFTPs may contribute to genetic susceptibility to RSV severity. However, the predominant involvement of SFTPA1 and/or SFTPA2 SNPs in these interactions underscores their significance in RSV severity.

Prognostic performance of Krebs von den Lungen-6, surfactant protein A, surfactant protein D levels in the serum and bronchoalveolar lavage fluid in chronic fibrosing interstitial pneumonia: a retrospective study.

BACKGROUND: The serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP. METHODS: Among 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups. RESULTS: Among the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan-Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses. CONCLUSIONS: Our results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP.

Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease.

BACKGROUND: Childhood interstitial lung disease (chILD) encompasses a group of rare heterogeneous respiratory conditions associated with significant morbidity and mortality. Reports suggest that many patients diagnosed with chILD continue to have potentially progressive or fibrosing disease into adulthood. Over the last decade, the spectrum of conditions within chILD has widened substantially, with the discovery of novel entities through advanced genetic testing. However, most evidence is often limited to small case series, with reports disseminated across an array of subspecialty, clinical and molecular journals. In particular, the frequency, management and outcome of paediatric pulmonary fibrosis is not well characterised, unlike in adults, where clear diagnosis and treatment guidelines are available. METHODS AND RESULTS: This review assesses the current understanding of pulmonary fibrosis in chILD. Based on registry data, we have provisionally estimated the occurrence of fibrosis in various manifestations of chILD, with 47 different potentially fibrotic chILD entities identified. Published evidence for fibrosis in the spectrum of chILD entities is assessed, and current and future issues in management of pulmonary fibrosis in childhood, continuing into adulthood, are considered. CONCLUSIONS: There is a need for improved knowledge of chILD among pulmonologists to optimise the transition of care from paediatric to adult facilities. Updated evidence-based guidelines are needed that incorporate recommendations for the diagnosis and management of immune-mediated disorders, as well as chILD in older children approaching adulthood.

Humanized L184Q Mutated Surfactant Protein C Gene Alters Alveolar Type 2 Epithelial Cell Fate.

Alveolar type 2 epithelial (AT2) cells synthesize surfactant protein C (SPC) and repair an injured alveolar epithelium. A mutated surfactant protein C gene (SftpcL184Q, Gene ID: 6440) in newborns has been associated with respiratory distress syndrome and pulmonary fibrosis. However, the underlying mechanisms causing Sftpc gene mutations to regulate AT2 lineage remain unclear. We utilized three-dimensional (3D) feeder-free AT2 organoids in vitro to simulate the alveolar epithelium and compared AT2 lineage characteristics between WT (C57BL/6) and SftpcL184Q mutant mice using colony formation assays, immunofluorescence, flow cytometry, qRT-PCR, and Western blot assays. The AT2 numbers were reduced significantly in SftpcL184Q mice. Organoid numbers and colony-forming efficiency were significantly attenuated in the 3D cultures of primary SftpcL184Q AT2 cells compared to those of WT mice. Podoplanin (PDPN, Alveolar type 1 cell (AT1) marker) expression and transient cell count was significantly increased in SftpcL184Q organoids compared to in the WT mice. The expression levels of CD74, heat shock protein 90 (HSP90), and ribosomal protein S3A1 (RPS3A1) were not significantly different between WT and SftpcL184Q AT2 cells. This study demonstrated that humanized SftpcL184Q mutation regulates AT2 lineage intrinsically. This regulation is independent of CD74, HSP90, and RPS3A1 pathways.

Exploring the associations between elevated plasma SP-D levels and OSCAR gene expression as potential biomarkers in patients with COPD: a cross-sectional study.

Background: Chronic obstructive pulmonary disease (COPD) imposes a substantial burden on patients and healthcare systems. Spirometry is the most widely used test to diagnose the disease; however, a surrogate marker is required to predict the disease pattern and progression. Objectives: The aim of the current study was to explore the association of elevated levels of plasma surfactant protein D (SP-D) with gene expression of osteoclast-associated receptor (OSCAR) and lung functions as potential diagnostic biomarkers of COPD. Methods: This cross-sectional study employed convenience sampling. As men compose the majority of patients in the outpatient department and with smoking being common among Pakistani men, choosing men offered a representative sample. Using a post-bronchodilator forced expiratory volume in the first second (FEV1) to a forced vital capacity (FVC) of less than 0.70 (FEV1/FVC <0.7), COPD patients were diagnosed on spirometry (n = 41). Controls were healthy individuals with FEV1/FVC >0.7 (n = 41). Plasma SP-D levels were measured using an enzyme-linked immunosorbent assay (ELISA). The gene expression of OSCAR was determined by real-time polymerase chain reaction (qPCR) and subsequently analyzed by the threshold cycle (Ct) method. Statistical Package for Social Sciences (SPSS) version 20 was used for statistical analysis. Results: The mean BMI of controls (25.66 ± 4.17 kg/m2) was higher than that of cases (23.49 ± 2.94 kg/m2 (p = .008)). The median age of controls was 49 years (interquartile range (IQR) 42.0-65.0 years) and that of cases was 65 years (IQR = 57.50-68.50). SP-D concentration was not significantly higher in COPD patients [4.96 ng/mL (IQR 3.26-7.96)] as compared to controls [3.64 ng/mL (IQR 2.60-8.59)] (p = .209). The forced expiratory ratio (FEV1/FVC) and FEV1 were related to gene expression of OSCAR (p = <.001). The gene expression of OSCAR was significantly related to SP-D (p = .034). A multiple regression model found FEV1 and FVC to have a significant effect on the gene expression of OSCAR (p-values <0.001 and 0.001, respectively). Conclusion: Gene expression of OSCAR was increased in COPD patients and related directly to SP-D levels and inversely to lung functions in cohort of this study, suggesting that OSCAR along with SP-D may serve as a diagnostic biomarker of COPD.

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis.

Introduction: Genetic mutations in critical nodes of pulmonary epithelial function are linked to the pathogenesis of pulmonary fibrosis (PF) and other interstitial lung diseases. The slow progression of these pathologies is often intermitted and accelerated by acute exacerbations, complex non-resolving cycles of inflammation and parenchymal damage, resulting in lung function decline and death. Excess monocyte mobilization during the initial phase of an acute exacerbation, and their long-term persistence in the lung, is linked to poor disease outcome. Methods: The present work leverages a clinical idiopathic PF dataset and a murine model of acute inflammatory exacerbations triggered by mutation in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene to spatially and phenotypically define monocyte/macrophage changes in the fibrosing lung. Results: SP-C mutation triggered heterogeneous CD68+ macrophage activation, with highly active peri-injured cells relative to those sampled from fully remodeled and healthy regions. Ingenuity pathway analysis of sorted CD11b-SigF+CD11c+ alveolar macrophages defined asynchronous activation of extracellular matrix re-organization, cellular mobilization, and Apolipoprotein E (Apoe) signaling in the fibrosing lung. Cell-cell communication analysis of single cell sequencing datasets predicted pro-fibrogenic signaling (fibronectin/Fn1, osteopontin/Spp1, and Tgfb1) emanating from Trem2/TREM2 + interstitial macrophages. These cells also produced a distinct lipid signature from alveolar macrophages and monocytes, characterized by Apoe expression. Mono- and di-allelic genetic deletion of ApoE in SP-C mutant mice had limited impact on inflammation and mortality up to 42 day after injury. Discussion: Together, these results provide a detailed spatio-temporal picture of resident, interstitial, and monocyte-derived macrophages during SP-C induced inflammatory exacerbations and end-stage clinical PF, and propose ApoE as a biomarker to identify activated macrophages involved in tissue remodeling.

Impact of acute stress disorder on surfactant protein D levels in acute lung injury.

Many people sustain acute lung injuries in road traffic collisions, but few studies have dealt with such injuries in live models. This study aimed to explore the basic pathophysiological and inflammatory changes in adult rabbits following acute thoracic trauma. We randomly assigned 50 rabbits to control and injury groups. Rabbits in the injury group were subjected to right chest pressure (2600 g) using a Hopkinson bar. Measurements were taken in the control group and 0, 24, 48, and 72 h after injury in the injury group. Injury severity was evaluated in gross view; with haematoxylin and eosin (H&E) staining; and through the serum changes of tumor necrosis factor alpha (TNF-α), surfactant protein D (SP-D), and neutrophils. Secretion changes in SP-D in right lung injured tissues were estimated by western blotting and qPCR. Serum TNF-α levels increased rapidly immediately after injury, gradually recovering after 24, 48, and 72 h (p < 0.01). The percentage of neutrophils in the accompanying blood showed a consistent trend. Gross necropsy and H&E staining indicated different levels of bleeding, alveoli exudation, and inflammatory transformation after impact. ELISA depicted the same trend in circulation (F = 22.902, p < 0.01). Western blotting showed that SP-D protein levels in tissues decreased at 0 h and increased at 24, 48, and 72 h. We demonstrate the feasibility of a model of impact lung injury. Primary impact caused injury without external signs. Inflammation began immediately, and the lungs began recovering at 24, 48, and 72 h, as shown by increased SP-D levels in circulation and tissues.With complaints of ALI and inflammation, SP-D may be a potential biomarker after chest trauma.

Functional Characterisation of Surfactant Protein A as a Novel Prophylactic Means against Oncogenic HPV Infections.

Human papillomavirus (HPV) infection poses a significant health challenge, particularly in low- and middle-income countries (LMIC), where limited healthcare access and awareness hinder vaccine accessibility. To identify alternative HPV targeting interventions, we previously reported on surfactant protein A (SP-A) as a novel molecule capable of recognising HPV16 pseudovirions (HPV16-PsVs) and reducing infection in a murine cervicovaginal HPV challenge model. Building on these findings, our current study aimed to assess SP-A's suitability as a broad-spectrum HPV-targeting molecule and its impact on innate immune responses. We demonstrate SP-A's ability to agglutinate and opsonise multiple oncogenic HPV-PsVs types, enhancing their uptake and clearance by RAW264.7 murine macrophages and THP-1 human-derived immune cells. The SP-A opsonisation of HPV not only led to increased lysosomal accumulation in macrophages and HaCaT keratinocytes but also resulted in a decreased infection of HaCaT cells, which was further decreased when co-cultured with innate immune cells. An analysis of human innate immune cell cytokine profiles revealed a significant inflammatory response upon SP-A exposure, potentially contributing to the overall inhibition of HPV infection. These results highlight the multi-layered impact of SP-A on HPV, innate immune cells and keratinocytes and lay the basis for the development of alternative prophylactic interventions against diverse HPV types.

Immature Surfactant Protein Type B and Surfactant Protein Type D Correlate with Coronary Heart Disease in Patients with Type 2 Diabetes.

BACKGROUND: Different specific surfactant proteins (SPs) have been associated with various pathological conditions, not only of the respiratory system, but also more recently with cardiovascular diseases, such as heart failure. The aim of the present study was to evaluate the role of SP-A, SP-D, and the precursor protein of SP-B (proSP-B) in the pathogenesis of cardiovascular damage in patients affected by type 2 diabetes (T2D). METHODS: The study considered 31 patients with T2D (DN group), 34 patients with both T2D and coronary heart disease (CHD) (DC group), and 30 patients without diabetes but with a diagnosis of CHD (NC group). SP-A, SP-D, and proSP-B concentrations were determined in plasma samples, and were statistically compared using parametric and multivariate methods. RESULTS: Higher plasma concentrations of SP-D and proSP-B were found in patients affected by both T2D and CHD (DC group), and in patients with CHD without diabetes (NC group), in comparison to T2D patients (DN group). A significant correlation, both with linear regression (r = 0.3565, p = 0.001) and Principal Component Analysis (PCA), was found between the plasma levels of SP-D and proSP-B in the overall cohort of patients. No differences in SP-A were observed among the three groups of subjects. CONCLUSION: The present study extends the knowledge on the role of plasma SPs' levels as possible indicators of the risk of CHD being linked to T2D disease progression.

Diagnostic Performance of Plasma SP-D, KL-6, and CC16 in Acutely Hospitalised Patients Suspected of Having Community-Acquired Pneumonia-A Diagnostic Accuracy Study.

Community-acquired pneumonia is a common cause of acute hospitalisation. Identifying patients with community-acquired pneumonia among patients suspected of having the disease can be a challenge, which causes unnecessary antibiotic treatment. We investigated whether the circulatory pulmonary injury markers surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and Club cell protein 16 (CC16) could help identify patients with community-acquired pneumonia upon acute admission. In this multi-centre diagnostic accuracy study, SP-D, KL-6, and CC16 were quantified in plasma samples from acutely hospitalised patients with provisional diagnoses of community-acquired pneumonia. The area under the receiver operator characteristics curve (AUC) was calculated for each marker against the following outcomes: patients' final diagnoses regarding community-acquired pneumonia assigned by an expert panel, and pneumonic findings on chest CTs. Plasma samples from 339 patients were analysed. The prevalence of community-acquired pneumonia was 63%. AUCs for each marker against both final diagnoses and chest CT diagnoses ranged between 0.50 and 0.56. Thus, SP-D, KL-6, and CC16 demonstrated poor diagnostic performance for community-acquired pneumonia in acutely hospitalised patients. Our findings indicate that the markers cannot readily assist physicians in confirming or ruling out community-acquired pneumonia.

Risk factors for severe immune-related pneumonitis after nivolumab plus ipilimumab therapy for non-small cell lung cancer.

BACKGROUND: The efficacy of anti-CTLA-4 antibody (ipilimumab) plus anti-programmed cell death 1 antibody (nivolumab) in treating advanced non-small cell lung cancer (NSCLC) is impeded by an elevated risk of severe immune-related adverse events. However, our understanding of associations among pre-existing fibrosis, emphysematous changes, and objective indicators as predictive factors is limited for severe pneumonitis in NSCLC patients receiving this combination therapy. Thus, we retrospectively investigated these associations, including overall tumor burden, before treatment initiation in the Japanese population. METHODS: We focused on patients (n = 76) with pre-existing interstitial lung disease (ILD) to identify predictors of severe pneumonitis. Variables included age, sex, smoking status, programmed cell death ligand 1 expression, overall tumor burden, chest computed tomography-confirmed fibrosis, serum markers, and respiratory function test results. RESULTS: Severe pneumonitis was more frequent in patients with squamous cell carcinoma, fibrosis, low diffusing capacity for carbon monoxide (%DLCO), and high surfactant protein D (SP-D) level. Notably, squamous cell carcinoma, baseline %DLCO, and SP-D level were significant risk factors. Our findings revealed the nonsignificance of tumor burden (≥85 mm) in predicting severe pneumonitis, emphasizing the importance of pre-existing ILD. Conversely, in cases without pre-existing fibrosis, severe pneumonitis was not associated with %DLCO or SP-D level (93.2% vs. 91.9%, and 63.3 vs. 40.9 ng/mL, respectively) and was more common in patients with a large overall tumor burden (97.5 vs. 70.0 mm). CONCLUSION: Vigilant monitoring and early intervention are crucial for patients with squamous cell carcinoma, high SP-D level, or low %DLCO undergoing ipilimumab plus nivolumab therapy.

Expression and basic biochemical characteristics of recombinant surfactant protein D of bottlenose dolphin (Tursiopstruncatus).

We previously identified surfactant protein D (SP-D) in the bottlenose dolphin Tursiops truncatus as a unique evolutionary factor of the cetacean pulmonary immune system. In this short report, recombinant SP-D of bottlenose dolphin (dSP-D) was synthesized in mammalian cells, and its properties were analyzed in vitro. The recombinant proteins were purified using Ni-carrier or Co-carrier. Sodium dodecyl sulfate poly-acrylamide gel electrophoresis and western blotting revealed a 50 kDa major band with minor secondary bands. Enzyme-linked immunosorbent assay-like methods revealed that recombinant dSP-D bonded to gram-positive and gram-negative bacterial walls. Our findings suggest the clinical usefulness of dSP-D for cetacean pneumonia.

Unraveling the enigma: The emerging significance of pulmonary surfactant proteins in predicting, diagnosing, and managing COVID-19.

BACKGROUND: Severe cases of COVID-19 often lead to the development of acute respiratory syndrome, a critical condition believed to be caused by the harmful effects of SARS-CoV-2 on type II alveolar cells. These cells play a crucial role in producing pulmonary surfactants, which are essential for proper lung function. Specifically focusing on surfactant proteins, including Surfactant protein A (SP-A), Surfactant protein B, Surfactant protein C, and Surfactant protein D (SP-D), changes in the levels of pulmonary surfactants may be a significant factor in the pathological changes seen in COVID-19 infection. OBJECTIVE: This study aims to gain insights into surfactants, particularly their impacts and changes during COVID-19 infection, through a comprehensive review of current literature. The study focuses on the function of surfactants as prognostic markers, diagnostic factors, and essential components in the management and treatment of COVID-19. FINDING: In general, pulmonary surfactants serve to reduce the surface tension at the gas-liquid interface, thereby significantly contributing to the regulation of respiratory mechanics. Additionally, these surfactants play a crucial role in the innate immune system within the pulmonary microenvironment. Within the spectrum of COVID-19 infections, a compelling association is observed, characterized by elevated levels of SP-D and SP-A across a range of manifestations from mild to severe pneumonia. The sudden decline in respiratory function observed in COVID-19 patients may be attributed to the decreased synthesis of surfactants by type II alveolar cells. CONCLUSION: Collectin proteins such as SP-A and SP-D show promise as biomarkers, offering potential avenues for predicting and monitoring pulmonary alveolar injury in the context of COVID-19. This clarification enhances our understanding of the molecular complexities contributing to respiratory complications in severe COVID-19 cases, providing a foundation for targeted therapeutic approaches using surfactants and refined clinical management strategies.

Immature Surfactant Protein B Increases in the Serum of Patients with Calcific Severe Aortic Stenosis.

Valvular disease is a complex pathological condition that impacts countless individuals around the globe. Due to limited treatments, it is crucial to understand its mechanisms to identify new targets. Valve disease may result in pulmonary venous hypertension, which is linked to compromised functioning of the alveolar and capillary membranes and hindered gas exchange. Nonetheless, the correlation between surfactant proteins (SPs) and valve disease remains unexplored. A total of 44 patients were enrolled in this study, with 36 undergoing aortic valve replacement and 8 needing a second aortic valve substitution due to bioprosthetic valve degeneration. Ten healthy subjects were also included. The results showed that patients who underwent both the first valve replacement and the second surgery had significantly higher levels of immature SP-B (proSP-B) compared to control subjects. The levels of the extra-lung collectin SP-D were higher in patients who needed a second surgery due to bioprosthetic valve degeneration, while SP-A levels remained unchanged. The research also showed that there was no reciprocal relationship between inflammation and SP-D as the levels of inflammatory mediators did not differ between groups. The present study demonstrates that circulating proSP-B serves as a reliable marker of alveolar-capillary membrane damage in patients with valvular heart disease.

Cooperation of immune regulators Tollip and surfactant protein A inhibits influenza A virus infection in mice.

BACKGROUND: Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated. METHODS: Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h. RESULTS: Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling. CONCLUSIONS: Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection.

Surfactant protein-D, diabetes mellitus, oxidative stress, infections and inflammation on the crossroad: A Systematic review.

Objective: To review the association of surfactant protein-D with type 2 diabetes mellitus, infections, oxidative stress and inflammation, and the changes in oxidative stress markers in type 2 diabetes mellitus. METHODS: The systematic review was conducted from April to September 2022, and comprised search on PubMed, Web of Sciences, Scopus, Science Direct and Google Scholar databases for relevant studies published in English language between January 1, 2000, and June 30, 2022. The search was updated in September 2022. After transferring literature to Mendeley, relevant data was extracted from the included studies. Quality assessment for eligible studies was done using Joanna Briggs Institute Critical Appraisal Checklist. Quality of evidences was assessed by using Grading of Recommendations Assessment, Development and Evaluation tool. RESULTS: Of the 203 studies identified, 18(8.9%) were analysed; 16(89%) with humans and 2(11%) with animals as subjects There were 5 (31.25%) studies for SP-D, of which 4 (80%) studies reported lower surfactant protein-D in type 2 diabetes mellitus cases than controls. Its significant negative association with glycated haemoglobin was reported by 1(20%) study and 2(40%) studies with fasting blood glucose levels. Higher surfactant protein-D in type 2 diabetes mellitus cases and its positive association with glycated haemoglobin was reported by 1(20%) study. Recurrent infections were frequent in type 2 diabetes mellitus patients. Malondialdehyde level was higher and superoxide dismutase activity was lower in type 2 diabetes mellitus cases, reflecting oxidative stress. Animal studies also showed that reactive oxygen species generating from hypochlorous acid during oxidative stress promoted the formation of non-disulfide linkages in surfactant protein-D structure, resulting in its decreased functionality. Conclusion: Surfactant protein-D, oxidative stress, inflammation and infections were found to be linked to each other for pathogenesis of infections in type 2 diabetes mellitus.

Human surfactant protein A inhibits SARS-CoV-2 infectivity and alleviates lung injury in a mouse infection model.

Introduction: SARS coronavirus 2 (SARS-CoV-2) infects human angiotensin-converting enzyme 2 (hACE2)-expressing lung epithelial cells through its spike (S) protein. The S protein is highly glycosylated and could be a target for lectins. Surfactant protein A (SP-A) is a collagen-containing C-type lectin, expressed by mucosal epithelial cells and mediates its antiviral activities by binding to viral glycoproteins. Objective: This study examined the mechanistic role of human SP-A in SARS-CoV-2 infectivity and lung injury in vitro and in vivo. Results: Human SP-A can bind both SARS-CoV-2 S protein and hACE2 in a dose-dependent manner (p<0.01). Pre-incubation of SARS-CoV-2 (Delta) with human SP-A inhibited virus binding and entry and reduced viral load in human lung epithelial cells, evidenced by the dose-dependent decrease in viral RNA, nucleocapsid protein (NP), and titer (p<0.01). We observed significant weight loss, increased viral burden, and mortality rate, and more severe lung injury in SARS-CoV-2 infected hACE2/SP-A KO mice (SP-A deficient mice with hACE2 transgene) compared to infected hACE2/mSP-A (K18) and hACE2/hSP-A1 (6A2) mice (with both hACE2 and human SP-A1 transgenes) 6 Days Post-infection (DPI). Furthermore, increased SP-A level was observed in the saliva of COVID-19 patients compared to healthy controls (p<0.05), but severe COVID-19 patients had relatively lower SP-A levels than moderate COVID-19 patients (p<0.05). Discussion: Collectively, human SP-A attenuates SARS-CoV-2-induced acute lung injury (ALI) by directly binding to the S protein and hACE2, and inhibiting its infectivity; and SP-A level in the saliva of COVID-19 patients might serve as a biomarker for COVID-19 severity.