Lung tissue expression of epithelial injury markers is associated with acute lung injury severity but does not discriminate sepsis from ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, and diffuse alveolar damage (DAD) is considered its histological hallmark. Sepsis is one of the most common aetiology of ARDS with the highest case-fatality rate. Identifying ARDS patients and differentiate them from other causes of acute respiratory failure remains a challenge. To address this, many studies have focused on identifying biomarkers that can help assess lung epithelial injury. However, there is scarce information available regarding the tissue expression of these markers. Evaluating the expression of elafin, RAGE, and SP-D in lung tissue offers a potential bridge between serological markers and the underlying histopathological changes. Therefore, we hypothesize that the expression of epithelial injury markers varies between sepsis and ARDS as well as according to its severity. METHODS: We compared the post-mortem lung tissue expression of the epithelial injury markers RAGE, SP-D, and elafin of patients that died of sepsis, ARDS, and controls that died from non-pulmonary causes. Lung tissue was collected during routine autopsy and protein expression was assessed by immunohistochemistry. We also assessed the lung injury by a semi-quantitative analysis. RESULTS: We observed that all features of DAD were milder in septic group compared to ARDS group. Elafin tissue expression was increased and SP-D was decreased in the sepsis and ARDS groups. Severe ARDS expressed higher levels of elafin and RAGE, and they were negatively correlated with PaO2/FiO2 ratio, and positively correlated with bronchopneumonia percentage and hyaline membrane score. RAGE tissue expression was negatively correlated with mechanical ventilation duration in both ARDS and septic groups. In septic patients, elafin was positively correlated with ICU admission length, SP-D was positively correlated with serum lactate and RAGE was correlated with C-reactive protein. CONCLUSIONS: Lung tissue expression of elafin and RAGE, but not SP-D, is associated with ARDS severity, but does not discriminate sepsis patients from ARDS patients.

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.

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.

Growth differentiation factor-15 and circulating biomarkers as predictors of periodontal treatment effects in patients with periodontitis: a randomized-controlled clinical trial.

BACKGROUND: During the last decades, in patients with periodontitis, periodontal treatment has been shown to reduce the potential release of local and systemic biomarkers linked to an early risk of systemic inflammatory disorders. This study evaluated the efficacy of non-surgical-periodontal treatment (NSPT) on growth differentiation factor 15 (GDF-15) and related circulating biomarkers such as glutathione peroxidase 1 (GPx-1), c-reactive protein (hs-CRP), and surfactant protein D (SP-D) in periodontal patients and explored whether subjects who had high GDF-15 levels at baseline showed increased clinical benefits following NSPT at 6-months follow-up. METHODS: For this two-arm, parallel randomized clinical trial, patients with periodontitis were randomly allocated to receive quadrant scaling and root-planing (Q-SRP, n = 23, median age 51 years old) or full-mouth disinfection (FMD, n = 23, median age 50 years old) treatment. Clinical and periodontal parameters were recorded in all enrolled patients. The primary outcome was to analyse serum concentrations changes of GDF-15 and of GPx-1, hs-CRP, and SP-D at baseline and at 30, 90, and 180-days follow-up after NSPT through enzyme-linked immunosorbent assay (ELISA) and nephelometric assay techniques. RESULTS: In comparison with FMD, patients of the Q-SRP group showed a significant improvement in clinical periodontal parameters (p < 0.05) and a reduction in the mean levels of GDF-15 (p = 0.005), hs-CRP (p < 0.001), and SP-D (p = 0.042) and an increase of GPx-1 (p = 0.025) concentrations after 6 months of treatment. At 6 months of treatment, there was a significant association between several periodontal parameters and the mean concentrations of GDF-15, GPx-1, hs-CRP, and SP-D (p < 0.05 for all parameters). Finally, the ANOVA analysis revealed that, at 6 months after treatment, the Q-SRP treatment significantly impacted the reduction of GDF-15 (p = 0.015), SP-D (p = 0.026) and the upregulation of GPx-1 (p = 0.045). CONCLUSION: The results evidenced that, after 6 months of treatment, both NSPT protocols improved the periodontal parameters and analyzed biomarkers, but Q-SRP was more efficacious than the FMD approach. Moreover, patients who presented high baseline GDF-15 and SP-D levels benefited more from NSPT at 6-month follow-up. TRIAL REGISTRATION: NCT05720481.

Comparison of frailty in patients with nontuberculous mycobacterial lung disease and bronchiectasis: a prospective cohort study.

BACKGROUND: The incidence of nontuberculous mycobacterial lung disease (NTM-LD) peaks in middle- and old age groups, coinciding with senescence; thus, chronic infectious diseases can accelerate frailty and worsen mental health in the elderly. In this study, we aimed to compare the prevalence of physical and psychiatric frailty between patients with NTM-LD and bronchiectasis (BE). METHODS: The Kihon Checklist Questionnaire (KCQ) was used to assess physical and psychiatric frailties and identify those at risk of requiring care among patients with newly diagnosed NTM-LD and BE. Additionally, the Hospital Anxiety and Depression Scale (HADS) scores and chronic inflammatory biomarkers of the alveolar region (surfactant protein [SP]-A, SP-D, and human cationic antibacterial protein [hCAP]/LL-37) were assessed and compared between NTM-LD and BE patients. RESULTS: There were no significant differences in the background characteristics between the 33 NTM and 36 BE patients recruited. The KCQ revealed that the proportion of frail NTM patients at diagnosis was higher than that of frail BE patients (48.5% vs. 22.2%, p = 0.026). HADS scores were significantly higher in the NTM group than in the BE group (p < 0.01). Bronchoalveolar lavage fluid (BALF) hCAP/LL-37 and SP-D levels were significantly higher (p = 0.001), but serum hCAP/LL-37 levels were significantly lower in the NTM group than in the BE group (p = 0.023). However, there were no significant differences in the BALF and serum SP-D levels between the two groups. CONCLUSIONS: The number of frail NTM patients at diagnosis was significantly higher than that of frail BE patients. Biomarker analysis suggested that the former had more localized lung inflammation than the latter. TRIAL REGISTRATION: This trial was prospectively registered in the Clinical Trials Registry (UMIN 000027652).

Labeled TEMPO-Oxidized Mannan Differentiates Binding Profiles within the Collectin Families.

Establishing the rapid and accurate diagnosis of sepsis is a key component to the improvement of clinical outcomes. The ability of analytical platforms to rapidly detect pathogen-associated molecular patterns (PAMP) in blood could provide a powerful host-independent biomarker of sepsis. A novel concept was investigated based on the idea that a pre-bound and fluorescent ligand could be released from lectins in contact with high-affinity ligands (such as PAMPs). To create fluorescent ligands with precise avidity, the kinetically followed TEMPO oxidation of yeast mannan and carbodiimide coupling were used. The chemical modifications led to decreases in avidity between mannan and human collectins, such as the mannan-binding lectin (MBL) and human surfactant protein D (SP-D), but not in porcine SP-D. Despite this effect, these fluorescent derivatives were captured by human lectins using highly concentrated solutions. The resulting fluorescent beads were exposed to different solutions, and the results showed that displacements occur in contact with higher affinity ligands, proving that two-stage competition processes can occur in collectin carbohydrate recognition mechanisms. Moreover, the fluorescence loss depends on the discrepancy between the respective avidities of the recognized ligand and the fluorescent mannan. Chemically modulated fluorescent ligands associated with a diversity of collectins may lead to the creation of diagnostic tools suitable for multiplex array assays and the identification of high-avidity ligands.

Role of surfactant protein-D in ocular bacterial infection.

PURPOSE: Our review explains the role of surfactant protein D (SP-D) in different kinds of bacterial infection based on its presence in different ocular surface tissues. We discuss the potential role of SP-D against invasion by pathogens, with the aim of identifying new prospects for the possible mechanism of SP-D-mediated immune processes, and the diagnosis, prognosis, or treatment of ocular bacterial infection. METHODS: We reviewed articles about the role of SP-D in various ocular bacterial infections or infection-related ocular diseases through PubMed, Google Scholar, and the Web of Science databases. RESULTS: SP-D acts as an important immune factor that can resemble molecules in different polymerization states and that defends against pathogen invasion. The increased SP-D production and secretion in tear fluid and the cornea after ocular bacterial infections such as Staphylococcus aureus, Pseudomonas aeruginosa keratitis, and infection-related ocular diseases, was shown to have potential anti-inflammatory effects. The mechanisms of SP-D's action against ocular bacterial infections include presenting, aggregating, opsonizing, and phagocytizing antigens, as well as regulating anti-bacterial immunity processes, including toll-like receptor-5 (TLR-5) pathway and IL-8 effect, TLR-4 and TLR-2 pathways and other possible ways remained to be elucidated in more detail. The findings demonstrate the potential of SP-D as an important clinical diagnostic biomarker prognosis predictor, and target for ocular immunotherapy. CONCLUSION: SP-D participates in invasion by different ocular bacteria and infection-related ocular diseases through multiple immune mechanisms. This finding provides new prospects for the diagnosis, prognosis and treatment of ocular bacterial infection.

Expression of Surfactant Protein D Distinguishes Severe Pandemic Influenza A(H1N1) from Coronavirus Disease 2019.

The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.

A Recombinant Fragment of Human Surfactant Protein D Binds Spike Protein and Inhibits Infectivity and Replication of SARS-CoV-2 in Clinical Samples.

Coronavirus disease (COVID-19) is an acute infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human SP-D (surfactant protein D) is known to interact with the spike protein of SARS-CoV, but its immune surveillance against SARS-CoV-2 is not known. The current study aimed to examine the potential of a recombinant fragment of human SP-D (rfhSP-D) as an inhibitor of replication and infection of SARS-CoV-2. The interaction of rfhSP-D with the spike protein of SARS-CoV-2 and human ACE-2 (angiotensin-converting enzyme 2) receptor was predicted via docking analysis. The inhibition of interaction between the spike protein and ACE-2 by rfhSP-D was confirmed using direct and indirect ELISA. The effect of rfhSP-D on replication and infectivity of SARS-CoV-2 from clinical samples was assessed by measuring the expression of RdRp gene of the virus using quantitative PCR. In silico interaction studies indicated that three amino acid residues in the receptor-binding domain of spike protein of SARS-CoV-2 were commonly involved in interacting with rfhSP-D and ACE-2. Studies using clinical samples of SARS-CoV-2-positive cases (asymptomatic, n = 7; symptomatic, n = 8) and negative control samples (n = 15) demonstrated that treatment with 1.67 µM rfhSP-D inhibited viral replication by ∼5.5-fold and was more efficient than remdesivir (100 µM) in Vero cells. An approximately two-fold reduction in viral infectivity was also observed after treatment with 1.67 µM rfhSP-D. These results conclusively demonstrate that the rfhSP-D mediated calcium independent interaction between the receptor-binding domain of the S1 subunit of the SARS-CoV-2 spike protein and human ACE-2, its host cell receptor, and significantly reduced SARS-CoV-2 infection and replication in vitro.

Increased serum SP-D in identification of high-risk smokers at high risk of COPD.

Pulmonary surfactant protein D (SP-D) is an important component of the pulmonary innate immune system with the ability to dampen cigarette smoke-induced lung inflammation. However, cigarette smoking mediates translocation of SP-D from the lung to the blood, and serum SP-D (sSP-D) has therefore previously been suggested as marker for smoke-induced lung injury. In support of this notion, associations between high sSP-D and low lung function measurements have previously been demonstrated in smokers and in chronic obstructive lung disease (COPD). The present investigations employ a 12-yr longitudinal Danish twin study to test the hypothesis that baseline sSP-D variation has the capacity to identify smokers with normal baseline lung function who are at high risk of significant future smoke-induced lung function decline. We find that sSP-D is significantly increased in those with normal lung function at baseline who develop lung function decline during follow-up compared with those who stay lung healthy. Moreover, we demonstrate that it is the smoke-induced baseline sSP-D level, and not the constitutional level, which has capacity as biomarker, and which is linearly increased with the decline in lung function during follow-up. In conclusion, we here present first observation of increased sSP-D for identification of high-risk smokers.