Surfactant Protein Research Articles

Biomarker trajectory for earlier detection of lung cancer

To determine whether an algorithm based on repeated measurements of a panel of four circulating protein biomarkers (4MP) for lung cancer risk assessment results in improved performance over a single time measurement. We conducted data analysis of the 4MP consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in pre-diagnostic sera from 2483 ever-smoker participants (389 cases and 2094 randomly selected non-cases) in the Prostate, Lung, Colorectal, Ovarian (PLCO) Study who had at least two sequential blood collections over 6 years. A parametric empirical Bayes (PEB) algorithm, which incorporates participant biomarker history at each time point, was compared to a single-threshold (ST) method. Among ever-smoker participants, the PEB approach yielded an additional 4% improvement in the AUC compared to the ST approach (P-value: 0.009). When considering an ≥10 PY smoking history and at a fixing the specificity corresponding to 1% 6-year lung cancer risk, PEB resulted in significant improvement in the sensitivity (SenPEB:96.3% vs SenST:91.0%; P-value: 6.7e-3). The PEB algorithm identified 17 of the 35 cases that remained ST negative, at an average of 1.26 years before diagnosis. Ten case individuals who were positive based on ST at an average of 1.03 years prior to diagnosis were identified earlier by PEB, at an average of 2.70 years. An algorithm based on repeated measurements of the 4MP improves sensitivity and results in an earlier detection of lung cancer compared to a single-threshold method. This study was supported by NIH Grant Nos. U01CA271888, U01CA194733, U01CA213285, NCI EDRN U01 CA200468, P30CA016672, and U24CA086368; the Cancer Prevention & Research Institute of Texas RP180505 and RP160693; the SPORE P50CA140388; the CCTS TR000371; and the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program and the Lyda Hill Foundation.

The value of surfactant protein a in evaluating the severity and prognosis in community-acquired pneumonia patients

BackgroundPrevious research has discovered that surfactant protein A (SP-A) is involved in the pathophysiology processes of certain lung illnesses. However, no definitive clinical studies have delved into the function of SP-A in individuals afflicted with community-acquired pneumonia (CAP). A prospective cohort study was used to investigate the relationships between blood SP-A levels and the severity and prognosis among CAP patients.Materials and methodsThis study included 260 patients with CAP. Clinical traits and demographic data were examined during hospitalization. The concentrations of serum SP-A and serum interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). In addition, to evaluate the severity of CAP, a variety of scores, including the CURB-65, PSI, SMART-COP, and APACHE II, were employed.ResultsThe serum levels of SP-A at admission exhibited a gradual decline as the severity scores of CAP increased. Through Spearman correlation analysis, we observed an association between serum SP-A and some clinical indicators among CAP patients. Furthermore, results from a multiple linear regression model suggested changes in PSI scores (-17.868 scores, 95% CI: -32.743, -2.993) affect serum SP-A more than CURB-65 (-0.547 scores, 95% CI: -0.964, -0.131), SMART-COP (-1.097 scores, 95% CI: -1.889, -0.304) and APACHE II (-3.475 scores, 95% CI: -5.874, -1.075) with age, hypertension, diabetes mellitus, cerebral infarction, coronary heart disease, and bronchitis adjusted. In addition, the prognosis in CAP patients was monitored. Throughout their hospital stay, higher serum levels of SP-A decreased the risks of mechanical ventilation (RR: 0.315; 95% CI: 0.106, 0.937), vasoactive agents (RR: 0.165; 95% CI: 0.034, 0.790), intensive care unit (ICU) admissions (RR: 0.218; 95% CI: 0.066, 0.717) and longer hospital stays (RR: 0.397; 95% CI: 0.167, 0.945).ConclusionIn CAP patients, inverse dose-response correlations exist between serum SP-A levels with severity scores as well as prognosis at admission, suggesting that SP-A may take part in the CAP pathophysiological processes. Moreover, lower serum SP-A on admission is associated with an elevated prognostic risk of mechanical ventilation, the use of vasoactive agents, longer hospital stays, ICU admission, and mortality. Therefore, as a biomarker, SP-A may have the potential to predict the severity and poor prognosis of CAP patients.

BCAP31 Alleviates Lipopolysaccharide-Mediated Acute Lung Injury via Induction of PINK1/Parkin in Alveolar Epithelial Type II Cell.

Background: B-cell receptor-associated protein 31 (BCAP31) has protective effects against alveolar epithelial type II cells (AECII) damage by inhibiting mitochondrial injury in acute lung injury (ALI) induced by lipopolysaccharide (LPS), whereas the precise mechanism is still unclear. It is known that PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy can remove damaged mitochondria selectively, which may be involved in BCAP31 protection against mitochondrial injury. Methods: In the current study, ALI mice models were established by using surfactant protein C (Sftpc)-BCAP31 transgenic mice (BCAP31TG mice) and AECII-specific BCAP31 knockout mice (BCAP31CKO mice) treated with LPS. Results: BCAP31 expression in lung tissue and AECII were inhibited in ALI mice. Under LPS challenge, lower level of BCAP31 was found to correlate positively with pathological injury of the lung, respiratory dysfunction, mortality rates, inflammation response, and AECII damage. Further study showed that down-regulation of BCAP31 induced decreased phosphorylation of PINK1 via reduced binding to PINK1, thereby restraining PINK1/Parkin-mediated mitophagy. Down-regulation of mitophagy promoted mitochondrial injury, as shown by the increase in mitochondrial permeability transition pore opening rate, together with enhanced mitochondrial reactive oxygen species (mROS), which were accompanied by increased cellular apoptosis and reactive oxygen species (ROS). The increased cellular ROS contributed to the inflammatory response via activation of nuclear factor κB (NF-κB). In contrast, BCAP31 overexpression promoted phosphorylation of PINK1 and PINK1/Parkin-mediated mitophagy, thus blocking the mROS/ROS/NF-κB pathway, favoring a protective condition that ultimately led to the inhibition of AECII apoptosis and inflammatory response in LPS-induced ALI. Conclusion: Ultimately, BCAP31 alleviated ALI by activating PINK1/Parkin-mediated mitophagy and blocking the mROS/ROS/NF-κB pathway in AECII.

Could Serum Collectin-11, surfactant protein-A and D be suitable biomarkers for assessing pulmonary damage caused by Rhodococcus equi infection in foals on large farms?

Could Serum Collectin-11, surfactant protein-A and D be suitable biomarkers for assessing pulmonary damage caused by Rhodococcus equi infection in foals on large farms?

Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung Disease.

COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes ( SFTPA1 and SFTPA2 ) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A 2 , 6A 4 ) and SP-A2 (variants 1A 0 , 1A 3 ). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection in vivo . Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A 2 (6A 2 ), hACE2/6A 4 (6A 4 ), hACE2/1A 0 (1A 0 ), and hACE2/1A 3 (1A 3 ), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 10 3 PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A 0 mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A 0 , and 6A 2 mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as MyD88 , Stat3 , IL-18 , and Jak2 in the lungs of KO and 1A 0 mice. However, Mapk1 was significantly downregulated in 6A 2 versus 1A 0 mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6 and IL-1β were comparatively higher in the lungs and sera of KO and 1A 0 mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.

Engraftment of wild-type alveolar type II epithelial cells in surfactant protein C deficient mice.

Childhood interstitial lung disease (chILD) secondary to pulmonary surfactant deficiency is a devastating chronic lung disease in children. Clinical presentation includes mild to severe respiratory failure and fibrosis. There is no specific treatment, except lung transplantation, which is hampered by a severe shortage of donor organs, especially for young patients. Repair of lungs with chILD represents a longstanding therapeutic challenge but cell therapy is a promising strategy. As surfactant is produced by alveolar type II epithelial (ATII) cells, engraftment with normal or gene-corrected ATII cells might provide an avenue to cure. Here we used a chILD disease-like model, Sftpc -/- mice, to provide proof-of-principle for this approach. Sftpc -/- mice developed chronic interstitial lung disease with age and were hypersensitive to bleomycin. We could engraft wild-type ATII cells after low dose bleomycin conditioning. Transplanted ATII cells produced mature SPC and attenuated bleomycin-induced lung injury up to two months post-transplant. This study demonstrates that partial replacement of mutant ATII cells can promote lung repair in a mouse model of chILD-like disease.

Transamniotic Delivery of Surfactant Protein B mRNA in a Healthy Model

Introduction: We sought to determine whether exogenous surfactant protein B (SPB) mRNA could be incorporated and translated by the fetal lung after simple transamniotic administration. Methods: Fetuses (n = 149) of twelve time-dated dams underwent intra-amniotic injections of either human SPB (hSPB) mRNA encapsulated into lipopolyplex (mRNA, n = 99) or lipopolyplex without mRNA (control; n = 50) on gestational day 17 (E17, term = E21–22). Lungs were screened for hSPB by enzyme-linked immunosorbent assay daily until term. Phosphatidylcholine (PC) (a surrogate for surfactant production) was measured in the amniotic fluid by fluorometric assay. Statistical analysis included nonparametric Wilcoxon rank sum test. Results: Significantly improved survival in the mRNA group compared to controls was observed at E18 (100% vs. 85.7%) and E20 (100% vs. 83.3%) (both p < 0.001). When controlled by mRNA-free injections, hSPB protein was detected in the mRNA group’s lungs at E18, 19, and term (p = 0.002 to <0.001). Amniotic fluid PC levels were increased compared to control at term [285.9 (251.1, 363.9) μM versus 263.1 (222.8, 309.1) μM]; however, this did not reach significance (p = 0.33). Conclusions: Encapsulated exogenous SPB mRNA can be incorporated and translated by fetal lung cells following intra-amniotic injection in a healthy rat model. Transamniotic mRNA delivery could become a novel strategy for perinatal surfactant protein replacement.

The Role of Pulmonary Collectins, Surfactant Protein A (SP-A) and Surfactant Protein D (SP-D) in Cancer.

Surfactant proteins A and D (SP-A and SP-D) belong to the collectin subfamily of C-type oligomeric lectins. They are pattern-recognition molecules (PRMs), able to recognise pathogen- or danger-associated molecular patterns (PAMPs, DAMPs) in the presence of Ca2+ cations. That property enables opsonisation or agglutination of non-self or altered/abnormal self cells and contributes to their clearance. Like other collectins, SP-A and SP-D are characterised by the presence of four distinct domains: a cysteine-rich domain (at the N-terminus), a collagen-like region, an α-helical neck domain and a globular carbohydrate-recognition domain (CRD) (at the C-terminus). Pulmonary surfactant is a lipoprotein complex, preventing alveolar collapse by reducing surface tension at the air-liquid interface. SP-A and SP-D, produced by type II alveolar epithelial cells and Clara cells, are not only pattern-recognition molecules but also contribute to the surfactant structure and homeostasis. Moreover, they are expressed in a variety of extrapulmonary sites where they are involved in local immunity. The term "cancer" includes a variety of diseases: tumours start from uncontrolled growth of abnormal cells in any tissue which may further spread to other sites of the body. Many cancers are incurable, difficult to diagnose and often fatal. This short review summarises anti- and pro-tumorigenic associations of SP-A and SP-D as well as perspectives of their usefulness in cancer diagnosis and therapy.

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 single-nucleotide polymorphism (SNP)-SNP interactions remains unexplored. Therefore, we used 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, first, 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. We also observed, second, 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.NEW & NOTEWORTHY Although surfactant protein (SP) genetic variants are associated with respiratory syncytial virus (RSV) severity, the impact of single-nucleotide polymorphism (SNP)-SNP interactions of SP genes remained unexplored. Using advanced statistical models, we uncovered 22 SNP-SNP interactions associated with RSV severity, with notable involvement of SFTPA1 and SFTPA2 SNPs. This highlights the comprehensive role of all SPs in genetic susceptibility to RSV severity, shedding light on potential avenues for targeted interventions.

Influence of mesenchymal and biophysical components on distal lung organoid differentiation

BackgroundChronic lung disease of prematurity, called bronchopulmonary dysplasia (BPD), lacks effective therapies, stressing the need for preclinical testing systems that reflect human pathology for identifying causal pathways and testing novel compounds. Alveolar organoids derived from human pluripotent stem cells (hPSC) are promising test platforms for studying distal airway diseases like BPD, but current protocols do not accurately replicate the distal niche environment of the native lung. Herein, we investigated the contributions of cellular constituents of the alveolus and fetal respiratory movements on hPSC-derived alveolar organoid formation.MethodsHuman PSCs were differentiated in 2D culture into lung progenitor cells (LPC) which were then further differentiated into alveolar organoids before and after removal of co-developing mesodermal cells. LPCs were also differentiated in Transwell® co-cultures with and without human fetal lung fibroblast. Forming organoids were subjected to phasic mechanical strain using a Flexcell® system. Differentiation within organoids and Transwell® cultures was assessed by flow cytometry, immunofluorescence, and qPCR for lung epithelial and alveolar markers of differentiation including GATA binding protein 6 (GATA 6), E-cadherin (CDH1), NK2 Homeobox 1 (NKX2-1), HT2-280, surfactant proteins B (SFTPB) and C (SFTPC).ResultsWe observed that co-developing mesenchymal progenitors promote alveolar epithelial type 2 cell (AEC2) differentiation within hPSC-derived lung organoids. This mesenchymal effect on AEC2 differentiation was corroborated by co-culturing hPSC-NKX2-1+ lung progenitors with human embryonic lung fibroblasts. The stimulatory effect did not require direct contact between fibroblasts and NKX2-1+ lung progenitors. Additionally, we demonstrate that episodic mechanical deformation of hPSC-derived lung organoids, mimicking in situ fetal respiratory movements, increased AEC2 differentiation without affecting proximal epithelial differentiation.ConclusionOur data suggest that biophysical and mesenchymal components promote AEC2 differentiation within hPSC-derived distal organoids in vitro.

A Systematic Review of the Key Predictors of Progression and Mortality of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is an important extra-articular manifestation of rheumatoid arthritis (RA). Identifying patients at risk of progression and death is crucial for improving RA-ILD management and outcomes. This paper explores current evidence on prognostic factors in RA-ILD. We conducted a systematic literature review to examine the impact of clinical, radiological, and histological factors on lung function decline and the survival of RA-ILD patients. We searched electronic databases, including Medline and EMBASE, from inception to date. The incidence and prognosis of predictors were qualitatively analyzed, and univariate results were combined when feasible. Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines, our systematic literature review involved a five-step algorithm. Out of 2217 records, 48 studies were eligible. These studies reported various prognostic factors, including demographic variables, clinical risk factors, serum markers, and preexisting treatments. Lung function declined over time in 1225 subjects, with significant variability in smoking history and radiological/pathological UIP patterns. Severe lung fibrosis and abnormal pulmonary function tests (PFTs) were key univariate prognostic indicators, while age at initial presentation, RA disease activity, predicted DLCO percentage, and UIP pattern were the most reliable multivariate risk factors for ILD progression. Age, male gender, disease duration, RA activity, acute phase reactants, and specific serum biomarkers (Krebs vin den Lungen 6, surfactant protein D, and interleukin 6) were significantly associated with all-cause mortality. RA-ILD is a severe complication of RA characterized by significant prognostic variability. Key prognostic factors include extensive fibrosis observed on imaging, a marked decline in lung function, high RA disease activity, and specific biomarkers. These factors can guide treatment strategies and improve patient outcomes.

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

BackgroundThe 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.MethodsAmong 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.ResultsAmong 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.ConclusionsOur results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP.

Surfactant derived protein type B: a new biomarker linked to respiratory failure and lung damage in mild to moderate SARS-CoV-2 pneumonia

BackgroundThe COVID-19 pandemic has led to significant concern due to its impact on human health, particularly through pneumonia-induced lung damage. Surfactant proteins A and D (SP-A and SP-D) are implicated in COVID-19 lung damage, but the role of surfactant protein B (SP-B) remains unclear.MethodsWe conducted a single-center prospective observational study involving 73 hospitalised COVID-19 pneumonia patients. SP-B levels were measured within 48 h of admission, alongside SP-A and SP-D in a subset. Clinical data were collected, and follow-up visits were conducted after 6 months.ResultsAt hospitalisation, circulating immature SP-B levels measured in 73 patients (26.31 AU [14.27–41.31]), correlated significantly with lung involvement (r=0.447, p&lt;0.001) and oxygen support requirement (p=0.005). SP-B levels did not predict mechanical ventilation or ICU admission. SP-B decreased significantly (p&lt;0.001) from 25.53 AU [14.36–41.46] at the acute hospitalisation to 12.73 AU [9.12–20.23] at 6 months follow up, unlike SP-A and SP-D that did not change significantly. Immature SP-B (but not SP-A and SP-D) confirmed to be significantly associated with the need of oxygen support (n=26, 58%) during the hospitalisation (p&lt;0.05).ConclusionImmature SP-B emerges as a potential biomarker for COVID-19 pneumonia severity and prognosis. Its dynamic changes suggest utility in monitoring disease progression and long-term outcomes, despite limitations in predicting hard endpoints. Larger studies are needed to validate these findings and understand the underlying mechanisms of surfactant protein dysregulation in COVID-19 pathogenesis.

Recombinant fragment of human surfactant protein D to prevent neonatal chronic lung disease (RESPONSE): a protocol for a phase I safety trial in a tertiary neonatal unit

IntroductionChronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory...

Airway derived emphysema-specific alveolar type II cells exhibit impaired regenerative potential in COPD.

Emphysema, the progressive destruction of gas exchange surfaces in the lungs, is a hallmark of chronic obstructive pulmonary disease (COPD) that is presently incurable. This therapeutic gap is largely due to a poor understanding of potential drivers of impaired tissue regeneration, such as abnormal lung epithelial progenitor cells, including alveolar type II (ATII) and airway club cells. We discovered an emphysema-specific sub-population of ATII cells located in enlarged distal alveolar sacs, termed asATII cells. Single cell RNA-seq and in situ localisation revealed that asATII cells co-express the alveolar marker surfactant protein C (SPC) and the club cell marker secretaglobin-3A2 (SCGB3A2). A similar ATII sub-population derived from club cells was also identified in mouse COPD models using lineage labeling. Human and mouse ATII sub-populations formed 80-90% fewer alveolar organoids than healthy controls, indicating reduced progenitor function. Targeting asATII cells or their progenitor club cells could reveal novel COPD treatment strategies.

Interplay between host humoral pattern recognition molecules controls undue immune responses against Aspergillus fumigatus

Pentraxin 3 (PTX3), a long pentraxin and a humoral pattern recognition molecule (PRM), has been demonstrated to be protective against Aspergillus fumigatus, an airborne human fungal pathogen. We explored its mode of interaction with A. fumigatus, and the resulting implications in the host immune response. Here, we demonstrate that PTX3 interacts with A. fumigatus in a morphotype-dependent manner: (a) it recognizes germinating conidia through galactosaminogalactan, a surface exposed cell wall polysaccharide of A. fumigatus, (b) in dormant conidia, surface proteins serve as weak PTX3 ligands, and (c) surfactant protein D (SP-D) and the complement proteins C1q and C3b, the other humoral PRMs, enhance the interaction of PTX3 with dormant conidia. SP-D, C3b or C1q opsonized conidia stimulated human primary immune cells to release pro-inflammatory cytokines and chemokines. However, subsequent binding of PTX3 to SP-D, C1q or C3b opsonized conidia significantly decreased the production of pro-inflammatory cytokines/chemokines. PTX3 opsonized germinating conidia also significantly lowered the production of pro-inflammatory cytokines/chemokines while increasing IL-10 (an anti-inflammatory cytokine) released by immune cells when compared to the unopsonized counterpart. Overall, our study demonstrates that PTX3 recognizes A. fumigatus either directly or by interplaying with other humoral PRMs, thereby restraining detrimental inflammation. Moreover, PTX3 levels were significantly higher in the serum of patients with invasive pulmonary aspergillosis (IPA) and COVID-19-associated pulmonary aspergillosis (CAPA), supporting previous observations in IPA patients, and suggesting that it could be a potential panel-biomarker for these pathological conditions caused by A. fumigatus.

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.

Biomarkers of lung congestion and injury in acute heart failure.

Acute heart failure (AHF) classification and management are primarily based on lung congestion and/or hypoperfusion. The quantification of the vascular and tissue lung damage is not standard practice though biomarkers of lung injury may play a relevant role in this context. Haemodynamic stress promotes alveolar and vascular derangement with loss of functional units, impaired lung capillary permeability and fluid swelling. This culminates in a remodelling process with activation of inflammatory and cytokines pathways. Four families of lung surfactant proteins (i.e., SP-A, SP-B, SP-C, and SP-D), essential for the membrane biology and integrity are released by alveolar type II pneumocites. With deregulation of fluid handling and gas exchange pathways, SPs become sensitive markers of lung injury. We report the pathobiology of lung damage; the pathophysiological and clinical implications of alveolar SPs along with the newest evidence for some classical HF biomarkers that have also shown to reflect a vascular and/or a tissue lung-related activity.

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 (2600g) using a Hopkinson bar. Measurements were taken in the control group and 0, 24, 48, and 72h 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 72h (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 0h and increased at 24, 48, and 72h. 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 72h, 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.

Changes in surfactant protein A and D in ovine ovaries related to follicle development.

Surfactant protein A (SP-A) and Surfactant protein D (SP-D) glycoproteins play a crucial role in maintaining lung homeostasis and lung host defense. Interestingly, these proteins are also expressed in extra-pulmonary tissues, including the female genital tract. The ovarian tissue, where SP-A and SP-D expression increases with follicular development, may serve as the primary site of defense for this tissue. However, their functions in these tissues are not well understood and are currently an active area of research. Therefore, the objective of this study is to investigate the expression of SP-A and SP-D in the ovine ovary throughout the ovarian cycle using immunohistochemistry by semiquantitative intensity classification and Western blotting techniques. These findings revealed the presence of SP-A and SP-D in various compartments of the ovary, such as the follicular epithelium, granulosa cells, cumulus cells, theca cells, oocyte I, follicular fluid, and luteal cells of Graafian follicles, excluding the corpus albicans. SP-A and SP-D likely act as a first line of defense against potential pathogens that infiltrate the ovaries. Further investigation of the differential expression of SP-A and SP-D proteins in ovarian follicles will provide a basis for understanding their interactions with key proteins involved in oogenesis.