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Cardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung’s alveolar spaces due to an elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Some studies claim that these patients may have higher levels of surfactant protein B in the bloodstream. The correct approach to patients with CPE should include a detailed medical history and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paper reviews the pathophysiology, clinical presentation, and management of CPE.

BACKGROUND: Optimal functionality of synthetic lung surfactant for treatment of respiratory distress syndrome in preterm infants largely depends on the quality and quantity of the surfactant protein B (SP-B) peptide mimic and the lipid mixture. B-YL peptide is a 41-residue sulfur-free SP-B mimic with its cysteine and methionine residues replaced by tyrosine and leucine, respectively, to enhance its oxidation resistance. AIM: Testing the structural and functional stability of the B-YL peptide in synthetic surfactant lipids after long-term storage. METHODS: The structural and functional properties of B-YL peptide in surfactant lipids were studied using three production runs of B-YL peptides in synthetic surfactant lipids. Each run was held at 5 °C ambient temperature for three years and analyzed with structural and computational techniques, i.e., MALDI-TOF mass spectrometry, ATR-Fourier Transform Infrared Spectroscopy (ATR-FTIR), secondary homology modeling of a preliminary B-YL structure, and tertiary Molecular Dynamic simulations of B-YL in surfactant lipids, and with functional methods, i.e., captive bubble surfactometry (CBS) and retesting in vivo surface activity in surfactant-deficient young adult rabbits. RESULTS: MALDI-TOF mass spectrometry showed no degradation of the B-YL peptide as a function of stored time. ATR-FTIR studies demonstrated that the B-YL peptide still assumed stable alpha-helical conformations in synthetic surfactant lipids. These structural findings correlated with excellent in vitro surface activity during both quasi-static and dynamic cycling on CBS after three years of cold storage and in vivo surface activity of the aged formulations with improvements in oxygenation and dynamic lung compliance approaching those of the positive control surfactant Curosurf®. CONCLUSIONS: The structure of the B-YL peptide and the in vitro and in vivo functions of the B-YL surfactant were each maintained after three years of refrigeration storage.

BackgroundMany premature infants with respiratory failure are deficient in surfactant, but the relationship to occurrence of bronchopulmonary dysplasia (BPD) is uncertain.MethodsTracheal aspirates were collected from 209 treated and control infants enrolled at 7-14 days in the Trial of Late Surfactant. The content of phospholipid, surfactant protein B, and total protein were determined in large aggregate (active) surfactant.ResultsAt 24 h, surfactant treatment transiently increased surfactant protein B content (70%, p

Surfactant protein B (SFTPB) deficiency is a fatal disease affecting newborn infants. Surfactant is produced by alveolar type II cells which can be differentiated in vitro from patient specific induced pluripotent stem cell (iPSC)-derived lung organoids. Here we show the differentiation of patient specific iPSCs derived from a patient with SFTPB deficiency into lung organoids with mesenchymal and epithelial cell populations from both the proximal and distal portions of the human lung. We alter the deficiency by infecting the SFTPB deficient iPSCs with a lentivirus carrying the wild type SFTPB gene. After differentiating the mutant and corrected cells into lung organoids, we show expression of SFTPB mRNA during endodermal and organoid differentiation but the protein product only after organoid differentiation. We also show the presence of normal lamellar bodies and the secretion of surfactant into the cell culture medium in the organoids of lentiviral infected cells. These findings suggest that a lethal lung disease can be targeted and corrected in a human lung organoid model in vitro.

BackgroundMutations in the NK2 homeobox 1 (NKX2-1) gene are associated with lung disease in infants and children. We hypothesize that disruption of normal surfactant gene expression with these mutations contributes to the respiratory phenotypes observed.MethodsTo assess transactivational activity, cotransfection of luciferase reporter vectors containing surfactant protein B or C (SFTPB or SFTPC) promoters with NKX2-1 plasmids was performed and luciferase activity was measured. To assess the binding of mutated proteins to target DNA, electrophoretic mobility shift assays (EMSA) were performed using nuclear protein labeled with oligonucleotide probes representing NKX2-1 consensus binding sequences followed by gel electrophoresis. The effect of overexpression of wild-type (WT) and mutant NKX2-1 on SFTPB and SFTPC was evaluated with quantitative real-time PCR.ResultsDecreased transactivation of the SFTPB promoter by both mutants and decreased transactivation of the SFTPC promoter by the L197P mutation was observed. EMSA demonstrated decreased DNA binding of both mutations to NKX2-1 consensus binding sequences. Transfection of A549 cells with NKX2-1 expression vectors demonstrated decreased stimulation of SFTPB and SFTPC expression by mutant proteins compared with that of WT.ConclusionDisruption of transcriptional activation of surfactant protein genes by these DNA-binding domain mutations is a plausible biological mechanism for disruption of surfactant function and subsequent respiratory distress.

Surfactant protein B (SP-B; 79 residues) is a member of the saposin superfamily and plays a pivotal role in lung function. The N- and C-terminal regions of SP-B, cross-linked by two disulfides, were theoretically predicted to fold as charged amphipathic helices, suggesting participation in surfactant activities. Previous studies with oxidized Super Mini-B (SMB), a construct based on the N- and C-regions of SP-B (i.e., residues 1-25 and 63-78) joined with a designer turn (-PKGG-) and two disulfides, indicated that freshly prepared SMB in lipids folded as a surface active, α-helix-hairpin. Because other peptides modeled on α-helical SP domains lost helicity and surfactant activity on storage, experiments were here performed on oxidized SMB in surfactant liposomes stored at ~2-8°C for ≤5.5years. Captive bubble surfactometry confirmed low minimum surface tensions for fresh and stored SMB preparations. FTIR spectroscopy of fresh and stored SMB formulations showed secondary structures compatible with the peptide folding as α-helix-hairpin. A homology (I-TASSER) model of oxidized SMB demonstrated a globular protein, exhibiting a core of hydrophobic residues and a surface of polar residues. Since mass spectroscopy indicated that the disulfides were maintained on storage, the stability of SMB may be partly due to the disulfides bringing the N- and C-α-helices closer. Mass spectroscopy of stored SMB preparations showed some methionine oxidation, and also partial deacylation of surfactant phospholipids to form lyso-derivatives. However, the stable conformation and activity of stored SMB surfactant suggest that the active helix-hairpin resists these chemical changes which otherwise may lead to surfactant inhibition.

IntroductionThe physiologic vitamin D (VD), 1α,25(OH)2D3 (1,25D) is a local paracrine/autocrine effecter of fetal lung maturation. By stimulating alveolar type II cell and lipofibroblast proliferation and differentiation, parenterally administered 1,25D has been shown to enhance neonatal lung maturation; but due to the potential systemic side effects of the parenteral route, the translational value of these findings might be limited. To minimize the possibility of systemic toxicity, we examined the effects of VD on neonatal lung maturation, when delivered directly to lungs via nebulization.MethodsOne-day-old rat pups were administered three different doses of 1,25D and its physiologic precursor 25(OH)D (25D), or the diluent, via nebulization daily for 14 days. Pups were sacrificed for lung, kidneys, and blood collection to determine markers of lung maturation, and serum 25D and calcium levels.ResultsCompared to controls, nebulized 25D and 1,25D enhanced lung maturation as evidenced by the increased expression of markers of alveolar epithelial (SP-B, leptin receptor), mesenchymal (PPARγ, C/EBPα), and endothelial (VEGF, FLK-1) differentiation, surfactant phospholipid synthesis, and lung morphology without any significant increases in serum 25D and calcium levels.ConclusionsInhaled VD is a potentially safe and effective novel strategy to enhance neonatal lung maturation.

BackgroundPulmonary surfactant provides an alveolar surface-active film that is critical for normal lung function. Our objective was to determine in vitro film formation properties of therapeutic and infant surfactants and the influence of surfactant protein (SP)-B content.MethodsWe used a multiwell fluorescent assay measuring maximum phospholipid surface accumulation (Max), phospholipid concentration required for half-maximal film formation (½Max), and time for maximal accumulation (tMax).ResultsAmong five therapeutic surfactants, calfactant (highest SP-B content) had film formation values similar to natural surfactant, and addition of SP-B to beractant (lowest SP-B) normalized its Max value. Addition of budesonide to calfactant did not adversely affect film formation. In tracheal aspirates of preterm infants with evolving chronic lung disease, SP-B content correlated with ½Max and tMax values, and SP-B supplementation of SP-B-deficient infant surfactant restored normal film formation. Reconstitution of normal surfactant indicated a role for both SP-B and SP-C in film formation.ConclusionFilm formation in vitro differs among therapeutic surfactants and is highly dependent on SP-B content in infant surfactant. The results support a critical role of SP-B for promoting surface film formation.

Objective To explore the difference of SP-B content in alveolar lavage fluid (ALF) between immature lung and mature lung at the same time point after lung blast injury, and investigate the significance and pathophysiological characteristics of related indexes. Methods The experimental animals (both sexes) included 40 healthy young New Zealand rabbits, weighting 442.10±55.30 g (young rabbit group), and 40 healthy New Zealand rabbits, aged 24 weeks, weighting 2 018.15±145.80 g (adult rabbits group). The experimental model was established under different driving pressures to ensure that the severity of injury was consistent (drive pressure: 4.5 MPa for young rabbit group and 4.0 MPa for adult rabbit group). After injury, the ALF content of SP-B was measured with ELISA at the immediate (0), 2, 4, 6, 12, 24, 48 and 72 h after injury, and the lungs were observed for gross anatomy and pathological changes. The tissue water content and other physiological indicators were determined at the same time. Results The severity of lung injury was consistent between the 2 groups (P>0.05). The SP-B concentration in the young rabbit group was lower than that in the adult rabbit group at all time points (P < 0.05); the alveolar wall rupture and injury were more commonly observed in the young rabbits, and the alveolar interstitial hemorrhage and inflammatory cell infiltration were more common in the adult rabbits; the lung water content at 2 h after injury (82.68±0.58 vs 81.06±0.34) and the oxygen saturation at 0.5 h after injury (75.00±18.52 vs 42.20±21.84) were higher in young rabbits group than adult rabbits group (P < 0.05). The percentage of neutrophils in the young rabbits group at 6 (36.92±16.01 vs 60.30±12.09), 12 (31.42±11.30 vs 46.40±14.15), 24 (29.48±4.76 vs 35.52±9.77) and 48 h (25.70±11.66 vs 37.68±9.11) after injury were lower than adult rabbits group (P < 0.05). Conclusion Compared with mature lungs of adult rabbits after lung blast injury, the immature lungs of young rabbits recover faster and have milder inflammatory reaction, but the SP-B content is lower, the synthesis and secretion function recover slowly, which may lead to the recovery of respiratory function slow. Our results may be used to guide the treatment for injury in immature and mature lungs.

New Findings: What is the central question of this study?It is reported that polymorphism of the gene for pulmonary surfactant‐associated protein B (SFTPB) is associated with chronic obstructive pulmonary disease (COPD): what are the function and mechanism of action of SFTPB in COPD?What is the main finding and its importance?Under stimulation of the risk factors of COPD, SFTPB expression is decreased, which may be involved in the formation of COPD. The progress of COPD induces an inflammatory response and reduces SFTPB expression. Levels of prostaglandin‐endoperoxide synthase‐2 (PTGS2) and inflammatory responses are changed by SFTPB, which indicates that SFTPB promotes the progression of COPD by PTGS2 and inflammation. Pulmonary surfactant‐associated protein B (SFTPB) is a critical protein for lung homeostasis, and polymorphism of its gene is associated with chronic obstructive pulmonary disease (COPD). However, few studies have so far confirmed the functional involvement of SFTPB in COPD. Serum SFTPB and inflammatory cytokine levels were measured in 54 patients with acute exacerbation of COPD and 29 healthy controls. A549 cells were induced using 10% cigarette smoke extract (CSE) and treated with dexamethasone to investigate the effect of inflammation on SFTPB expression, and the effect of SFTPB overexpression and silencing on inflammatory cytokines was measured using real‐time PCR and enzyme‐linked immunosorbent assay. SFTPB expression was assessed in mouse lung tissues using immunofluorescence. Serum levels of SFTPB were significantly lower in COPD patients than in controls (P = 0.009). Conversely, levels of interleukin (IL)‐6 and prostaglandin‐endoperoxide synthase‐2 (PTGS2) were increased in COPD patients (IL‐6: P = 0.006; PTGS2: P = 0.043). After CSE treatment, SFTPB mRNA and protein levels were significantly decreased compared to controls (mRNA: P = 0.002; protein: P = 0.011), while IL‐6, IL‐8 and PTGS2 were elevated. Dexamethasone treatment increased SFTPB levels. Following overexpression of SFTPB in A549 cells, mRNA and protein levels of IL‐6, IL‐8 and PTGS2 were significantly reduced, while gene silencing induced the opposite effect. SFTPB levels were significantly reduced in the lung tissue of a mouse model of COPD compared to controls. Reduced SFTPB levels may induce PTGS2 and inflammatory responses in COPD and SFTPB could be a key protein for evaluation of COPD progression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B)-containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants ≤1,000 g birth weight (BW). METHODS: We randomized 85 preterm infants ventilated at 7-14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL). RESULTS: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02). CONCLUSION: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes.

BackgroundMutations of genes affecting surfactant homeostasis, such as SFTPB, SFTPC and ABCA3, lead to diffuse lung disease in neonates and children. Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription factor-1 (TTF-1)--critical for lung, thyroid and central nervous system morphogenesis and function--causes a rare form of progressive respiratory failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in this syndrome are heterogeneous and poorly explored. We report a novel TTF-1 molecular defect causing recurrent respiratory failure episodes in an infant.MethodsThe subject was an infant with severe neonatal respiratory distress syndrome followed by recurrent respiratory failure episodes, hypopituitarism and neurological abnormalities. Lung histology and ultrastructure were assessed by surgical biopsy. Surfactant-related genes were studied by direct genomic DNA sequencing and array chromatine genomic hybridization (aCGH). Surfactant protein expression in lung tissue was analyzed by confocal immunofluorescence microscopy. For kinetics studies, surfactant protein B and disaturated phosphatidylcholine (DSPC) were isolated from serial tracheal aspirates after intravenous administration of stable isotope-labeled (2)H(2)O and (13)C-leucine; fractional synthetic rate was derived from gas chromatography/mass spectrometry (2)H and (13)C enrichment curves. Six intubated infants with no primary lung disease were used as controls.ResultsLung biopsy showed desquamative interstitial pneumonitis and lamellar body abnormalities suggestive of genetic surfactant deficiency. Genetic studies identified a heterozygous ABCA3 mutation, L941P, previously unreported. No SFTPB, SFTPC or NKX2.1 mutations or deletions were found. However, immunofluorescence studies showed TTF-1 prevalently expressed in type II cell cytoplasm instead of nucleus, indicating defective nuclear targeting. This pattern has not been reported in human and was not found in two healthy controls and in five ABCA3 mutation carriers. Kinetic studies demonstrated a marked reduction of SP-B synthesis (43.2 vs. 76.5 ± 24.8%/day); conversely, DSPC synthesis was higher (12.4 vs. 6.3 ± 0.5%/day) compared to controls, although there was a marked reduction of DSPC content in tracheal aspirates (29.8 vs. 56.1 ± 12.4% of total phospholipid content).ConclusionDefective TTF-1 signaling may result in profound surfactant homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous ABCA3 missense mutations may act as disease modifiers in other genetic surfactant defects.

Pulmonary surfactants, a complex assembly of phospholipids and surfactant proteins such as SP-B and SP-C, are critical for maintaining respiratory system functionality by lowering surface tension (ST) and preventing alveolar collapse. Our study introduced five synthetic SP-B peptides and one SP-C peptide, leading to the synthesis of CHAsurf candidates (CHAsurf-1 to CHAsurf-5) for evaluation. We utilized a modified Wilhelmy balance test to assess the surface tension properties of the surfactants, measuring spreading rate, surface adsorption, and ST-area diagrams to comprehensively evaluate their performance. Animal experiments were performed on New Zealand white rabbits to test the efficacy of CHAsurf-4B, a variant chosen for its economic viability and promising ST reduction properties, comparable to Curosurf®. The study confirmed that higher doses of SP-B in CHAsurf-4 are associated with improved ST reduction. However, due to cost constraints, CHAsurf-4B was selected for in vivo assessment. The animal model revealed that CHAsurf-4B could restore alveolar structure and improve lung elasticity, akin to Curosurf®. Our research highlights the significance of cysteine residues and disulfide bonds in the structural integrity and function of synthetic SP-B analogues, offering a foundation for future surfactant therapy in respiratory disorders. This study's findings support the potential of CHAsurf-4B as a therapeutic agent, meriting further investigation to solidify its role in clinical applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Treatment of neonatal respiratory distress syndrome (RDS) using animal-derived lung surfactant preparations has reduced the mortality of handling premature infants with RDS to a 50th of that in the 1960s. The supply of animal-derived lung surfactants is limited and only a part of the preterm babies is treated. Thus, there is a need to develop well-defined synthetic replicas based on key components of natural surfactant. A synthetic product that equals natural-derived surfactants would enable cost-efficient production and could also facilitate the development of the treatments of other lung diseases than neonatal RDS. Recently the first synthetic surfactant that contains analogues of the two hydrophobic surfactant proteins B (SP-B) and SP-C entered clinical trials for the treatment of neonatal RDS. The development of functional synthetic analogues of SP-B and SP-C, however, is considerably more challenging than anticipated 30 years ago when the first structural information of the native proteins became available. For SP-B, a complex three-dimensional dimeric structure stabilized by several disulphides has necessitated the design of miniaturized analogues. The main challenge for SP-C has been the pronounced amyloid aggregation propensity of its transmembrane region. The development of a functional non-aggregating SP-C analogue that can be produced synthetically was achieved by designing the amyloidogenic native sequence so that it spontaneously forms a stable transmembrane α-helix. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611–-620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for "lumping and splitting" are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147–-155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939). Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS. Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of β2-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257). [ABSTRACT FROM AUTHOR]

Cardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung's alveolar spaces due to an elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Some studies claim that these patients may have higher levels of surfactant protein B in the bloodstream. The correct approach to patients with CPE should include a detailed medical history and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paper reviews the pathophysiology, clinical presentation, and management of CPE.

Background: Respiratory distress syndrome (RDS) is a severe pulmonary disease predominantly affects preterm newborns. Polymorphisms of surfactant-protein genes have been mostly evaluated as the candidate contributors in genetics of RDS. However the results are divers in different studies. We aimed at investigating the association of surfactant protein B (SPB) gene 9306 A/G polymorphism (rs7316) with RDS development.Method: Three hundred and eighty newborns with gestational age of less than 34 weeks were included in a multicenter case-control study. Respiratory distress (RD) was scored according to Downes' scoring system. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping.Result: One hundred and eighty-four neonates showed RDS and 196 did not. Gestational age (GA) was significantly lower in the RDS group compared with the controls. AA genotype and A allele were found more frequently in the RDS group than the controls (96.2% versus 63.8% and 98.1% versus 80.6%, respectively) (p =.0001).Conclusions: This is the first report of association of SFTPB rs7316 polymorphism with RDS development in Iranian newborns. The current study suggests that GA <28-weeks is the most important factor in predisposition to RDS. Genetic background in terms of SP-B gene might be involved in predisposition to RDS in premature neonates. [ABSTRACT FROM AUTHOR]

Hyperglycemia during pregnancy is associated with fetal lung development disorders and surfactant protein (SP) deficiency. Here, we examined the role of FOXA2 and Akt signaling in fetal lung development during diabetic pregnancy. Sprague‐Dawley rats were injected with streptozocin (STZ) during pregnancy to induce diabetes (DM). DM‐exposed fetal lungs exhibited reduced numbers of alveoli, irregularities in the appearance and thickness of the alveolar septum, increased levels of glycogen and lipids in type II alveolar epithelial cells, fewer microvilli and mature lamellar bodies, and swollen mitochondria. SP‐B and SP‐C in DM amniotic fluid and DM lungs were lower than in the control group (P < 0.05). DM lung nuclear FOXA2 was lower compared with the control group (P < 0.05), but p‐FOXA2 was higher (P < 0.05). In murine lung epithelial (MLE) 12 cells, p‐AKT levels were increased by high glucose/insulin, but decreased by the Akt inhibitor MK2206 (P < 0.05). Expression of nuclear FOXA2 was increased by MK2206 compared with the high glucose/insulin group (P < 0.05). These results suggest that maternal diabetes induces fetal lung FOXA2 phosphorylation through the Akt pathway, and also affects the maturation of alveolar epithelial cells and reduces levels of SP‐B and SP‐C in the fetal lungs. An Akt inhibitor reversed the changes in SP expression in vitro. [ABSTRACT FROM AUTHOR]

Alveolar type II (AT2) epithelial cells are uniquely specialized to produce surfactant in the lung and act as progenitor cells in the process of repair after lung injury. AT2 cell injury has been implicated in several lung diseases, including idiopathic pulmonary fibrosis and bronchopulmonary dysplasia. The inability to maintain primary AT2 cells in culture has been a significant barrier in the investigation of pulmonary biology. We have addressed this knowledge gap by developing a three-dimensional (3D) organotypic coculture using primary human fetal AT2 cells and pulmonary fibroblasts. Grown on top of matrix-embedded fibroblasts, the primary human AT2 cells establish a monolayer and have direct contact with the underlying pulmonary fibroblasts. Unlike conventional two-dimensional (2D) culture, the structural and functional phenotype of the AT2 cells in our 3D organotypic culture was preserved over 7 days of culture, as evidenced by the presence of lamellar bodies and by production of surfactant proteins B and C. Importantly, the AT2 cells in 3D cocultures maintained the ability to replicate, with approximately 60% of AT2 cells staining positive for the proliferation marker Ki67, whereas no such proliferation is evident in 2D cultures of the same primary AT2 cells. This organotypic culture system enables interrogation of AT2 epithelial biology by providing a reductionist in vitro model in which to investigate the response of AT2 epithelial cells and AT2 cell–fibroblast interactions during lung injury and repair. [ABSTRACT FROM AUTHOR]

Prosurfactant protein B (pro-SFTPB) and surfactant protein D (SFTPD) are markers of lung inflammation and damage. We estimated geometric mean pro-SFTPB and SFTPD levels in 500 human immunodeficiency virus (HIV)-infected and 300 HIV-uninfected injection drug users, adjusting for smoking and other covariates. Pro-SFTPB levels were significantly higher among people with HIV (PWH) (adjusted geometric mean, 21.4 vs 18.1 ng/mL; P = .03), and were higher with lower CD4 counts (P trend = .001), higher HIV RNA (P trend = .05), and without highly active antiretroviral therapy (P = .03). These associations were not observed for SFTPD. Serum levels of pro-SFTPB are elevated among PWH and are associated with immunosuppression and uncontrolled viremia. [ABSTRACT FROM AUTHOR]

Background/Aims: Radiotherapy is applied to patients with inoperable cancer types including advanced stage non-small cell lung cancer (NSCLC) and radioresistance functions as a critical obstacle in radiotherapy. This study was aimed to investigate the mechanism of radioresistance regulated by surfactant protein B (SP-B). Methods: To investigate the role of SP-B in radioresistance, ΔSFTPB A549 cell line was established and SP-B expression was analyzed. In response to ionizing radiation (IR), the change of SP-B expression was analyzed in A549 and NCI-H441 cell lines. Conditioned media (CM) from NSCLC cells were utilized to evaluate the downstream signaling pathway. The in vivo effects of SP-B were assessed through mouse xenograft model with intratumoral injection of CM. Results: In response to IR, NSCLC cell lines showed decreased SP-B regulated by the TGF-β signaling and decreased SP-B stimulated cell survival and epithelial-mesenchymal transition. Treatment with CM from irradiated cells activated sPLA2, enhanced protein kinase Cδ-MAPKs signaling pathway, and increased arachidonic acid production. We confirmed the in vivo roles of SP-B through mouse xenograft model. Conclusion: Our results revealed that down-regulation of SP-B was involved in the radiation-induced metastatic conversion of NSCLC and provided evidence that SP-B acted as a suppressor of NSCLC progression. [ABSTRACT FROM AUTHOR]

The N-terminal 25 amino-acid residues of pulmonary surfactant protein B (SP-B1-25) induces unusual lipid polymorphisms in a model lipid system, 4:1 DPPC/POPG, mirroring the lipid composition of native pulmonary surfactant. It is widely suggested that SP-B1-25-induced lipid polymorphisms within the alveolar aqueous subphase provide a structural platform for rapid lipid adsorption to the air-water interface. Here, we characterize in detail the phase behavior of DPPC and POPG in hydrated lipid assemblies containing therapeutic levels of SP-B1-25 using 2H and 31P solid state NMR spectroscopy. The appearance of a previously observed isotropic lipid phase is found to be highly dependent on the thermal cycling of the samples. Slow heating of frozen samples leads to phase separation of DPPC into a lamellar phase whereas POPG lipids interact with the peptide to form an isotropic phase at physiologic temperature. Rapid heating of frozen samples to room temperature leads to strongly isotropic phase behavior for both DPPC and POPG lipids, with DPPC in exchange between isotropic and interdigitated phases. 31P T2 relaxation times confirm the isotropic phase to be consistent with a lipid cubic phase. The observed phases exhibit thermal stability up to physiologic temperature (37 °C) and are consistent with the formation of a ripple phase containing a large number of peptide-induced membrane structural defects enabling rapid transit of lipids between lipid lamellae. The coexistance of a lipid cubic phase with interdigitated lipids suggests a specific role for the highly conserved N-terminus of SP-B in stabilizing this unusual lipid polymorphism. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) induced by placental restriction (PR) in the sheep negatively impacts lung and pulmonary surfactant development during fetal life. Using a sheep model of low birth weight (LBW), we found that there was an increase in mRNA expression of surfactant protein (SP)-A, -B and -C in the lung of LBW lambs but no difference in the protein expression of SP-A or -B. LBW also resulted in increased lysosome-associated membrane glycoprotein (LAMP)-3 mRNA expression, which may indicate an increase in either the density of type II Alveolar epithelial cells (AEC) or maturity of type II AECs. Although there was an increase in glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase (11βHSD)-1 mRNA expression in the lung of LBW lambs, we found no change in the protein expression of these factors, suggesting that the increase in SP mRNA expression is not mediated by increased GC signalling in the lung. The increase in SP mRNA expression may, in part, be mediated by persistent alterations in hypoxia signalling as there was an increase in lung HIF-2α mRNA expression in the LBW lamb. The changes in the hypoxia signalling pathway that persist within the lung after birth may be involved in maintaining SP production in the LBW lamb. [ABSTRACT FROM AUTHOR]

Background: Expression of surfactant protein (SP)-B, which assures the structural stability of the pulmonary surfactant film, is influenced by various stimuli, including glucocorticoids; however, the role that cell-cell contact plays in SP-B transcription remains unknown. The aim of the current study was to investigate the impact of cell-cell contact on SP-B mRNA and mature SP-B expression in the lung epithelial cell line H441. Methods: Different quantities of H441 cells per growth area were either left untreated or incubated with dexamethasone. The expression of SP-B, SP-B transcription factors, and tight junction proteins were determined by qPCR and immunoblotting. The influence of cell density on SP-B mRNA stability was investigated using the transcription inhibitor actinomycin D. Results: SP-B mRNA and mature SP-B expression levels were significantly elevated in untreated and dexamethasone-treated H441 cells with increasing cell density. High cell density as a sole stimulus was found to barely have an impact on SP-B transcription factor and tight junction mRNA levels, while its stimulatory ability on SP-B mRNA expression could be mimicked using SP-B-negative cells. SP-B mRNA stability was significantly increased in high-density cells, but not by dexamethasone alone. Conclusion: SP-B expression in H441 cells is dependent on cell-cell contact, which increases mRNA stability and thereby potentiates the glucocorticoid-mediated induction of transcription. Loss of cell integrity might contribute to reduced SP-B secretion in damaged lung cells via downregulation of SP-B transcription. Cell density-mediated effects should thus receive greater attention in future cell culture-based research. [ABSTRACT FROM AUTHOR]

Background Surfactant proteins (SP’s) have been described as inherent proteins of the human central nervous system (CNS). Their distribution pattern in brain tissue and altered cerebrospinal fluid (CSF) – concentrations in different CNS pathologies are indicative of their immunological and rheological importance. The aim of this study has been to investigate when – compared to the lungs – SP’s are expressed in the developing rat brain and which functional components in the CNS participate in their production. Material and methods Brain and lung tissue from embryonal (days 10, 12, 14, 16, 17 and 20), newborn, and adult rats were harvested and investigated for expression of SP-A, SP-B, SP-C and SP-D using immunofluorescence microscopy in order to identify and compare the time points of their occurence in the respective tissue. To better identify the location of SP expression in the rat brain, SP’s were colocalized with use of an astrocyte marker (GFAP), a neuronal marker (NeuN), an endothelial marker (CD31) and an axonal marker (NF). Results and conclusion SP-A and SP-C are expressed in the CNS of rats during early embryonic age whereas SP-B and SP-D are first present in the adult rat brain. All SP’s are expressed in cells adjacent to CSF spaces, probably influencing and maintaining physiological CSF flow. SP’s A and C are abundant at the site of the blood brain barrier (BBB). [ABSTRACT FROM AUTHOR]

Lung surfactant protein B (SP-B), a 79 residue, hydrophobic protein from the saposin superfamily, plays an essential role in breathing. Because of the extreme hydrophobicity of SP-B, the experimental structure of this protein has not yet been determined. Here, we run all-atom molecular dynamics simulations using the OPLS-AA force field in GROMACS to study SP-B's structure and mechanisms for promoting lipid reorganization. Firstly, we find that the final structures indicate the need for some fine-tuning of the homology-based secondary structure predictions. Secondly, we find energetically feasible structures 1) with SP-B's helices in the plane of the bilayer, 2) with SP-B's helices inclined with respect to the bilayer, and 3) with SP-B in a closed structure interacting peripherally with the bilayer. Interestingly, SP-B structures that were bent at the hinge region between the pairs of helices promoted and/or stabilized defects in the lipid bilayer. Finally, particular salt bridge patterns and structural plasticity in the central loop and adjacent region of SP-B appeared to be involved in SP-B's lipid reorganization abilities. [ABSTRACT FROM AUTHOR]

Surfactant protein B (SP-B; 79 residues) is a member of the saposin superfamily and plays a pivotal role in lung function. The N- and C-terminal regions of SP-B, cross-linked by two disulfides, were theoretically predicted to fold as charged amphipathic helices, suggesting participation in surfactant activities. Previous studies with oxidized Super Mini-B (SMB), a construct based on the N- and C-regions of SP-B (i.e., residues 1–25 and 63–78) joined with a designer turn (-PKGG-) and two disulfides, indicated that freshly prepared SMB in lipids folded as a surface active, α-helix-hairpin. Because other peptides modeled on α-helical SP domains lost helicity and surfactant activity on storage, experiments were here performed on oxidized SMB in surfactant liposomes stored at ~ 2–8 °C for ≤ 5.5 years. Captive bubble surfactometry confirmed low minimum surface tensions for fresh and stored SMB preparations. FTIR spectroscopy of fresh and stored SMB formulations showed secondary structures compatible with the peptide folding as α-helix-hairpin. A homology (I-TASSER) model of oxidized SMB demonstrated a globular protein, exhibiting a core of hydrophobic residues and a surface of polar residues. Since mass spectroscopy indicated that the disulfides were maintained on storage, the stability of SMB may be partly due to the disulfides bringing the N- and C-α-helices closer. Mass spectroscopy of stored SMB preparations showed some methionine oxidation, and also partial deacylation of surfactant phospholipids to form lyso-derivatives. However, the stable conformation and activity of stored SMB surfactant suggest that the active helix-hairpin resists these chemical changes which otherwise may lead to surfactant inhibition. [ABSTRACT FROM AUTHOR]

Background There is a strong link between smaller air pollution particles and a range of serious health conditions. Thus, there is a need for understanding the impacts of airborne fine particulate matter (PM) with an aerodynamic diameter of < 1 μm (PM 1 ) on lung alveolar epithelial cells. In the present study, mouse lung epithelial type II cell MLE-12 cells were used to examine the intracellular oxidative responses and the surfactant protein expressions after exposure to various concentrations of PM 1 collected from an urban site and a steel-factory site (referred as uPM 1 and sPM 1 hereafter, respectively). Methods Physicochemical characterization of PM 1 was performed by using scanning electron microscopy and transmission electron microscopy. Cytotoxicity and autophagy induced by PM 1 were assessed by using comprehensive approaches after MLE-12 cells were exposed to different concentrations of PM 1 for various times. Expression of surfactant proteins B and C in MLE-12 cells was determined by Western blotting. Results All of the tested PM 1 induced cytotoxicity evidenced by significant decrease of cell viability and increase of lactate dehydrogenase (LDH) release in a time- and concentration-dependent manner in the exposed cells compared with the unexposed cells. A similar pattern of increase of intercellular reactive oxygen species (ROS) generation and decrease of superoxide dismutase (SOD) and catalase (CAT) activities was also observed. PM 1 -induced autophagy was evidenced by an increase in microtubule-associated protein light chain-3 (LC3) puncta, accumulation of LC3II, and increased levels of beclin1. Data from Western blotting showed significant decrease of surfactant protein B and C expressions. Relatively high concentrations of transition metals, including Fe, Cu and Mn, may be responsible for the higher toxicity of sPM 1 compared with uPM 1 . Moreover, pretreatment with N -acetylcysteine (NAC) or Chelex (a metal chelating agent, which removes a large suite of metals from PM 1 ) prevented the increase of PM 1 -inudced ROS generation and autophagy, and down-regulated the expression of surfactant proteins B and C. Conclusion PM 1 , particularly PM 1 with high concentrations of transition metals, such as Fe, Cu and Mn, induces oxidative damage and autophagy, as well as inhibits surfactant protein B and C expressions in lung alveolar type II epithelial cells. General significance This study will help to understand the mechanism underlying the toxicological effects of PM 1 in lung alveolar type II epithelial cells. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the role of pulmonary surfactant-associated protein B (SP-B) expression in the pathogenesis of neonatal respiratory distress syndrome (RDS) via detecting the protein and mRNA expression of SP-B. Methods: A total of 60 unrelated neonates who died of RDS were chosen as the RDS group and then subgrouped into ≤32 weeks group, 32∼37 weeks group and ≥37 weeks group (n=20). Sixty neonates who died of other diseases were enrolled as controls and subdivided into 3 matched groups based on the gestational age. Western blot assay and RT-PCR were employed. Results: In the RDS group, SP-B protein expression was reduced or deficient in 8 neonates of which 6 had no SP-B protein expression. In the control group, only 1 had reduced SP-B protein expression. The reduced or deficient SP-B protein expression in 9 neonates of both groups was noted in the ≥37 weeks group. In the RDS group, the SP-B mRNA expression was significantly lower than that in the control group. In the ≤37 weeks group, SP-B mRNA expression was comparable between the RDS group and control group. In the 32∼37 weeks group, the SP-B mRNA expression in the RDS group was significantly reduced when compared with the control group. In the ≥37 weeks group, the SP-B mRNA expression in the RDS group was dramatically lower than that in the control group. Conclusions: Alteration of SP-B expression is present at transcriptional and translational levels. Reduction of SP-B mRNA and protein expression is involved in the pathogenesis of RDS.

Background and Objectives: Newborns delivered late-preterm (between 340/7 and 366/7 weeks of gestation) are at increased risk of respiratory distress syndrome (RDS). Polymorphisms within the surfactant protein (SP) A and B gene have been shown to predispose to RDS in preterm neonates. The aim of this study was to investigate whether specific SP-A and/or SP-B genetic variants are also associated with RDS in infants born late-preterm. Methods: This prospective cross-sectional study included 56 late-preterm infants with and 60 without RDS. Specific SP-A1/SP-A2 haplotypes and SP-B Ile131Thr polymorphic alleles were determined in blood specimens using polymerase-chain-reaction and DNA sequencing. Results: The SP-A1 6A4 and the SP-A2 1A5 haplotypes were significantly overrepresented in newborns with RDS compared to controls (OR 2.86, 95%CI 1.20–6.83 and OR 4.68, 95%CI 1.28–17.1, respectively). The distribution of the SP-B Ile131Thr genotypes was similar between the two late-preterm groups. Overall, the SP-A1 6A4 or/and SP-A2 1A5 haplotype was present in 20 newborns with RDS (35.7%), resulting in a 4.2-fold (1.60–11.0) higher probability of RDS in carriers. Multivariable regression analysis revealed that the effect of SP-A1 6A4 and SP-A2 1A5 haplotypes was preserved when adjusting for known risk or protective factors, such as male gender, smaller gestational age, smaller weight, complications of pregnancy, and administration of antenatal corticosteroids. Conclusions: Specific SP-A genetic variants may influence the susceptibility to RDS in late-preterm infants, independently of the effect of other perinatal factors. [ABSTRACT FROM AUTHOR]

Growing interest raised on circulating biomarkers of structural alveolar–capillary unit damage and very recent data support surfactant protein type B (SP-B) as the most promising candidate in this setting. With respect to other proteins proposed as possible markers of lung damage, SP-B has some unique qualities: it is critical for the assembly of pulmonary surfactant, making its lack incompatible with life; it has no other known site of synthesis except alveolar epithelial cells different from other surfactant proteins; and, it undergoes a proteolytic processing in a pulmonary-cell-specific manner. In the recent years circulating SP-B isoforms, mature or immature, have been demonstrated to be detectable in the circulation depending on the magnitude of the damage of alveolar capillary membrane. In the present review, we summarize the recent knowledge on SP-B regulation, function and we discuss its potential role as reliable biological marker of alveolar capillary membrane (dys)function in the context of heart failure. [ABSTRACT FROM AUTHOR]

Assembly of pulmonary surfactant lipid-protein complexes depends on conformational changes coupled with proteolytic maturation of proSP-B, the precursor of pulmonary surfactant protein B (SP-B), along the surfactant biogenesis pathway in pneumocytes. Conformational destabilization of the N-terminal propeptide of proSP-B (SP-BN) triggers exposure of the mature SP-B domain for insertion into surfactant lipids. We have studied the conformational stability during GdmCl- or urea-promoted unfolding of SP-BN with trp fluorescence and circular dichroism spectroscopies. Binding of the intermediate states to bis-ANS suggests their molten globule-like character. ΔG0H2O was ~ 12.7 kJ·mol-1 either with urea or GdmCl. None of the thermal transitions of SP-BN detected by CD correspond to protein unfolding. Differential scanning calorimetry of SP-BN evidenced two endothermic peaks involved in oligomer dissociation as confirmed with 2 M urea. Ionic strength was relevant since at 150 mM NaCl, the process originating the endotherm at the highest temperature was irreversible (Tm2 = 108.5°C) with an activation energy of 703.8 kJ·mol-1. At 500 mM NaCl the process became reversible (Tm2 = 114.4°C) and data were fitted to the Non-two States model with two subpeaks. No free thiols in the propeptide could be titrated by DTNB with or without 5.7 M GdmCl, indicating disulfide bonds establishment. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant is a complex fluid that comprises phospholipids and four proteins (SP-A, SP-B, SP-C, and SP-D) with different biological functions. SP-B, SP-C, and SP-D are essential for the lungs' surface tension function and for the organization, stability and metabolism of lung parenchyma. SP-A and SP-D, which are also known as pulmonary collectins, have an important function in the host's lung immune response; they act as opsonins for different pathogens via a C-terminal carbohydrate recognition domain and enhance the attachment to phagocytic cells or show their own microbicidal activity by increasing the cellular membrane permeability. Interactions between the pulmonary collectins and bacteria or viruses have been extensively studied, but this is not the same for fungal pathogens. SP-A and SP-D bind glucan and mannose residues from fungal cell wall, but there is still a lack of information on their binding to other fungal carbohydrate residues. In addition, both their relation with immune cells for the clearance of these pathogens and the role of surfactant proteins' regulation during respiratory fungal infections remain unknown. Here we highlight the relevant findings associated with SP-A and SP-D in those respiratory mycoses where the fungal infective propagules reach the lungs by the airways. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that vitamin D deficiency has a detrimental impact on lung development. In this study, we aimed to identify the mechanisms linking vitamin D with lung development using a mouse model of dietary manipulation.Methods: Female offspring were euthanized at different time-points; embryonic day (E)14.5, E17.5 or postnatal day (P)7. Lung tissue was collected for mass spectrometry-based proteomic analysis. Label-free quantitation was used to identify the differentially expressed proteins and ELISA confirmed the expression of selected proteins. Lungs from separate groups of mice were fixed and processed for stereological assessment of lung structure.Results: No differences in protein expression between vitamin D deficient and replete mice were detected at E14.5 and E17.5, whereas 66 proteins were differentially expressed in P7 lungs. The expression of pulmonary surfactant-associated protein B (SP-B) and peroxiredoxin 5 (PRDX5) were reduced in P7 lungs of vitamin D deficient mice, while the production of collagen type Ι alpha 1 (COL1A1) was higher in lungs of vitamin D deficient mice. There were no differences in lung volume, parenchymal volume, volume of airspaces or surface area of airspaces between vitamin D deficient and vitamin D replete mice across three time-points.Conclusions: The difference in protein expression during the early postnatal time-point suggests that vitamin D deficiency may induce alterations of lung structure and function in later life during alveolarization stage through impaired pulmonary surfactant production and anti-oxidative stress ability as well as enhanced collagen synthesis. These data provided a plausible mechanism linking maternal vitamin D deficiency with altered postnatal lung function. [ABSTRACT FROM AUTHOR]

Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo . A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50 μl of Pseudomonas aeruginosa solution (1 × 10 6 CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 h post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo . [ABSTRACT FROM AUTHOR]

Background Gas exchange abnormalities are part of the heart failure (HF) syndrome and growing interest raised on possible biomarkers of alveolar–capillary unit damage. The present pilot single-center study sought to investigate the prognostic values of circulating surfactant protein type B (SP-B) in a cohort of systolic HF patients. Methods One hundred and fifty-one HF stable outpatients and 37 healthy subjects underwent a full clinical assessment, including pulmonary function and lung diffusion for carbon monoxide (DLco), maximal cardiopulmonary exercise test and measurements for both circulating immature and mature forms of SP-B. Study end-points were hospitalization due to HF worsening and cardiovascular mortality. Results Immature SP-B, but not the mature form, was significantly higher in HF patients than in controls and was independently related to DLco, peak oxygen uptake and ventilatory efficiency. During the follow-up (median: 995 days; interquartile range: 739–1247 days), 97 patients experimented at least one HF hospitalization and 9 died for cardiovascular causes. At univariate analysis immature SP-B levels were significantly related to both cardiovascular death (p = 0.033) and HF hospitalization (p < 0.001). At multivariate analysis, immature SP-B levels remained independently associated to HF hospitalization (hazard ratio: 2.304; 95% confidence interval 1.858–3.019; p < 0.001). Conclusions Present data confirm a strong relationship between circulating immature SP-B levels, gas exchange abnormalities and exercise limitations in stable HF as well as they are consistent with the use of immature SP-B in HF clinical risk assessment. Larger prospective studies are needed to confirm its prognostic role as well as to evaluate whether immature SP-B plasma concentration varies in response to specific treatment. [ABSTRACT FROM AUTHOR]