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Seminars in Fetal & Neonatal Medicine Dec 2023Drug delivery using a surfactant vehicle has the potential to prevent systemic side effects by delivering therapeutic agents directly to the respiratory system. The... (Review)
Review
Drug delivery using a surfactant vehicle has the potential to prevent systemic side effects by delivering therapeutic agents directly to the respiratory system. The inherent chemical properties of surfactant allows it to readily distribute throughout the respiratory system. Therapeutic agents delivered by surfactant can primarily confer additional benefits but have potential to improve surfactant function. It is critically important that additional agents do not interefere with the innate surface tension lowering function of surfactant. Systemic evaluation through benchtop, translational and human trials are required to translate this potential technique into clinical practice.
Topics: Humans; Infant, Newborn; Surface-Active Agents; Drug Carriers; Pulmonary Surfactants; Drug Delivery Systems; Lipoproteins; Respiratory Distress Syndrome, Newborn
PubMed: 38040583
DOI: 10.1016/j.siny.2023.101499 -
JAMA Sep 2023The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified.
OBJECTIVE
To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age.
DESIGN, SETTING, AND PARTICIPANTS
Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022.
INTERVENTIONS
Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment.
MAIN OUTCOMES AND MEASURES
The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years.
RESULTS
Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]).
CONCLUSIONS AND RELEVANCE
In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12611000916943.
Topics: Female; Humans; Infant; Infant, Newborn; Dyspnea; Follow-Up Studies; Infant, Premature; Lipoproteins; Pulmonary Surfactants; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Sounds; Surface-Active Agents; Catheterization; Minimally Invasive Surgical Procedures; Continuous Positive Airway Pressure; Male; Child, Preschool
PubMed: 37695601
DOI: 10.1001/jama.2023.15694 -
European Journal of Pediatrics Aug 2020Preterm neonates with respiratory distress syndrome (RDS) are commonly treated with surfactant by intubate surfactant extubate (InSurE) technique. Mode of surfactant... (Comparative Study)
Comparative Study Randomized Controlled Trial
Minimally invasive surfactant therapy versus InSurE in preterm neonates of 28 to 34 weeks with respiratory distress syndrome on non-invasive positive pressure ventilation-a randomized controlled trial.
Preterm neonates with respiratory distress syndrome (RDS) are commonly treated with surfactant by intubate surfactant extubate (InSurE) technique. Mode of surfactant administration has evolved towards less invasive technique in the last few years. We randomised 58 preterm infants of 28-34 weeks of gestation with RDS within 6 h of birth to receive surfactant by InSurE or minimally invasive surfactant therapy (MIST). Non-invasive positive pressure ventilation (NIPPV) was used as primary respiratory support. The main objective was to compare the need of invasive mechanical ventilation (IMV) in first 72 h of life and secondarily hemodynamically significant patent ductus arteriosus (hsPDA), intraventricular haemorrhage (IVH) (> grade 2), bronchopulmonary dysplasia (BPD) and composite outcome of BPD/mortality. We did not find any difference in need of IMV in first 72 h between MIST and InSurE (relative risk with MIST, 0.62; 95% confidence interval, 0.22 to 1.32). No difference was observed in terms of hs PDA, IVH (> grade 2), BPD and composite outcome of BPD/mortality.Conclusion: There is no difference between MIST and InSurE in preterm neonates with RDS with NIPPV as a primary mode of respiratory support. Larger multicentre studies are needed to further explore differences in treatment failure and other secondary outcomes.Trial registration: www.ctri.nic.in id CTRI/2019/03/017992, registration date March 8, 2019. What is Known • InSurE is commonly used for many years for treatment of RDS in preterm neonates. • MIST has been introduced as a newer tool. What is New • MIST with feeding tube is comparable with InSurE in preterm infants with RDS in developing countries. •NIPPV can be used as primary respiratory support for MIST.
Topics: Combined Modality Therapy; Female; Humans; Infant, Newborn; Infant, Premature; Intubation, Intratracheal; Male; Noninvasive Ventilation; Positive-Pressure Respiration; Prospective Studies; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Treatment Outcome
PubMed: 32462483
DOI: 10.1007/s00431-020-03682-9 -
Frontiers in Immunology 2023Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar... (Review)
Review
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar macrophages (AMs) have been identified as playing a pivotal role in the pathogenesis of PAP. In most of PAP cases, the disease is triggered by impaired cholesterol clearance in AMs that depend on granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in defective alveolar surfactant clearance and disruption of pulmonary homeostasis. Currently, novel pathogenesis-based therapies are being developed that target the GM-CSF signaling, cholesterol homeostasis, and immune modulation of AMs. In this review, we summarize the origin and functional role of AMs in PAP, as well as the latest therapeutic strategies aimed at addressing this disease. Our goal is to provide new perspectives and insights into the pathogenesis of PAP, and thereby identify promising new treatments for this disease.
Topics: Humans; Pulmonary Alveolar Proteinosis; Macrophages, Alveolar; Granulocyte-Macrophage Colony-Stimulating Factor; Pulmonary Alveoli; Pulmonary Surfactants; Rare Diseases; Surface-Active Agents
PubMed: 37388737
DOI: 10.3389/fimmu.2023.1195988 -
Frontiers in Immunology 2022Pulmonary surfactant constitutes an important barrier that pathogens must cross to gain access to the rest of the organism the respiratory surface. The presence of... (Review)
Review
Pulmonary surfactant constitutes an important barrier that pathogens must cross to gain access to the rest of the organism the respiratory surface. The presence of pulmonary surfactant prevents the dissemination of pathogens, modulates immune responses, and optimizes lung biophysical activity. Thus, the application of pulmonary surfactant for the treatment of respiratory diseases provides an effective strategy. Currently, several clinical trials are investigating the use of surfactant preparations to treat patients with coronavirus disease 2019 (COVID-19). Some factors have been considered in the application of pulmonary surfactant for the treatment COVID-19, such as mechanical ventilation strategy, timing of treatment, dose delivered, method of delivery, and preparation utilized. This review supplements this list with two additional factors: accurate measurement of surfactants in patients and proper selection of pulmonary surfactant components. This review provides a reference for ongoing exogenous surfactant trials involving patients with COVID-19 and provides insight for the development of surfactant preparations for the treatment of viral respiratory infections.
Topics: Humans; Lung; Pulmonary Surfactants; Respiration, Artificial; Surface-Active Agents; COVID-19 Drug Treatment
PubMed: 35592339
DOI: 10.3389/fimmu.2022.842453 -
Biochimica Et Biophysica Acta.... Jun 2022Pulmonary surfactant is a mixture of lipids and proteins, consisting of 90% phospholipid, and 10% protein by weight, found predominantly in pulmonary alveoli of... (Review)
Review
Pulmonary surfactant is a mixture of lipids and proteins, consisting of 90% phospholipid, and 10% protein by weight, found predominantly in pulmonary alveoli of vertebrate lungs. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), are present within the alveoli at very high concentrations, and exert anti-inflammatory effects by regulating multiple Toll like receptors (TLR2/1, TLR4, and TLR2/6) by antagonizing cognate ligand-dependent activation. POPG also attenuates LPS-induced lung injury in vivo. In addition, these lipids bind directly to RSV and influenza A viruses (IAVs) and block interaction between host cells and virions, and thereby prevent viral replication in vitro. POPG and PI also inhibit RSV and IAV infection in vivo, in mice and ferrets. The lipids markedly inhibit SARS-CoV-2 infection in vitro. These findings suggest that both POPG and PI have strong potential to be applied as both prophylaxis and post-infection treatments for problematic respiratory viral infections.
Topics: Animals; Anti-Inflammatory Agents; Antiviral Agents; Ferrets; Lung; Mice; Phospholipids; Pulmonary Surfactants; SARS-CoV-2; Toll-Like Receptor 2; COVID-19 Drug Treatment
PubMed: 35240310
DOI: 10.1016/j.bbalip.2022.159139 -
Cellular & Molecular Biology Letters Nov 2023The pulmonary surfactant that lines the air-liquid surface within alveoli is a protein-lipid mixture essential for gas exchange. Surfactant lipids and proteins are...
BACKGROUND
The pulmonary surfactant that lines the air-liquid surface within alveoli is a protein-lipid mixture essential for gas exchange. Surfactant lipids and proteins are synthesized and stored in the lamellar body (LB) before being secreted from alveolar type II (AT2) cells. The molecular and cellular mechanisms that regulate these processes are incompletely understood. We previously identified an essential role of general control of amino acid synthesis 5 like 1 (GCN5L1) and the biogenesis of lysosome-related organelle complex 1 subunit 1 (BLOS1) in surfactant system development in zebrafish. Here, we explored the role of GCN5L1 in pulmonary surfactant regulation.
METHOD
GCN5L1 knockout cell lines were generated with the CRISPR/Cas9 system. Cell viability was analyzed by MTT assay. Released surfactant proteins were measured by ELISA. Released surfactant lipids were measured based on coupled enzymatic reactions. Gene overexpression was mediated through lentivirus. The RNA levels were detected through RNA-sequencing (RNA-seq) and quantitative reverse transcription (qRT)- polymerase chain reaction (PCR). The protein levels were detected through western blotting. The cellular localization was analyzed by immunofluorescence. Morphology of the lamellar body was analyzed through transmission electron microscopy (TEM), Lysotracker staining, and BODIPY phosphatidylcholine labeling.
RESULTS
Knocking out GCN5L1 in MLE-12 significantly decreased the release of surfactant proteins and lipids. We detected the downregulation of some surfactant-related genes and misregulation of the ROS-Erk-Foxo1-Cebpα axis in mutant cells. Modulating the activity of the axis or reconstructing the mitochondrial expression of GCN5L1 could partially restore the expression of these surfactant-related genes. We further showed that MLE-12 cells contained many LB-like organelles that were lipid enriched and positive for multiple LB markers. These organelles were smaller in size and accumulated in the absence of GCN5L1, indicating both biogenesis and trafficking defects. Accumulated endogenous surfactant protein (SP)-B or exogenously expressed SP-B/SP-C in adenosine triphosphate-binding cassette transporterA3 (ABCA3)-positive organelles was detected in mutant cells. GCN5L1 localized to the mitochondria and LBs. Reconstruction of mitochondrial GCN5L1 expression rescued the organelle morphology but failed to restore the trafficking defect and surfactant release, indicating specific roles associated with different subcellular localizations.
CONCLUSIONS
In summary, our study identified GCN5L1 as a new regulator of pulmonary surfactant that plays a role in the biogenesis and positioning/trafficking of surfactant-containing LBs.
Topics: Animals; Mice; Alveolar Epithelial Cells; Lamellar Bodies; Lipids; Pulmonary Surfactants; RNA; Surface-Active Agents; Zebrafish
PubMed: 37936104
DOI: 10.1186/s11658-023-00506-0 -
American Journal of Respiratory and... Jan 2023Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including...
Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. We collected 147 blood, 9 lung tissue, and 36 BAL fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on BAL fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19 but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. Our data suggest that patients with severe COVID-19 harbor IgA autoantibodies against pulmonary surfactant proteins B and C and that these autoantibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation.
Topics: Humans; Pulmonary Surfactants; COVID-19; Bronchoalveolar Lavage Fluid; Surface-Active Agents; Autoantibodies; Immunoglobulin A
PubMed: 35926164
DOI: 10.1164/rccm.202201-0011OC -
American Journal of Perinatology Jan 2024The standard of care in treating respiratory distress syndrome in preterm infants is respiratory support with nasal continuous positive airway pressure or a combination... (Review)
Review
The standard of care in treating respiratory distress syndrome in preterm infants is respiratory support with nasal continuous positive airway pressure or a combination of continuous positive airway pressure and exogenous surfactant replacement. Endotracheal intubation, the conventional method for surfactant administration, is an invasive procedure associated with procedural and mechanical ventilation complications. The INSURE (intubation, surfactant administration, and extubation soon after) technique is an accepted method aimed at reducing the short-term complications and long-term morbidities related to mechanical ventilation but does not eliminate risks associated with endotracheal intubation and mechanical ventilation. Alternative methods of surfactant delivery that can overcome the problems associated with the INSURE technique are surfactant through a laryngeal mask, surfactant through a thin intratracheal catheter, and aerosolized surfactant delivered using nebulizers. The three alternative methods of surfactant delivery studied in the last two decades have advantages and limitations. More than a dozen randomized controlled trials have aimed to study the benefits of the three alternative techniques of surfactant delivery compared with INSURE as the control arm, with promising results in terms of reduction in mortality, need for mechanical ventilation, and bronchopulmonary dysplasia. The need to find a less invasive surfactant administration technique is a clinically relevant problem. Before broader adoption in routine clinical practice, the most beneficial technique among the three alternative strategies should be identified. This review aims to summarize the current evidence for using the three alternative techniques of surfactant administration in neonates, compare the three techniques, highlight the knowledge gaps, and suggest future directions. KEY POINTS: · The need to find a less invasive alternative method of surfactant delivery is a clinically relevant problem.. · Clinical trials that have studied alternative surfactant delivery methods have shown promising results but are inconclusive for broader adoption into clinical practice.. · Future studies should explore novel clinical trial methodologies and select clinically significant long term outcomes for comparison..
Topics: Infant, Newborn; Humans; Infant, Premature; Surface-Active Agents; Pulmonary Surfactants; Respiration, Artificial; Continuous Positive Airway Pressure; Respiratory Distress Syndrome, Newborn; Intubation, Intratracheal; Randomized Controlled Trials as Topic
PubMed: 36539205
DOI: 10.1055/a-2001-9139 -
Colloids and Surfaces. B, Biointerfaces Feb 2022Pulmonary fungal infections lead to damage of the endogenous lung surfactant system. However, the molecular mechanism underlying surfactant inhibition is unknown....
Pulmonary fungal infections lead to damage of the endogenous lung surfactant system. However, the molecular mechanism underlying surfactant inhibition is unknown. β-D-glucan is the major component of pathogenic fungal cell walls and is also present in organic dust, which increases the risk of respiratory diseases. The objective of this study was to characterize the interaction of this D-glucopyranose polymer with pulmonary surfactant. Our results show that β-D-glucan induced a concentration-dependent inhibition of the surface adsorption, respreading, and surface tension-lowering activity of surfactant preparations containing surfactant proteins SP-B and SP-C. Our data support a new mechanism of surfactant inhibition that consists in the extraction of phospholipid molecules from surfactant membranes by β-D-glucan. As a result, surfactant membranes became more fluid, as demonstrated by fluorescence anisotropy, and showed decreased T and transition enthalpy. Surfactant preparations containing surfactant protein A (SP-A) were more resistant to β-D-glucan inhibition. SP-A bound to different β-D-glucans with high affinity (K = 1.5 ± 0.1 nM), preventing and reverting β-D-glucan inhibitory effects on surfactant interfacial adsorption and partially abrogating β-D-glucan inhibitory effects on surfactant's reduction of surface tension. We conclude that β-D-glucan inhibits the biophysical function of surfactant preparations lacking SP-A by subtraction of phospholipids from surfactant bilayers and monolayers. The increased resistance of SP-A-containing surfactant preparations to β-D-glucan reinforces its use in surfactant replacement therapy.
Topics: Glucans; Phospholipids; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants
PubMed: 34836708
DOI: 10.1016/j.colsurfb.2021.112237