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Pulmonary alveolar proteinosis (PAP) is a life-threatening, rare lung syndrome for which there is no cure and no approved therapies. PAP is a disease of lipid accumulation characterized by alveolar macrophage foam cell formation. While much is known about the clinical presentation, there is a paucity of information regarding temporal changes in lipids throughout the course of disease. Our objectives were to define the detailed lipid composition of alveolar macrophages in PAP patients at the time of diagnosis and during treatment. We performed comprehensive mass spectrometry to profile the lipid signature of alveolar macrophages obtained from three independent mouse models of PAP and from PAP and non-PAP patients. Additionally, we quantified changes in macrophage-associated lipids during clinical treatment of PAP patients. We found remarkable variations in lipid composition in PAP patients, which were consistent with data from three independent mouse models. Detailed lipidomic analysis revealed that the overall alveolar macrophage lipid burden inversely correlated with clinical improvement and response to therapy in PAP patients. Specifically, as PAP patients experienced clinical improvement, there was a notable decrease in the total lipid content of alveolar macrophages. This crucial observation suggests that the levels of these macrophage-associated lipids can be utilized to assess the efficacy of treatment. These findings provide valuable insights into the dysregulated lipid metabolism associated with PAP, offering the potential for lipid profiling to serve as a means of monitoring therapeutic interventions in PAP patients.

Background: The Subglottic Cysts (SGCs) are a rare cause of respiratory distress in infants. Typical risk factors include male gender, extreme prematurity, gastro-oesophageal reflux and invasive ventilation, the latter being associated with mucosal damage and blockage of the subglottic cysts' ducts. We describe a case of acquired subglottic cysts in a premature infants presented with respiratory distress. Case presentation: A premature male infant was born at 25 weeks + 2 days with a history of monochorionic diamniotic twin pregnancy with twin-to-twin transfusion syndrome. During hospitalization, invasive mechanical ventilation was necessary for a total of 18 days; the patient was discharged at postmenstrual age of 40 weeks + 1 day in good condition. At 43 weeks post-menstrual age, he presented to our department with mixed stridor and worsening of respiratory dynamics. A laryngotracheoscopy evaluation was performed. The exam showed the presence of multiple SGCs causing an almost complete obstruction of the airway. Because of the significant reduction of the airway's patency, the child underwent a tracheotomy and thereafter cysts' removal using cold steel microinstruments. A better airway patency was restored although a slight glottic edema persisted. The histopathology confirmed the benign nature of the lesions. Successive controls showed a completely patent airway and absence of SGCs. Conclusion: In conclusion, SGCs should be considered in preterm infants with respiratory distress previously intubated, which cannot be explained by the most common causes. Early diagnosis and treatment are fundamental to reducing the morbidity and mortality associated with this disease. [ABSTRACT FROM AUTHOR]

Additives in vaping products, such as flavors, preservatives, or thickening agents, are commonly used to enhance user experience. Among these, Vitamin E acetate (VEA) was initially thought to be harmless but has been implicated as the primary cause of e-cigarette or vaping product use-associated lung injury, a serious lung disease. In our study, VEA serves as a proxy for other e-cigarette additives. To explore its harmful effects, we developed an exposure system to subject a pulmonary surfactant (PSurf) model to VEA-rich vapor. Through detailed analysis and atomic-level simulations, we found that VEA tends to cluster into aggregates on the PSurf surface, inducing deformations and weakening its essential elastic properties, critical for respiratory cycle function. Apart from VEA, our experiments also indicate that propylene glycol and vegetable glycerin, widely used in e-liquid mixtures, or their thermal decomposition products, alter surfactant properties. This research provides molecular-level insights into the detrimental impacts of vaping product additives on lung health. [ABSTRACT FROM AUTHOR]

Introduction: Hyaline Membrane Disease (HMD) is a major cause of respiratory distress in preterm neonates due to a deficiency in pulmonary surfactant. Continuous Positive Airway Pressure (CPAP) serves as an effective non-invasive respiratory support that can reduce the necessity for invasive ventilation. This study evaluated the efficacy and outcomes of nasal CPAP in preterm neonates with HMD. Materials & Methods: After receiving IEC approval, a 12-month retrospective and prospective observational study was conducted. The study involved 50 intramural neonates, aged 28-36 weeks gestation, admitted to the NICU at IMCHRC with clinical and radiological signs of HMD. These neonates were treated with nasal CPAP and categorized into two groups: CPAP success (weaned off CPAP) and CPAP failure (required mechanical ventilation). Statistical analyses compared outcomes between these groups. Results: Among 227 preterm deliveries, 62 inborn neonates were diagnosed with HMD, and 50 received CPAP within 0-6 hours of birth. CPAP was successful in 82% of cases, while the remaining 18% required advanced ventilation. The mean CPAP duration was 37.5 ± 15.40 hours for the success group and 9.2 ± 1.56 hours for the failure group. CPAP effectiveness was 100% for mild, 93.10% for moderate, and 46.67% for severe HMD. Furthermore, 90% of those needing ventilation were under 32 weeks gestation. Conclusion: In developing countries, where prematurity and limited antenatal steroid use increase HMD risk, early nasal CPAP effectively treats mild to moderate HMD but is less effective for severe cases. It offers a safe, cost-effective alternative to invasive ventilation, reducing mechanical ventilation requirements, hospital stays, complications, and mortality. [ABSTRACT FROM AUTHOR]

Background: Pulmonary surfactant (PS) plays an important role in the treatment of sepsis-induced acute lung injury (ALI). Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, improves the secretion and function of PS in ALI, but the underlying mechanism remains unknown. This study aimed to investigate how liraglutide regulates PS secretion in ALI. Methods: C57BL/6 mice were injected subcutaneously with normal saline containing different concentrations of liraglutide after the establishment of the ALI model. MLE-12 cells were treated with liraglutide after LPS stimulation. The survival rate of mice, wet/dry weight ratio, inflammatory factors in bronchoalveolar lavage fluid (BALF), pulmonary injury, and apoptosis were analyzed. Cell viability, proliferation, apoptosis, the expression of SP-A, SP-B, and expression of autophagy-related proteins in cells were measured. Results: ALI mice showed reduced pulmonary injury, less apoptosis, and less inflammation compared to the controls. Liraglutide prolonged survival, decreased the wet/dry weight ratio, reduced inflammatory responses, and attenuated pulmonary edema compared with the ALI group. Moreover, LPS-induced cell damage and reduction of SP-A and SP-B expression were markedly reversed by liraglutide in MLE-12 cells. Furthermore, the protective effects of liraglutide were reversed by rapamycin. Conclusion: Liraglutide alleviate sepsis-induced ALI by inhibiting autophagy and regulating PS. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) can be idiopathic or driven by a specific insult, genetic susceptibility, or disease process. Inflammation plays a role in the pathophysiology, the extent of which remains a longstanding topic of debate. More recently, there has been increasing interest in a potential inciting role for aberrant lipid metabolism. Lipids are essential for the structure and function of all cell membranes, but specifically in the lung for surfactant composition, intra- and intercellular lipid mediators, and lipofibroblasts. Clinically, there is evidence of increased lipid deposition in the subpleural space and at a whole-lung tissue level in PF. There is evidence of increased parenchymal lipid deposition and abnormal mediastinal fat shape on chest computed tomography. A protective role for cholesterol-lowering drugs, including statins and ezetimibe, has been described in PF. At a cellular level, fatty acid, phospholipid, and glucose metabolism are disordered, as is the production of lipid mediators. Here we put forward the argument that there is substantive clinical and biological evidence to support a role for aberrant lipid metabolism and lipid mediators in the pathogenesis of PF. [ABSTRACT FROM AUTHOR]

Lamellar bodies (LBs) are tissue-specific lysosome-related organelles in type II alveolar cells that are the main site for the synthesis, storage, and secretion of pulmonary surfactants. Defects in pulmonary surfactants lead to a variety of respiratory and immune-related disorders. LB biogenesis is closely related to their function, but the underlying regulatory mechanism is largely unclear. Here, we found that deficiency of HPS6, a subunit of BLOC-2 (biogenesis of lysosome-related organelles complex-2), led to a reduction of the steady-state concentration of vacuolar-type H+-ATPase and an increase in the luminal pH of LBs. Furthermore, we observed increased LB size, accumulated surfactant proteins, and altered lipid profiling of lung tissue and BAL fluid due to HPS6 deficiency. These findings suggest that HPS6 regulates the distribution of vacuolar-type H+-ATPase on LBs to maintain its luminal acidity and LB homeostasis. This may provide new insights into the LB pathology. [ABSTRACT FROM AUTHOR]

Simple Summary: Pulmonary surfactant prevents alveolar collapse by reducing surface tension at the air–liquid interface. It contains two hydrophilic lectins, called SP-A and SP-D. They are factors of innate immune defence but also contribute to the surfactant structure and homeostasis. SP-A and SP-D recognise pathogen- or danger-associated molecular patterns (PAMPs, DAMPs), which enables opsonisation or agglutination of non-self or altered/abnormal self cells and contributes to their clearance. The term "cancer" includes a variety of diseases, often incurable, difficult to diagnose and 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. 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. [ABSTRACT FROM AUTHOR]

Background: To evaluate the impact of implementation of 2019 European respiratory distress syndrome (RDS) guidelines on the incidence of bronchopulmonary dysplasia (BPD). Method: We retrospectively collected the clinical data of very preterm infants (VPIs) born before 32 gestational weeks from January 1st 2018 to December 31st 2021. VPIs were divided into group A and group B according to their birth date which was before or at/after January 1st 2020, when the 2019 European RDS guidelines were introduced. BPD is considered as primary outcome. We statistically analyzed all the data, and we compared the general characteristics, ventilation support, medication, nutrition and the outcomes between the two groups. Results: A total of 593 VPIs were enrolled, including 380 cases in group A and 213 cases in group B. There were no statistic differences regarding to gender ratio, gestational age, birth weight and delivery mode between the two groups. Compared with group A, group B showed higher rate of antenatal corticosteroid therapy (75.1% vs. 65.5%). The improvement of ventilation management in these latter patients included lower rate of invasive ventilation (40.4% vs. 50.0%), higher rate of volume guarantee (69.8% vs. 15.3%), higher positive end expiratory pressure (PEEP) [6 (5, 6) vs. 5 (5, 5) cmH2O] and higher rate of synchronized nasal intermittent positive pressure ventilation (sNIPPV) (36.2% vs. 5.6%). Compared with group A, group B received higher initial dose of pulmonary surfactant [200 (160, 200) vs. 170 (130, 200) mg/Kg], shorter antibiotic exposure time [13 (7, 23) vs. 17 (9, 33) days], more breast milk (86.4% vs. 70.3%) and earlier medication for hemodynamically significant patent ductus arteriosus (hsPDA) treatment [3 (3, 4) vs. 8 (4, 11) days] (p < 0.05). As the primary outcome, the incidence of BPD was significantly decreased (16.9% vs. 24.2%) (p < 0.05), along with lower extrauterine growth retardation (EUGR) rate (39.0% vs. 59.7%), while there were no statistic differences regarding to other secondary outcomes, including mortality, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of preterm (ROP) and necrotizing enterocolitis (NEC). However, in the subgroups of infants less than 28 gestational weeks or infants less than 1,000 g, the incidence of BPD was not significantly decreased (p > 0.05). Conclusions: After implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants who are less than 28 gestational weeks or less than 1,000 g. [ABSTRACT FROM AUTHOR]

Objective Administering surfactant timely and appropriately is important to minimize lung injury but remains challenging in preterm neonates with respiratory distress syndrome. The published literature supports that lung ultrasound (LUS) score can predict surfactant need. Neonatal LUS scanning specification and parameter setting guidelines have been recently published for standardization. However, variations in scanning protocols and machine settings hinder its clinical implementation widely. This observational study aims to internally validate the suggested LUS protocol in a neonatal intensive care unit to establish a correlation between LUS scores and surfactant need as the first step of integrating LUS in the clinical practice. Study Design LUS was performed on 40 eligible preterm neonates within 3 hours after birth or before surfactant administration between May 2020 and March 2021. The neonates were between 27 and 32 weeks' gestational age, and all had respiratory distress. Neonates with known congenital anomalies were excluded. A high-frequency linear probe was used to obtain LUS images from six lung zones which were scored using a 0 to 3 system, yielding a maximum of 18 points. Treating physicians were blinded to the LUS score. Receiver operating characteristic analysis determined the optimal LUS score cut-off for predicting surfactant need. Results Fifteen of the 40 neonates (38%) required higher oxygen fraction and received surfactant. In our cohort, an LUS score ≥10 was identified as the optimal cut-off for predicting surfactant need, with a sensitivity of 80% and specificity of 84%. The area under the curve was 0.8 (p = 0.0003). LUS predicted surfactant need at a median of 3.5 hours earlier than traditional clinical decision (p < 0.0037). Conclusion LUS is a helpful adjunct for predicting surfactant need in preterm neonates. This study describes an approach to implement the LUS protocol and score for clinical decision-making in the clinical practice. Key Points LUS is a helpful adjunct for predicting surfactant need in preterm neonates. Machine setting variation and probe selection may affect LUS image and score. LUS score should be validated at the local unit before clinical implementation. [ABSTRACT FROM AUTHOR]

A thin film of pulmonary surfactant lines the surface of the airways and alveoli, where it lowers the surface tension in the peripheral lungs, preventing collapse of the bronchioles and alveoli and reducing the work of breathing. It also possesses a barrier function for maintaining the blood-gas interface of the lungs and plays an important role in innate immunity. The surfactant film covers the epithelium lining both large and small airways, forming the first line of defense between toxic airborne particles/pathogens and the lungs. Furthermore, surfactant has been shown to relax airway smooth muscle (ASM) after exposure to ASM agonists, suggesting a more subtle function. Whether surfactant masks irritant sensory receptors or interacts with one of them is not known. The relaxant effect of surfactant on ASM is absent in bronchial tissues denuded of an epithelial layer. Blocking of prostanoid synthesis inhibits the relaxant function of surfactant, indicating that prostanoids might be involved. Another possibility for surfactant to be active, namely through ATP-dependent potassium channels and the cAMP-regulated epithelial chloride channels [cystic fibrosis transmembrane conductance regulators (CFTRs)], was tested but could not be confirmed. Hence, this review discusses the mechanisms of known and potential relaxant effects of pulmonary surfactant on ASM. This review summarizes what is known about the role of surfactant in smooth muscle physiology and explores the scientific questions and studies needed to fully understand how surfactant helps maintain the delicate balance between relaxant and constrictor needs. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β2‐agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2‐related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways. [ABSTRACT FROM AUTHOR]

Background: Thirty years ago, the first attempt by Saliba and colleagues was made to reduce the negative effects (hypercarbia) of exogenous surfactant (ES) by slowing its administration. Sixteen years later, we observed the first less invasive surfactant administration (LISA) attempt by Kribs and colleagues. Many studies, since that time, have tried to minimize the invasiveness of ES and subsequent cerebral blood flow perturbations through studies using near-infrared spectroscopy (NIRS). We sought to address this medical challenge by identifying a less problematic modality of ES administration by delivering multiple aliquots of ES instead of a single one, as typically performed. The aim of this study was to test the hypothesis that a different way of administering ES using more aliquots could be a safe alternative that should be assessed in further studies. Methods: Patients between 26 + 0 and 35 + 6 weeks of gestational age (GA) requiring ES administration were enrolled (April 2023–February 2024). Differently fractioned doses were delivered according to an arbitrary standard dosage (0.3 mL per aliquot in babies < 29 weeks; 0.6 mL in babies ≥ 29 weeks), while NIRS and transcutaneous CO2 (tCO2) monitoring were always performed. ES's effectiveness was assessed based on the reduction in the Oxygen Saturation Index (OSI) after administration. Persistent desaturation, bradycardia, and airway obstruction were defined as adverse effects and used to evaluate safety during ES administration, as well as variability in NIRS-rSO2 values and tCO2. Results: Twenty-four patients were enrolled with a median GA of 29 weeks (IQR 4.5) and BW of 1223 ± 560 g. In addition, 50% of the cohort received fewer than three aliquots, whereas the other 50% received more than three. Monitoring was started before the procedure and continued 30′ after the last ES aliquot administration. The variability in NIRS-SpO2 values was significantly higher in the group (p = 0.007) with a lower number of aliquots administered. Similarly, increased NIRS-rSO2 values (p = 0.003) and increased tCO2 levels (p = 0.005) were observed in infants who underwent an ES split after the administration of a low number of aliquots. Conclusions: Our data obtained from the group with > 3 fractionated doses of ES seem to justify the preparation of a more robust study, as the combination of reduced NIRS variability and reduced tCO2 maximum levels is consistent with more stable cerebral blood flow during the challenging time of ES administration. [ABSTRACT FROM AUTHOR]

Purpose: Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments. Methods: A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals. Results: The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7–17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min. Conclusions: A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS. [ABSTRACT FROM AUTHOR]

Introduction: Surfactant therapy has revolutionized the management of respiratory distress syndrome (RDS) in preterm neonates, significantly improving outcomes for this vulnerable population. When assessing the need for surfactant in preterm infants, especially those whose mothers received antenatal steroids, it is crucial to understand the interplay between these two interventions. Antenatal corticosteroids are known to enhance fetal lung maturation and reduce the incidence and severity of RDS. However, despite this benefit, some preterm infants still develop RDS, potentially necessitating surfactant administration. This article explores the factors influencing surfactant requirements in preterm neonates whose mothers have undergone antenatal steroid therapy, aiming to clarify the role of surfactant in this context and optimise neonatal care strategies. Aim and objective: To access the need of surfactant in preterm babies whose mother received antenatal steroids. Material and methods: The present observational study was conducted in Paediatric outpatient department of Acharya Shri Chander College of Medical Sciences and Hospitals and included a total of 121 babies who were delivered in the hospital over a period of three months, w.e.f. 1st April, 2024 to 31st June, 2024. The data was collected with the help of a structured clinical pro-forma. The collected data was recorded in Microsoft Excel sheet and statistical analysis was done with the help of SPSS version 21.0. Result: In our study, a total of 121 babies were delivered to 109 women in the study period with 97 singleton, 12 twins and no triplet or quadruple deliveries. All records were available and retrieved within the study period where only 43 babies were delivered prematurely between 26 weeks to 34 weeks and the majority of the babies 27 were born at 32-34 weeks of gestation (62.8%), followed by 14 babies were delivered at 28-32 weeks (32.6%), followed by 2 were delivered between 26-28 weeks (4.6%). Out of 43 babies, 24 babies (55.8%) were exposed to full course of dexamethasone antenatally and 7 babies (16.3%) received single dose of antenatal corticosteroids and remaining 12 babies (27.9%) were delivered prematurely didn’t receive antenatal corticosteroids. There was no baby who received a repeat course of antenatal corticosteroids. And it was found that out of 24 babies who received full course of antenatal corticosteroids developed respiratory distress and 18 required surfactant administration and rest 6 babies were managed only on CPAP mode of ventilation. Conclusion: The present study concludes reinforced the rationale behind the common practice of giving antenatal corticosteroids in preterm birth and also demonstrated the decrease in respiratory distress syndrome and use of surfactant for lung compliance. [ABSTRACT FROM AUTHOR]

COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were used—mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population (Krt8+ and Cldn4+). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from β-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure. NEW & NOTEWORTHY: COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that β-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure. [ABSTRACT FROM AUTHOR]

Abstract Additives in vaping products, such as flavors, preservatives, or thickening agents, are commonly used to enhance user experience. Among these, Vitamin E acetate (VEA) was initially thought to be harmless but has been implicated as the primary cause of e-cigarette or vaping product use-associated lung injury, a serious lung disease. In our study, VEA serves as a proxy for other e-cigarette additives. To explore its harmful effects, we developed an exposure system to subject a pulmonary surfactant (PSurf) model to VEA-rich vapor. Through detailed analysis and atomic-level simulations, we found that VEA tends to cluster into aggregates on the PSurf surface, inducing deformations and weakening its essential elastic properties, critical for respiratory cycle function. Apart from VEA, our experiments also indicate that propylene glycol and vegetable glycerin, widely used in e-liquid mixtures, or their thermal decomposition products, alter surfactant properties. This research provides molecular-level insights into the detrimental impacts of vaping product additives on lung health.

Waterproofing sprays can cause acute respiratory symptoms after inhalation, including coughing and dyspnoea shortly after use. Here, we describe two cases where persons used the same brand of waterproofing spray product. In both cases the persons followed the instructions on the product and maximized the ventilation by opening windows and doors; however, they still became affected during the application of the product. Products with the same batch number as that used in one case were tested for their effect on respiration patterns of mice in whole-body plethysmographs and lung surfactant function inhibition in vitro. The product was used in spraying experiments to determine the particle size distribution of the aerosol, both using a can from one case and a can with an identical batch number. In addition, the aerosols in the mouse exposure chamber were measured. Aerosol data from a small-scale exposure chamber and data on the physical and temporal dimensions of the spraying during one case were used to estimate the deposited dose during the spraying events. All collected data point to the spraying of the waterproofing product being the reason that two people became ill, and that the inhibition of lung surfactant function was a key component of this illness.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell--intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic. [ABSTRACT FROM AUTHOR]

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

Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND: A multidisciplinary comprehensive protocol to use bubble continuous positive airway pressure (bCPAP) as the primary respiratory support in the delivery room (DR) and the NICU was introduced. With this study, we aimed to assess the association of this change with respiratory outcomes over time. METHODS: Infants with gestational age <32 weeks and birth weight <1250 g admitted between January 2012 and June 2020 were included and categorized into 4 periods, including preimplementation (P0: 2012-2014), and post-implementation (P1: 2014-2016, P2: 2016-2018, P3: 2018-2020). The primary outcome was the rates of death and severe bronchopulmonary dysplasia (BPD), and the secondary outcomes included the rates of DR and NICU intubation ≤7 days of age, need of surfactant, and pneumothorax. Multivariate logistic regression models accounting for relevant risk factors were used to calculate adjusted odds ratios (ORs). RESULTS: The study included 440 infants (P0 = 90, P1 = 91, P2 = 128, P3 = 131). Over time, more infants were free of BPD (P < .001), and the rates of death and severe BPD decreased significantly: P1 = OR 1.21 (95% confidence interval [CI] 0.56-2.67), P2 = OR 0.45 (95% CI 0.20-0.99), and P3 = OR 0.37 (95% CI 0.15-0.84). DR intubation decreased from 66% (P0) to 24% (P3) in the entire cohort (P < .001) and from 96% (P0) to 40% (P3) in infants <26 weeks of age (P < .001). The need for NICU intubation was similar (P = .98), with a decreased need for surfactant (P 5 .001) occurring at higher FiO2 (P0 = 0.35 vs P3 = 0.55, P < .001). Pneumothorax rates were unchanged. CONCLUSIONS: In very preterm infants, the implementation of a comprehensive bCPAP protocol led to a significant and consistent improvement in respiratory practices and the rates of death and severe BPD. [ABSTRACT FROM AUTHOR]

Waterproofing sprays can cause acute respiratory symptoms after inhalation, including coughing and dyspnoea shortly after use. Here, we describe two cases where persons used the same brand of waterproofing spray product. In both cases the persons followed the instructions on the product and maximized the ventilation by opening windows and doors; however, they still became affected during the application of the product. Products with the same batch number as that used in one case were tested for their effect on respiration patterns of mice in whole-body plethysmographs and lung surfactant function inhibition in vitro. The product was used in spraying experiments to determine the particle size distribution of the aerosol, both using a can from one case and a can with an identical batch number. In addition, the aerosols in the mouse exposure chamber were measured. Aerosol data from a small-scale exposure chamber and data on the physical and temporal dimensions of the spraying during one case were used to estimate the deposited dose during the spraying events. All collected data point to the spraying of the waterproofing product being the reason that two people became ill, and that the inhibition of lung surfactant function was a key component of this illness. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to quantify the influence of maternal sociodemographic, medical, and pregnancy characteristics on not receiving maternal and neonatal interventions with deliveries occurring at 22 to 23 weeks of gestation. Study design This was a case–control study of U.S. live births at 22 0/6 to 23 6/7 weeks of gestation using vital statistics birth records from 2012 to 2016. We analyzed births that received no interventions for periviable delivery. Births were defined as having no interventions if they did not receive maternal (cesarean delivery, maternal hospital transfer, or antenatal corticosteroid administration) or neonatal interventions (neonatal intensive care unit admission, surfactant administration, antibiotic administration, or assisted ventilation). Logistic regression estimated the influence of maternal and pregnancy factors on the receipt of no interventions when delivery occurred at 22 to 23 weeks. Results Of 19,844,580 U.S. live births in 2012–2016, 24,379 (0.12%) occurred at 22 to 23 weeks; 54.3% of 22-week deliveries and 15.7% of 23-week deliveries received no interventions. Non-Hispanic Black maternal race was associated with no maternal interventions at 22 and 23 weeks. Private insurance, singleton pregnancy, and small for gestational age were associated with receiving no neonatal interventions at 22 and 23 weeks of gestation. Conclusion Withholding or refusing maternal and neonatal interventions occurs frequently at the threshold of viability. Our data highlight various sociodemographic, pregnancy, and medical factors associated with decisions to not offer or receive maternal or neonatal interventions when birth occurs at the threshold of viability. The data elucidate observed practices and may assist in the development of further research. Key Points Non-Hispanic Black race was associated with receiving no maternal interventions. Indicators of high socioeconomic status were associated with no neonatal inventions. Patient-level factors influence the receipt of no interventions for periviable birth. [ABSTRACT FROM AUTHOR]

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

Purpose: Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants. Methods: This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP‐B and SP‐C, or natural surfactant Poractant alfa (Curosurf®, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated. Results: Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls. Conclusions: This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects. [ABSTRACT FROM AUTHOR]

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality among term newborns globally. Infants born through meconium-stained amniotic fluid are at risk of developing meconium aspiration syndrome (MAS) and HIE. Simultaneous occurrence of MAS and HIE is a perilous combination for newborns due to the risk of persistent pulmonary hypertension of the newborn (PPHN). Moreover, therapeutic hypothermia (TH), which is the current standard of care for the management of HIE, may increase pulmonary vascular resistance (PVR) and worsen PPHN. Infants with MAS and HIE require close cardiorespiratory and hemodynamic monitoring for PPHN. Therapeutic strategies, including oxygen supplementation, ventilation, use of surfactant, inhaled nitric oxide and other pulmonary vasodilators, and systemic vasopressors, play a critical role in the management of PPHN in MAS, HIE, and TH. While TH reduces death or disability in infants with HIE, infants with MAS and HIE undergoing TH need close hemodynamic monitoring for PPHN. [ABSTRACT FROM AUTHOR]

This systematic review aimed to summarize the available data on the treatment of pulmonary contusions with exogenous surfactants, determine whether this treatment benefits patients with severe pulmonary contusions, and evaluate the optimal type of surfactant, method of administration, and drug concentration. Three databases (MEDline, Scopus, and Web of Science) were searched using the following keywords: pulmonary surfactant, surface‐active agents, exogenous surfactant, pulmonary contusion, and lung contusion for articles published between 1945 and February 2023, with no language restrictions. Four reviewers independently rated the studies for inclusion, and the other four reviewers resolved conflicts. Of the 100 articles screened, six articles were included in the review. Owing to the limited number of papers on this topic, various types of studies were included (two clinical studies, two experiments, and two case reports). In all the studies, surfactant administration improved the selected ventilation parameters. The most frequently used type of surfactant was Curosurf® in the concentration of 25 mg/kg of ideal body weight. In most studies, the administration of a surfactant by bronchoscopy into the segmental bronchi was the preferable way of administration. In both clinical studies, patients who received surfactants required shorter ventilation times. The administration of exogenous surfactants improved ventilatory parameters and, thus, reduced the need for less aggressive artificial lung ventilation and ventilation days. The animal‐derived surfactant Curosurf® seems to be the most suitable substance; however, the ideal concentration remains unclear. The ideal route of administration involves a bronchoscope in the segmental bronchi. [ABSTRACT FROM AUTHOR]

Purpose: This study investigates how surfactants affect the in-vitro anti-infective efficacy of micafungin, caspofungin, anidulafungin, and amphotericin B in treating pulmonary mycoses. Methods: MIC values for antifungal agents were determined against Candida krusei (now Pichia kudriavzevii) ATCC 6258, Candida albicans ATCC 90028, and 18 clinical isolates using the broth microdilution method in RPMI medium, following EUCAST recommendations. MIC assays included testing with and without Curosurf® surfactant at 1 mg/mL for C. krusei ATCC 6258 and all C. krusei isolates. Subsequent Time-kill studies in Sabouraud broth involved testing both C. albicans ATCC 90028 and C. krusei ATCC 6258 strains at concentrations equal their respective MIC values, with and without surfactant, using all four antifungals. CFU/mL were assessed at multiple time points up to 24 h. TKCs with different surfactant concentrations for C. krusei ATCC 6258 and mini-TKCs at various concentrations relative to the MIC of C. krusei isolates and the reference strain were conducted with micafungin, anidulafungin, and caspofungin. Results: MIC results showed that 1 µg/mL surfactant reduced killing of micafungin and anidulafungin against C. krusei, while caspofungin was unaffected. Amphotericin B's MIC decreased by half. TKCs demonstrated significant effects of surfactant on micafungin and anidulafungin against C. krusei, with complete abolition of anidulafungin's activity against C. albicans. Conclusion: This in-vitro study highlights the concentration-dependent inhibitory effect of surfactant on antifungal activity against C. krusei and, to some extent, C. albicans, necessitating further clinical validation for invasive lung mycoses treatment. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained manner. Nebulization is a suitable method of NP delivery, particularly in patients whose ability to breathe is impaired due to lung diseases. However, there are limited studies evaluating the physicochemical properties of NPs after they are passed through a nebulizer. High shear stress generated during nebulization could potentially affect the surface properties of NPs, resulting in the loss of encapsulated drugs and alteration in the release kinetics. Herein, we thoroughly examined the physicochemical properties as well as the therapeutic effectiveness of Infasurf lung surfactant (IFS)-coated PLGA NPs previously developed by us after passing through a commercial Aeroneb® vibrating-mesh nebulizer. Nebulization did not alter the size, surface charge, IFS coating and bi-phasic release pattern exhibited by the NPs. However, there was a temporary reduction in the initial release of encapsulated therapeutics in the nebulized compared to non-nebulized NPs. This underscores the importance of evaluating the drug release kinetics of NPs using the inhalation method of choice to ensure suitability for the intended medical application. The cellular uptake studies demonstrated that both nebulized and non-nebulized NPs were less readily taken up by alveolar macrophages compared to lung cancer cells, confirming the IFS coating retention. Overall, nebulization did not significantly compromise the physicochemical properties as well as therapeutic efficacy of the prepared nanotherapeutics. [ABSTRACT FROM AUTHOR]

Objective: To discuss the predictive value of lung ultrasound score (LUS) for the use of mechanical ventilation (MV) and pulmonary surfactant (PS) in the preterm infants with late-onset respiratory distress syndrome (RDS). Methods: The prospective analysis was conducted on the late-onset preterm infants (gestational age 340/7-366/7 weeks) complicated with RDS; in total, 67 late-onset infants complicated with RDS were included. The infants were divided into MV group (n=36), non-MV group (n=31), PS group (n=30), and non-PS group (n=37) based on the necessity to use MV and PS within 48 h after birth. Lung ultrasound examination was performed on all the infants 2 h after admission, and before the application of PS, and the LUS for 6-zone, 10-zone, and 12-zone partitions were calculated. Receiver operating characteristic (ROC) curve for the prediction of MV and PS application in the infants with late-onset RDS were drawn by LUS with different partitions, and the predictive values of different partition methods were compared by DeLong method. Results: Compared with non-PS group, the birth weight, LUS, positive end expiratory pressure (PEEP), mean airway pressure (MAP), MAP×fraction of inspired oxygen (FiO2 )/PaO2 value, duration of mechanical ventilation, and hospital stay of the infants in PS group were increased (P<0. 05), and the ratio of PaO2/FiO2 was decreased (P<0. 01). Compared with non-MV group, the birth weight, LUS, PEEP, MAP, MAP × FiO2/PaO2 value, duration of mechanical ventilation and hospital stay of the infants in MV group were increased (P<0. 05), and the ratio of PaO2/FiO2 was decreased (P<0. 01). PEEP, MAP, and LUS were identified as the influencing factors for application of PS in the late-onset preterm infants complicated with RDS when employing 6-zone LUS to predict the application of PS [odds ratio (OR)>1, P<0. 05]. When employing 10-zone and 12-zone LUS for the use of PS, MAP × FiO2/PaO2 and LUS were the influencing factors (OR>1, P<0. 05). The area under curve (AUC) for predicting the application of PS in the late-onset infants complicated with RDS by 6-zone, 10-zone, and 12-zone LUS were 0. 909, 0. 904, and 0. 915, respectively, all showing good predictive values; the AUCs for predicting the application of MV by 6-zone, 10-zone, and 12-zone LUS were 0. 868, 0. 872, and 0. 887, respectively, all showing good predictive values as well. Conclusion: LUS can effectively predict the necessity for whether or not applying MV and PS in the lateonset infants complicated with RDS, and MAP combined with LUS can enhance the capability to predict the application of MV. [ABSTRACT FROM AUTHOR]

Abstract Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β2‐agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2‐related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways.

This article discusses the importance of pulmonary surfactant (PS) in lung function and breathing. PS is a lipid-protein complex that reduces surface tension in the lungs, making breathing easier. The production and secretion of PS is dependent on the acidification of lamellar bodies (LBs), which are organelles that store PS. The article focuses on a study that links Hermansky-Pudlak syndrome (HPS), a group of lysosomal-related diseases, to deficiencies in LB acidification. The study found that the lack of HPS6, a protein associated with LB biogenesis, led to changes in LB morphology, altered lipid composition of PS, and increased surfactant proteins. The article highlights the importance of acidic pH in the biogenesis of PS complexes and the role of protein trafficking in maintaining LB homeostasis. The findings have implications for understanding respiratory pathogenesis and developing therapies. [Extracted from the article]

The article focuses on the administration of antenatal steroids (AS). Topics discussed include the first demonstration of the benefits to infants receiving AS in the late 1960s in experiments using sheep, effect of steroid when delivered prematurely, and trends revealed by investigations in Ontario about the administration of AS.

Objective To investigate the effects of different angles of pulmonary surfactant (PS) administration on the incidence of bronchopulmonary dysplasia and intracranial hemorrhage in preterm infants. Methods A prospective study was conducted on 146 preterm infants (gestational age <32 weeks) admitted to the Department of Neonatology, Provincial Hospital Affiliated to Anhui Medical University from January 2019 to May 2023. The infants were randomly assigned to different angles for injection of pulmonary surfactant groups: 0° group (34 cases), 30° group (36 cases), 45° group (38 cases), and 60° group (38 cases). Clinical indicators and outcomes were compared among the groups. Results The oxygenation index was lower in the 60° group compared with the other three groups, with shorter invasive ventilation time and oxygen use time, and a lower incidence of bronchopulmonary dysplasia than the other three groups (P<0.05). The incidence of intracranial hemorrhage was lower in the 60° group compared to the 0° group (P<0.05). The cure rate in the 60° group was higher than that in the 0° group and the 30° group (P<0.05). Conclusions The clinical efficacy of injection of pulmonary surfactant at a 60° angle is higher than other angles, reducing the incidence of intracranial hemorrhage and bronchopulmonary dysplasia in preterm infants. [ABSTRACT FROM AUTHOR]

Inhalation of liposomes formulated with phospholipids similar to endogenous lung surfactants and lipids offers biocompatibility and versatility within the pulmonary medicine field to treat a range of diseases such as lung cancer, cystic fibrosis and lung infections. Manipulation of the physicochemical properties of liposomes enables innovative design of the carrier to meet specific delivery, release and targeting requirements. This delivery system offers several benefits: improved pharmacokinetics with reduced toxicity, enhanced therapeutic efficacy, increased delivery of poorly soluble drugs, taste masking, biopharmaceutics degradation protection and targeted cellular therapy. This section provides an overview of liposomal formulation and delivery, together with their applications for different disease states in the lung. [ABSTRACT FROM AUTHOR]

Background: We assessed the incidence of and risk factors for acute kidney injury (AKI) in very low birthweight infants (VLBW) in a center with a specific neonatal management protocol focusing on avoidance of early mechanical ventilation (MV). Methods: This retrospective single center analysis includes 128 infants born in 2020 with a gestational age ≥ 22 weeks who were screened for AKI using the nKDIGO criteria. Results: AKI was identified in 25/128 patients (19.5%) with eight of them (6.3%) presenting with severe AKI. Low gestational age, birthweight and 10-minute Apgar score as well as high CRIB-1 score were all associated with incidence of AKI. Forty-five percent of the infants with MV developed AKI vs. 8.9% of those without MV (p < 0.001). Early onset of MV and administration of more than 3 dosages of NSAIDs for patent duct were identified as independent risk factors for AKI in a logistic regression analysis. Conclusions: We report a substantially lower frequency of AKI in VLBW infants as compared to previous studies, along with a very low rate of MV. A neonatal protocol focusing on avoidance of MV within the first days of life may be a key factor to decrease the risk of AKI in immature infants. [ABSTRACT FROM AUTHOR]

Severe cases of hydrocarbon aspiration requiring Extracorporeal Membrane Oxygenation (ECMO) are rarely reported in pediatrics, and 90% of hospitalized patients have a relatively benign clinical course. We describe a 14 month-old female with accidental hydrocarbon ingestion and aspiration due to organic makeup brush cleaner that suffered severe ARDS and multiorgan failure, successfully managed with ECMO and surfactant. She was decannulated after a total of 72 hours on ECMO, extubated on hospital day 15 (HD 15), and discharged home in her normal state of health after one month in the hospital. ECMO and adjunctive therapies such as surfactant may be helpful in the management of severe hydrocarbon pneumonitis and there are limited reports of ECMO as a supportive method for these pediatric patients. [ABSTRACT FROM AUTHOR]

Objective Premature infants are at the risk of developing respiratory distress syndrome (RDS). Beractants and poractants are two commonly used natural surfactants. This retrospective cohort study aims to compare the incidence of pulmonary complications between beractant and poractant treatment groups. Study Design This study evaluated 29 patients treated with beractant and 49 patients treated with poractant. The primary outcome was the incidence of air leak syndrome (ALS) and pulmonary hemorrhage. Secondary outcomes included mortality and pulmonary outcomes, such as mechanical ventilation duration, oxygen dependence duration, fraction of inspired oxygen, and mean airway pressure (MAP) requirement. Logistic regression analyses were conducted to identify independent risk factors for significant primary outcomes. Results No significant difference was found in the demographics between the two groups. A significantly higher incidence of pulmonary hemorrhage was observed in the poractant group (14.3 vs. 0.0%, p = 0.038). The difference in the incidence of ALS between the groups was insignificant (p = 0.536). Logistic regression for the incidence of pulmonary hemorrhage identified coagulopathy as the only significant independent risk factor (odds ratio 39.855, 95% confidence interval [2.912–545.537]; p = 0.006). Secondary outcomes in both treatment groups were similar, except that patients in the poractant group had a higher MAP before surfactant therapy (9 vs. 8 cmH 2 O, p < 0.001). Conclusion This study showed a significantly higher incidence of pulmonary hemorrhage in the poractant group. Coagulopathy was identified as an independent risk factor for pulmonary hemorrhage. Future long-term prospective studies are essential to establish the temporal and causal relationships between coagulopathy and pulmonary hemorrhage in premature infants receiving surfactant therapy for RDS; hence, there is the need for a screening protocol before surfactant administration. Key Points A higher incidence of pulmonary hemorrhage was found in the poractant group. Coagulopathy was the only significant risk factor that was related to the incidence of pulmonary hemorrhage. A screening protocol might be useful to avoid pulmonary hemorrhage in infants receiving surfactant. [ABSTRACT FROM AUTHOR]

This study addressed the efficacy of a liposome-encapsulated nine amino acid peptide [peroxiredoxin 6 PLA2 inhibitory peptide-2 (PIP-2)] for the prevention or treatment of acute lung injury (ALI) +/− sepsis. PIP-2 inhibits the PLA2 activity of peroxiredoxin 6 (Prdx6), thereby preventing rac release and activation of NADPH oxidases (NOXes), types 1 and 2. Female Yorkshire pigs were infused intravenously with lipopolysaccharide (LPS) + liposomes (untreated) or LPS + PIP-2 encapsulated in liposomes (treated). Pigs were mechanically ventilated and continuously monitored; they were euthanized after 8 h or earlier if preestablished humane endpoints were reached. Control pigs (mechanical ventilation, no LPS) were essentially unchanged over the 8 h study. LPS administration resulted in systemic inflammation with manifestations of clinical sepsis-like syndrome, decreased lung compliance, and a marked decrease in the arterial P o 2 with vascular instability leading to early euthanasia of 50% of untreated animals. PIP-2 treatment significantly reduced the requirement for supportive vasopressors and the manifestations of lung injury so that only 25% of animals required early euthanasia. Bronchoalveolar lavage fluid from PIP-2-treated versus untreated pigs showed markedly lower levels of total protein, cytokines (TNF-α, IL-6, IL-1β), and myeloperoxidase. Thus, the porcine LPS-induced sepsis-like model was associated with moderate to severe lung pathophysiology compatible with ALI, whereas treatment with PIP-2 markedly decreased lung injury, cardiovascular instability, and early euthanasia. These results indicate that inhibition of reactive oxygen species (ROS) production via NOX1/2 has a beneficial effect in treating pigs with LPS-induced ALI plus or minus a sepsis-like syndrome, suggesting a potential role for PIP-2 in the treatment of ALI and/or sepsis in humans. NEW & NOTEWORTHY: Currently available treatments that can alter lung inflammation have failed to significantly alter mortality of acute lung injury (ALI). Peroxiredoxin 6 PLA2 inhibitory peptide-2 (PIP-2) targets the liberation of reactive O2 species (ROS) that is associated with adverse cell signaling events, thereby decreasing the tissue oxidative injury that occurs early in the ALI syndrome. We propose that treatment with PIP-2 may be effective in preventing progression of early disease into its later stages with irreversible lung damage and relatively high mortality. [ABSTRACT FROM AUTHOR]

Polyhexamethylene guanidine (PHMG) is a guanidine-based chemical that has long been used as an antimicrobial agent. However, recently raised concerns regarding the pulmonary toxicity of PHMG in humans and aquatic organisms have led to research in this area. Along with PHMG, there are concerns about the safety of non-guanidine 5-chloro-2-methylisothiazol-3(2H)-one/2-methylisothiazol-3(2H)-one (CMIT/MIT) in human lungs; however, the safety of such chemicals can be affected by many factors, and it is difficult to rationalize their toxicity. In this study, we investigated the adsorption characteristics of CMIT/MIT on a model pulmonary surfactant (lung surfactant, LS) using a Langmuir trough attached to a fluorescence microscope. Analysis of the π-A isotherms and lipid raft morphology revealed that CMIT/MIT exhibited minimal adsorption onto the LS monolayer deposited at the air/water interface. Meanwhile, PHMG showed clear signs of adsorption to LS, as manifested by the acceleration of the Lo phase growth with increasing surface pressure. Consequently, in the presence of CMIT/MIT, the interfacial properties of the model LS monolayer exhibited significantly fewer changes than PHMG. [ABSTRACT FROM AUTHOR]

Background Before the advent of antenatal steroids, early non-invasive respiratory support (NIV), and intratracheal surfactant, antenatal terbutaline was also used to improve lung compliance and reduce the incidence of respiratory distress syndrome (RDS). Objectives The objective of this paper was to study the association between antenatal terbutaline and endotracheal intubation (ET) within the first 24 hours of life, RDS, bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH) in infants with the gestational age (GA) of <32 weeks, and to study the association between antenatal terbutaline, and ET or NIV within the first 24 hours of life, and RDS in infants with the GA of 32 to 36 weeks. Method This was a retrospective medical record review of preterm infants delivered at a single tertiary care center from October 2016 to December 2020. Multivariable logistic regression was used to explore the association between antenatal terbutaline and neonatal respiratory support. Result 1,794 infants were included, 234 (13.0%) had the GA of <32 weeks and 1,560 (86.9%) had the GA of 32 to 36 weeks. Antenatal terbutaline, corticosteroid, or both agents were administered in 561 (31.3%), 1,461 (81.4%), and 555 (30.9%), respectively. Antenatal terbutaline was significantly associated with a reduction in ET (adjusted odds ratio [aOR] = 0.40, 95% confident interval [CI] 0.19–0.82, p = 0.012) in infants with the GA of <32 weeks, but not in infants with the GA of 32–36 weeks. Antenatal terbutaline was not associated with RDS or BPD but was significantly associated with a reduction in grade III-IV IVH (aOR 0.11, CI 0.01–0.98; p = 0.048), in infants with the GA of <32 weeks. Conclusion In a state-of-the-art neonatal care setting, antenatal terbutaline was associated with a reduction in ET during the first 24 hours in infants with the GA of <32 weeks. The use of antenatal terbutaline to improve acute neonatal respiratory outcomes merits reconsideration. Key Points The neonatal respiratory benefits of antenatal terbutaline in the era of antenatal corticosteroids were uncertain. Terbutaline is associated with a reduction in endotracheal intubation in a modern care setting. The role of terbutaline, and potentially other betamimetics, to improve neonatal respiratory outcomes merits reconsideration. [ABSTRACT FROM AUTHOR]

Early diagnosis of neonatal respiratory distress syndrome (nRDS) is important in reducing the mortality of preterm babies. Knowledge of the ratio of two components of lung surfactant, dipalmitoylphosphatidylcholine (DPPC), and sphingomyelin (SM) can be used as biomarkers of lung maturity and inform treatment. Raman spectroscopy is a powerful tool to analyze vibrational spectra of organic molecules which requires only limited sample preparation steps and, unlike IR spectroscopy, is not masked by water absorption. In this paper, we explore the potential of using Raman spectroscopy as a tool to estimate the ratio of DPPC and SM from aqueous vesicles of binary mixture of DPPC and SM. We demonstrate that the ratio of DPPC and SM can be estimated by estimating the ratio of intensity of C=O stretch of DPPC and C=C stretch of SM as well as C=O stretch of DPPC and amide I of SM. Further, we employ a partial least squares regression (PLSR) model to automate the estimation and demonstrate that PLSR method can predict the DPPC and SM ratio with an R² value of 0.968. [ABSTRACT FROM AUTHOR]

The clinical benefits of using exogenous pulmonary surfactant (EPS) as a carrier of budesonide (BUD), a non-halogenated corticosteroid with a broad anti-inflammatory effect, have been established. Using various experimental techniques (differential scanning calorimetry DSC, small- and wide- angle X-ray scattering SAXS/WAXS, small- angle neutron scattering SANS, fluorescence spectroscopy, dynamic light scattering DLS, and zeta potential), we investigated the effect of BUD on the thermodynamics and structure of the clinically used EPS, Curosurf®. We show that BUD facilitates the Curosurf® phase transition from the gel to the fluid state, resulting in a decrease in the temperature of the main phase transition (Tm) and enthalpy (ΔH). The morphology of the Curosurf® dispersion is maintained for BUD < 10 wt% of the Curosurf® mass; BUD slightly increases the repeat distance d of the fluid lamellar phase in multilamellar vesicles (MLVs) resulting from the thickening of the lipid bilayer. The bilayer thickening (~0.23 nm) was derived from SANS data. The presence of ~2 mmol/L of Ca2+ maintains the effect and structure of the MLVs. The changes in the lateral pressure of the Curosurf® bilayer revealed that the intercalated BUD between the acyl chains of the surfactant's lipid molecules resides deeper in the hydrophobic region when its content exceeds ~6 wt%. Our studies support the concept of a combined therapy utilising budesonide—enriched Curosurf®. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process. Here, we show that loss of the mechanosensitive channels TMEM63A and TMEM63B (TMEM63A/B) resulted in atelectasis and respiratory failure in mice due to a deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of the lamellar body (LB), a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated the release of surfactant and ATP from LBs fused with the plasma membrane. The released ATP evoked Ca2+ signaling in AT2 cells and potentiated exocytic fusion of more LBs. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels in preparing the lungs for the first breath at birth and maintaining respiration throughout life. [ABSTRACT FROM AUTHOR]

Background & Objective: Preterm birth is the most important cause of neonatal mortality and morbidity. Finding the best treatment regimen, of antenatal corticosteroids, has been under serious concern. To compare the efficacy of intravascular versus intramuscular betamethasone phosphate on neonatal outcomes in the cases of imminent preterm. Materials & Methods: A double-blind randomized clinical trial was performed on 136 eligible pregnant women with gestational age of 26-34 weeks and imminent preterm birth (delivery within 24 hours). They were randomly assigned into two groups. Group A received intramuscular betamethasone phosphate, and group B received a similar dose of betamethasone phosphate intravenously. Women were followed up to delivery, and their neonatal outcomes were compared. Results: Women of the two groups (68 women in each group), did not show a significant difference in maternal age, BMI, gravidity and parity, gestational age at the time of admission and delivery, history of miscarriage and assisted reproductive techniques, delivery route, sex and weight of newborns, and Apgar score in minutes 1 and 5. The need for NICU admission, duration of hospitalization, neonatal respiratory distress syndrome, surfactant requirement, and intubation were lower in the IV betamethasone group. There were no significant differences between the two groups according to necrotizing enterocolitis, intraventricular hemorrhage, and neonatal death. Conclusion: Using IV betamethasone, in cases where there is no enough time to complete the 24-hour betamethasone course due to the possibility of impending delivery, may reduce neonatal complications due to quicker onset of action. [ABSTRACT FROM AUTHOR]