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Background Surfactant decreases surface tension in the peripheral airways and plays a role in regulating the lung’s immune responses. Several reports have documented changes in surfactant proteins levels, especially surfactant protein D (SP-D) and surfactant protein A (SP-A), suggesting their potential as biomarkers for asthma. However, the results of these studies are controversial. This systematic review was done to assess the levels of surfactant proteins in asthmatic patients compared to healthy individuals. Methods A systematic review was conducted according to PRISMA guidelines. Searches were performed in the Medline/PubMed, Web of Science, Embase, and ScienceDirect databases to identify studies that assessed surfactants proteins levels in asthmatic patients. Pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using R version 4.4.3 meta package. Results A total of 16 studies met the inclusion criteria and were thus considered for this systematic review. Among these, SP-D was the most frequently studied protein in relation to asthma, asthma severity, and lung function parameters in asthmatic patients. Serum and sputum levels of SP-D in asthmatic patients were slightly elevated compared to non-asthmatic individuals. However, these differences were not statistically significant; the pooled SMDs were 0.27 (95% CI: -0.034 to 0.574, P  = 0.082) for serum levels and 1.47 (95% CI, -0.197 to 3.103, P  = 0.084) for sputum levels. Similarly, no significant difference was detected for the analysis of serum SP-A levels, with SMD = 0.18 (95% CI, -0.505 to 0.866, P  = 0.606). Though, some of the reviewed studies showed an association between SP-D levels and disease severity in asthmatic patients. Conclusion Although alterations have been observed in asthma and proposed as biomarkers, this systematic review did not find significant differences in the levels between asthmatics and healthy individuals. However, some studies have suggested an association between SP-D levels and asthma severity. Given the limited number of studies investigating this association, further research is needed to validate the clinical relevance of correlation between SP-D levels and asthma severity.

Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in RAB5B was identified in the Ras/Rab GTPases family nucleotide binding domain, p.Asp136His. Functional studies were performed in Caenorhabditis elegans by knocking the proband variant into the conserved position (Asp135) of the ortholog, rab-5. Genetic analysis demonstrated that rab-5[Asp135His] is damaging, producing a strong dominant negative gene product. rab-5[Asp135His] heterozygotes were also defective in endocytosis and early endosome (EE) fusion. Immunostaining studies of the proband’s lung biopsy revealed that RAB5B and EE marker EEA1 were significantly reduced in alveolar type II cells and that mature SP-B and SP-C were significantly reduced, while proSP-B and proSP-C were normal. Furthermore, staining normal lung showed colocalization of RAB5B and EEA1 with proSP-B and proSP-C. These findings indicate that dominant negative–acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease, and that RAB5B and EEs normally function in the surfactant secretion pathway. Together, the data suggest a noncanonical function for RAB5B and identify RAB5B p.Asp136His as a genetic mechanism for a surfactant dysfunction disorder.

Background The amount of surfactant deposited in the lungs and its overall pulmonary distribution determine the therapeutic outcome of surfactant replacement therapy. Most of the currently available methods to determine the intrapulmonary distribution of surfactant are time-consuming and require surfactant labelling. Our aim was to assess the potential of Mass Spectrometry Imaging (MSI) as a label-free technique to qualitatively and quantitatively evaluate the distribution of surfactant to the premature lamb. Methods Twelve preterm lambs (gestational age 126-127d, term ~150d) were allocated in two experimental groups. Seven lambs were treated with an intratracheal bolus of the synthetic surfactant CHF5633 (200 mg/kg) and 5 lambs were managed with mechanical ventilation for 120 min, as controls. The right lung lobes of all lambs were gradually frozen while inflated to 20 cmH 2 O pressure for lung cryo-sections for MSI analysis. The intensity signals of SP-C analog and SP-B analog, the two synthetic peptides contained in the CHF5633 surfactant, were used to locate, map and quantify the intrapulmonary exogenous surfactant. Results Surfactant treatment was associated with a significant improvement of the mean arterial oxygenation and lung compliance ( p  < 0.05). Nevertheless, the physiological response to surfactant treatment was not uniform across all animals. SP-C analog and SP-B analog were successfully imaged and quantified by means of MSI in the peripheral lungs of all surfactant-treated animals. The intensity of the signal was remarkably low in untreated lambs, corresponding to background noise. The signal intensity of SP-B analog in each surfactant-treated animal, which represents the surfactant distributed to the peripheral right lung, correlated well with the physiologic response as assessed by the area under the curves of the individual arterial partial oxygen pressure and dynamic lung compliance curves of the lambs. Conclusions Applying MSI, we were able to detect, locate and quantify the amount of exogenous surfactant distributed to the lower right lung of surfactant-treated lambs. The distribution pattern of SP-B analog correlated well with the pulmonary physiological outcomes of the animals. MSI is a valuable label-free technique which is able to simultaneously evaluate qualitative and quantitative drug distribution in the lung.

Background. Enterobacter cloacae complex producing extended-spectrum beta-lactamase - ESBL (ECCOE) is a group of gram-negative pathogens responsible for nosocomial outbreaks in vulnerable patients, among whom neonatal patients represent one of the highest risk groups. Methods. We present data from an ECCOE outbreak identified at the Cremona hospital in January 2024, when a case of ECCOE bacteremia was diagnosed in patient admitted to the Neonatology ward. Following the identification of the index case, an infection prevention and control (IPC) program was implemented, based on: isolation of all positive patients with contact precautions, weekly screening of all hospitalized patients, environmental sampling, a program to improve adherence to hand hygiene, enhanced disinfection procedures, and regular data feedback to the ward staff. Results. The retrospective analysis identified a second infection in January 2024. In 2023, no clinical cases were identified and only one positivity for ECCOE emerged from 301 microbiological screening swabs (0.3%). The prospective analysis did not reveal other infections in the following 11 months. Patient surveillance through swabs showed a baseline prevalence of ECCOE of 15.4% in January, which rose to 30.8% in February, significantly decreased in March, then increased again to 38.5% in June and finally dropped to zero in August. The environmental sampling highlighted only one positivity out of 79 samples (1.3% of the samples). The consumption of alcohol hand rub solution, very low at the start of the outbreak (26 L/1,000 patient days - PD), increased to 113 L/1,000 PD, and then decreased by 70% after the outbreak ended. Conclusions. A rapid and complex IPC intervention focusing on improving hand hygiene can help control an ECCOE outbreak in neonatology. However, maintaining adequate adherence to hand hygiene over time remains very challenging.

ObjectiveCHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy.DesignMulticentre cohort study.PatientsForty infants from 27+0 to 33+6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO2) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg.Outcome measuresAdverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO2 after dosing and need for poractant-alfa rescue.ResultsRapid and sustained improvements in FiO2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected.ConclusionsBoth CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials.Trial registration numberClinicalTrials.gov NCT01651637.

This article includes an updated review of the classification, uses and side effects of surfactants for their application in the cosmetic, personal care and pharmaceutical industries. Based on their origin and composition, surfactants can be divided into three different categories: (i) synthetic surfactants; (ii) bio-based surfactants; and (iii) microbial biosurfactants. The first group is the most widespread and cost-effective. It is composed of surfactants, which are synthetically produced, using non-renewable sources, with a final structure that is different from the natural components of living cells. The second category comprises surfactants of intermediate biocompatibility, usually produced by chemical synthesis but integrating fats, sugars or amino acids obtained from renewable sources into their structure. Finally, the third group of surfactants, designated as microbial biosurfactants, are considered the most biocompatible and eco-friendly, as they are produced by living cells, mostly bacteria and yeasts, without the intermediation of organic synthesis. Based on the information included in this review it would be interesting for cosmetic, personal care and pharmaceutical industries to consider microbial biosurfactants as a group apart from surfactants, needing specific regulations, as they are less toxic and more biocompatible than chemical surfactants having formulations that are more biocompatible and greener.

CHF5633 is a novel synthetic clinical pulmonary surfactant preparation composed by two phospholipid species, dipalmitoyl phosphatidylcholine (DPPC) and palmitoyloleoyl phosphatidylglycerol (POPG), and synthetic analogues of the hydrophobic surfactant proteins SP-B and SP-C. In this study, the interfacial properties of CHF5633 in the absence and in the presence of inhibitory serum proteins have been assessed in comparison with a native surfactant purified from porcine lungs and with poractant alpha, a widely used clinical surfactant preparation. The study of the spreading properties of CHF5633 in a Wilhelmy balance, its ability to adsorb and accumulate at air-liquid interfaces as revealed by a multiwell fluorescence assay, and its dynamic behavior under breathing-like compression-expansion cycling in a Captive Bubble Surfactometer (CBS), all revealed that CHF5633 exhibits a good behavior to reduce and sustain surface tensions to values below 5 mN/m. CHF5633 shows somehow slower initial interfacial adsorption than native surfactant or poractant alpha, but a better resistance to inhibition by serum proteins than the animal-derived clinical surfactant, comparable to that of the full native surfactant complex. Interfacial CHF5633 films formed in a Langmuir-Blodgett balance coupled with epifluorescence microscopy revealed similar propensity to segregate condensed lipid domains under compression than films made by native porcine surfactant or poractant alpha. This ability of CHF5633 to segregate condensed lipid phases can be related with a marked thermotropic transition from ordered to disordered membrane phases as exhibited by differential scanning calorimetry (DSC) of CHF5633 suspensions, occurring at similar temperatures but with higher associated enthalpy than that shown by poractant alpha. The good interfacial behavior of CHF5633 tested under physiologically meaningful conditions in vitro and its higher resistance to inactivation by serum proteins, together with its standardized and well-defined composition, makes it a particularly useful therapeutic preparation to be applied in situations associated with lung inflammation and edema, alone or in combined strategies to exploit surfactant-facilitated drug delivery.

The mammalian lung´s structural design is optimized to serve its main function: gas exchange. It takes place in the alveolar region (parenchyma) where air and blood are brought in close proximity over a large surface. Air reaches the alveolar lumen via a conducting airway tree. Blood flows in a capillary network embedded in inter-alveolar septa. The barrier between air and blood consists of a continuous alveolar epithelium (a mosaic of type I and type II alveolar epithelial cells), a continuous capillary endothelium and the connective tissue layer in-between. By virtue of its respiratory movements, the lung has to withstand mechanical challenges throughout life. Alveoli must be protected from over-distension as well as from collapse by inherent stabilizing factors. The mechanical stability of the parenchyma is ensured by two components: a connective tissue fiber network and the surfactant system. The connective tissue fibers form a continuous tensegrity (tension + integrity) backbone consisting of axial, peripheral and septal fibers. Surfactant (surface active agent) is the secretory product of type II alveolar epithelial cells and covers the alveolar epithelium as a biophysically active thin and continuous film. Here, we briefly review the structural components relevant for gas exchange. Then we describe our current understanding of how these components function under normal conditions and how lung injury results in dysfunction of alveolar micromechanics finally leading to lung fibrosis.

As key components of innate immunity, lung antimicrobial proteins play a critical role in warding off invading respiratory pathogens. Lung surfactant protein A (SP-A) exerts synergistic antimicrobial activity with the N-terminal segment of the SP-B proprotein (SP-BN) against Klebsiella pneumoniae K2 in vivo. However, the factors that govern SP-A/SP-BN antimicrobial activity are still unclear. The aim of this study was to identify the mechanisms by which SP-A and SP-BN act synergistically against K. pneumoniae, which is resistant to either protein alone. The effect of these proteins on K. pneumoniae was studied by membrane permeabilization and depolarization assays and transmission electron microscopy. Their effects on model membranes of the outer and inner bacterial membranes were analyzed by differential scanning calorimetry and membrane leakage assays. Our results indicate that the SP-A/SP-BN complex alters the ultrastructure of K. pneumoniae by binding to lipopolysaccharide molecules present in the outer membrane, forming packing defects in the membrane that may favor the translocation of both proteins to the periplasmic space. The SP-A/SP-BN complex depolarized and permeabilized the inner membrane, perhaps through the induction of toroidal pores. We conclude that the synergistic antimicrobial activity of SP-A/SP-BN is based on the capability of this complex, but not either protein alone, to alter the integrity of bacterial membranes.