Surfactant Phospholipids Research Articles

Surfactant Phospholipid Kinetics in Ventilated Children after Therapeutic Surfactant Supplementation

Acute lung Injury leads to alterations in surfactant lipid composition and metabolism. Although several mechanisms contribute to dysregulated surfactant metabolism, studies investigating in vivo surfactant metabolism are limited. The aim of this study is to characterise surfactant phospholipid composition and flux utilising a stable isotope labelling technique in mechanically ventilated paediatric patients. Paediatric patients (<16 years of age) received 3.6 mg/kg intravenous methyl-D9-choline chloride followed by the endotracheal instillation of 100 mg/kg of exogenous surfactant after 24 h. Bronchioalveolar fluid samples were taken at baseline and 12, 24, 36, 48, 72 and 96 h after methyl-D9-choline infusion. Nine participants (median age of 48 days) were recruited. The primary phosphatidylcholine (PC) composition consisted of PC16:0/16:0 or DPPC (32.0 ± 4.5%). Surfactant supplementation resulted in a 30% increase in DPPC. Methyl-D9 PC enrichment was detected after 12 h and differed significantly between patients, suggesting variability in surfactant synthesis/secretion by the CDP-choline pathway. Peak enrichment was achieved (0.94 ± 0.15% of total PC) at 24 h after methyl-D9-choline infusion. There was a trend towards reduced enrichment with the duration of mechanical ventilation prior to study recruitment; however, this was not statistically significant (p = 0.19). In this study, we demonstrated the fractional molecular composition and turnover of surfactant phospholipids, which was highly variable between patients.

Magnitude of obesity alone does not alter the alveolar lipidome.

Obesity may lead to pulmonary dysfunction through complex and incompletely understood cellular and biochemical effects. Altered lung lipid metabolism has been identified as a potential mechanism of lung dysfunction in obesity. Although murine models of obesity demonstrate changes in pulmonary surfactant phospholipid composition and function, data in humans are lacking. We measured untargeted shotgun lipidomes in two bronchoalveolar lavages (BALs) from apical and anteromedial pulmonary subsegments of 14 adult subjects (7 males and 7 females) with body mass indexes (BMIs) ranging from 24.3 to 50.9 kg/m2. The lipidome composition was characterized at the class, species, and fatty acyl/alkyl level using total lipid molecular ion signal intensities normalized to BAL protein concentration and epithelial lining fluid volumes. Multivariate analyses were conducted to identify potential changes with increasing BMI. The alveolar lipidomes contained the expected composition of surfactant-associated phospholipids, sphingolipids, and sterols in addition to cardiolipin and intracellular signaling lipid species. No significant differences in lipidomes were detected between the two BAL regions. Though a small number of lipid species were associated with BMI in multivariate analyses, no robust differences in lipidome composition or specific lipid species were identified over the range of body habitus. The magnitude of obesity alone does not substantially alter the alveolar lipidome in patients without lung disease. Differences in lung function in patients with obesity and no lung disease are unlikely related to changes in alveolar lipid composition.NEW & NOTEWORTHY Altered lung lipid metabolism has been identified as a potential mechanism of lung dysfunction in obesity, but data in humans are lacking. We measured the alveolar lipidome in bronchoalveolar lavages from subjects with healthy lungs with a wide range of body mass index. There were no differences in lipidome composition in association with the magnitude of obesity. In patients with healthy lungs, obesity alone does not alter the alveolar lipidome.

Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

Surfactant system of the lungs in antiphospholipid syndrome under the conditions of administration of the immunosuppressive agent FTY-720

Antiphospholipid syndrome (APS) is a thrombophilic disease in the pathogenesis of which the leading role belongs to antibodies reacting with antigenic determinants of phospholipids. APS is a systemic autoimmune pathology that involves many organs and systems in the pathological process, including the respiratory system. Given the fact that the lung surfactant is mainly represented by phospholipids, it can be presented that the surfactant is damaged and its functioning is impaired in APS. The results of our experiments showed that in antiphospholipid syndrome, there was a decline in the functional activity of the surfactant and a change in its biochemical composition. The introduction of FTY-720 normalized the parameters of the lung surfactant system, which were changed during the modeling of antiphospholipid syndrome. The work shows the effectiveness of the therapy of this autoimmune pathology with immunosuppressor FTY-720, which is a structural analogue of endogenous sphingosine. The effect of the drug is based on the modulation of sphingosine-1 phosphate receptors of lymphocytes. The main effect of the immunosuppressor FTY-720 as a result of receptor interaction is a decrease in the number of circulating lymphocytes. The research involved 85 white random bred male rats: Group 1 (APS modeling) consisted of 30 rats who were intravenously injected with cardiolipin antigen at a total dose of 0.2-0.4 mg per rat every other day for three weeks; Group 2 (control) consisted of 25 rats who were injected with 0.9% NaCl solution according to the same scheme; and Group 3 including 30 rats in which APS was combined with the administration of the immunosuppressive agent FTY-720 (intraperitoneally 1 mg/kg of animal weight). Three weeks later, there was an operation conducted with the purpose of extraction of the bronchopulmonary complex. After extraction of the bronchopulmonary complex, its triple lavage was carried out with 0.9% NaCl solution. The material of the experimental study was a lavage liquid, in which the biophysical and biochemical parameters of the surfactant were studied. Langmuir–Blodgett method was used to identify static, minimal and maximal surface tension. These figures were used to identify integrative indicator reflecting surfactant characteristics – the Clements stability index. The fractional composition of surfactant phospholipids was determined by thin-layer chromatography. The results of our experiments showed that in antiphospholipid syndrome, there was a decline in the functional activity of the surfactant and a change in its biochemical composition. The introduction of FTY-720 normalized the parameters of the lung surfactant system, which were changed during the modeling of antiphospholipid syndrome.

Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation.

MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the 'reactive species interactome') to differentiate between groups of conservative and usual oxygen targets. After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D 9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTNISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

Multicentric investigations of the role in the disease severity of accelerated phospholipid changes in COVID-19 patient airway

ContextThe changes in host membrane phospholipids are crucial in airway infection pathogenesis. Phospholipase A2 hydrolyzes host cell membranes, producing lyso-phospholipids and free fatty acids, including arachidonic acid (AA), which contributes significantly to lung inflammation. AimFollow these changes and their evolution from day 1, day 3 to day 7 in airway aspirates of 89 patients with COVID-19-associated acute respiratory distress syndrome and examine whether they correlate with the severity of the disease. The patients were recruited in three French intensive care units. The analysis was conducted from admission to the intensive care unit until the end of the first week of mechanical ventilation. ResultsIn the airway aspirates, we found significant increases in the levels of host cell phospholipids, including phosphatidyl-serine and phosphatidyl-ethanolamine, and their corresponding lyso-phospholipids. This was accompanied by increased levels of AA and its inflammatory metabolite prostaglandin E2 (PGE2). Additionally, enhanced levels of ceramides, sphingomyelin, and free cholesterol were observed in these aspirates. These lipids are known to be involved in cell death and/or apoptosis, whereas free cholesterol plays a role in virus entry and replication in host cells. However, there were no significant changes in the levels of dipalmitoyl-phosphatidylcholine, the major surfactant phospholipid. A correlation analysis revealed an association between mortality risk and levels of AA and PGE2, as well as host cell phospholipids. ConclusionOur findings indicate a correlation between heightened cellular phospholipid modifications and variations in AA and PGE2 with the severity of the disease in patients. Nevertheless, there is no indication of surfactant alteration in the initial phases of the illness.

Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation

Background MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. Aim The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the ‘reactive species interactome’) to differentiate between groups of conservative and usual oxygen targets. Methods and design After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTN ISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

Surfactants for stabilization of dermal emulsions and their skin compatibility under UVA irradiation: Diacyl phospholipids and polysorbate 80 result in high viability rates of primary human skin cells

Phospholipids are versatile formulation compounds with high biocompatibility. However, no data on their effect on skin in combination with UVA radiation exist. Thus, it was the aim of this work to (i) develop o/w nanoemulsions (NEs) differing in surfactant type and to investigate their physicochemical stability at different storage temperatures, (ii) establish a standardized protocol for in vitro phototoxicity testing using primary human skin cells and (iii) investigate the phototoxicity of amphoteric phospholipids (S45, S75, E80, S100, LPC80), sodium lauryl ether sulfate (SLES) and polysorbate 80 (PS80). Satisfying systems were developed with all surfactants except S100 due to low zeta potential (-21.4 mV ± 4.69). SLES and PS80-type NEs showed the highest stability after eight weeks; temperature-dependent variations in storage stability were most noticeable for phospholipid surfactants. For phospholipid-based NEs, higher phosphatidylcholine content led to unstable formulations. Phototoxicity assays with primary skin fibroblasts confirmed the lack of UVA-related phototoxicity but revealed cytotoxic effects of LPC80 and SLES, resulting in cell viability as low as 2.7 % ±0.78 and 1.9 % ±1.57 compared to the control. Our findings suggest that surfactants S45, S75 and PS80 are the most promising candidates for skin-friendly emulsifiers in sensitive applications involving exposure to UV light.

Evolution of interfacial mechanics of lung surfactant mimics progression of acute respiratory distress syndrome.

How acute respiratory distress syndrome progresses from underlying disease or trauma is poorly understood, and there are no generally accepted treatments resulting in a 40% mortality rate. However, during the inflammation that accompanies this disease, the phospholipase A2 concentration increases in the alveolar fluids leading to the hydrolysis of bacterial, viral, and lung surfactant phospholipids into soluble lysolipids. We show that if the lysolipid concentration in the subphase reaches or exceeds its critical micelle concentration, the surface tension, γ, of dipalmitoyl phosphatidylcholine (DPPC) or Curosurf monolayers increases and the dilatational modulus, [Formula: see text], decreases to that of a pure lysolipid interface. This is consistent with DPPC being solubilized in lysolipid micelles and being replaced by lysolipid at the interface. These changes lead to [Formula: see text] which is the criterion for the Laplace instability that can lead to mechanical instabilities during lung inflation, potentially causing alveolar collapse. These findings provide a mechanism behind the alveolar collapse and uneven lung inflation during ARDS.

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD.

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

Surfactant Metabolism Dysfunction Type 3 (SMDP3)

Surfactant (surface-active-agent) is a compound of phospholipids and proteins which are synthesized and secreted into the alveolus by type II epithelial cells, where it functions to decrease surface tension, maintaining alveolar expansion, to facilitate pulmonary compliance. Surfactant proteins (SP)A, B, C, D represent around 8% of total components, but has vital role in optimizing rapid adsorption and spreading of phospholipids. ATP-binding cassette sub-family A member 3, protein that encoded by ABCA3 gene, which located in human chromosome 16p13.3, is synthesized in endoplasmic reticulum and migrated to lysosomal-derived organelles of alveolar type II cells, formally known as lamellar bodies. Once accumulate into the membrane, ABCA3 can directed surfactant phospholipid into the lumen of lamellar bodies and create tight packed of surfactant lipids and proteins. Mutation of the ATP-binding cassette transporter gene ABCA3 cause failure in lamellar body synthesis and result in decreased production of surfactant, along with respiratory distress syndrome, and fatal respiratory failure.

Lipid mediators in the regulation of innate and adaptive immunity.

Lipid mediators in the regulation of innate and adaptive immunity.

The anti-inflammatory and antiviral properties of anionic pulmonary surfactant phospholipids.

The pulmonary surfactant system of the lung is a lipid and protein complex, which regulates the biophysical properties of the alveoli to prevent lung collapse and the innate immune system in the lung. Pulmonary surfactant is a lipoprotein complex consisting of 90% phospholipids and 10% protein, by weight. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), exist at very high concentrations in the extracellular alveolar compartments. We have reported that one of the most dominant molecular species of PG, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and PI inhibit inflammatory responses induced by multiple toll-like receptors (TLR2/1, TLR3, TLR4, and TLR2/6) by interacting with subsets of multiprotein receptor components. These lipids also exert potent antiviral effects against RSV and influenza A, in vitro, by inhibiting virus binding to host cells. POPG and PI inhibit these viral infections in vivo, in multiple animal models. Especially noteworthy, these lipids markedly attenuate SARS-CoV-2 infection including its variants. These lipids are natural compounds that already exist in the lung and, thus, are less likely to cause adverse immune responses by hosts. Collectively, these data demonstrate that POPG and PI have strong potential as novel therapeutics for applications as anti-inflammatory compounds and preventatives, as treatments for broad ranges of RNA respiratory viruses.

Chronic Rhinosinusitis with Nasal Polyposis in an Adult with Homozygous Variants of Uncertain Significance in ABCA3 Gene

IntroductionThe role of surfactant proteins in pulmonary diseases has been studied extensively. However, little is known about its contribution in diseases involving the nasal mucosa. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common disease characterized by persistent inflammation of the nasal passage and paranasal sinuses. We present a case of CRSwNP and interstitial lung disease (ILD) with variants of uncertain significance (VUS) in adenosine triphosphate binding cassette subfamily A member 3 (ABCA3) identified as potential genetic etiology. Case DescriptionPatient was a 42-year-old female with chronic obstructive pulmonary disease (COPD) with oxygen-dependance, bronchiectasis, history of hospitalization for bronchiolitis obliterans organizing pneumonia (BOOP) in infancy, who presented for evaluation of CRSwNP and anosmia. Nasal polyps were first discovered around three years of age, requiring more than 25 nasal polypectomies in her lifetime. Evaluation for cystic fibrosis during childhood was unremarkable. She reported only one episode of wheezing and denied aspirin sensitivity. Despite her significant history of BOOP in infancy, the patient remained without pulmonary infections until four years prior to presentation. Since then, she had two episodes of pneumonia and was diagnosed with COPD, leading to chronic oxygen use. Recent spirometry showed severe airflow obstruction, hyperinflation and decreased diffusing capacity for carbon monoxide. Chest CT revealed diffuse bronchiectasis, mucous plugging, and mild ground glass opacity. Patient had negative sweat test and normal alpha-1 antitrypsin level. Genetic testing with Invitae PCD panel and Neonatal Respiratory Distress panel revealed homozygous VUS [c.155C>T (p. Pro52Leu)] in ABCA3 gene. ConclusionOur patient had an atypical course of ILD, remaining asymptomatic most of her life, and CRSwNP. ABCA3 variants are associated with autosomal recessive pulmonary diseases, such as pulmonary surfactant metabolism dysfunction, pediatric ILD and pulmonary fibrosis1. Surfactant phospholipids are known to lower the surface tension in the alveoli, but they also decrease mucus viscosity and help to eliminate inhaled pathogens2,3,4. The pathophysiology of CRSwNP is unclear and the clinical phenotype of the disease varies widely. While the pathogenicity of the variant is not defined, this case raises a possibility that patient’s ABCA3 genotype may contribute to CRSwNP with recalcitrant nasal polyps.

Efficacy of perinatal pharmacotherapeutic actions for survival of very preterm newborn rabbits at 26-day gestation.

Investigation of the pathophysiology of lung impairment and protection in very preterm neonates at birth requires adequate experimental models. This study aimed to elucidate the efficacy and mechanism of perinatal pharmacotherapeutic action in postnatal survival of very preterm rabbits. Pregnant New Zealand White rabbits on 25-day gestation (term 31 days) were given dexamethasone (D), or sham injection as control (C), and cesarean delivered 24 hours later on day 26. Newborns were anesthetized, intratracheally intubated, randomly received either saline or porcine surfactant (S), allocated to four groups (C, S, D, and DS), and ventilated with low tidal volume. Under the identical protocol, another four groups were added with nitric oxide (N) inhalation (CN, SN, DN, and DSN). Survival length, lung mechanics, histopathology, and pathobiology of lung tissue were measured for benefits and injury patterns. DSN had the longest median survival time (ST50, 10.3 h), whereas C had the shortest (3.5 h), with remaining groups in-between. The survival was mainly benefited by S, when additive effects with D and/or N were discernible, by improved lung mechanics and alveolar aeration, ameliorated lung injury severity and pneumothorax, and augmented lung phospholipid pools, with DSN being the most optimal. Variable mRNA expression profiles of alveolar epithelia-associated cytokines and inflammatory mediators further characterized injury and response patterns as phenotyping conditioned in pharmacotherapeutic actions. In conclusion, the combined regimens of perinatal medications achieved remarkable survival in very preterm rabbits with lung protective ventilation strategy, offering a unique model in investigation of very preterm birth-associated respiratory physiology and morbidities.NEW & NOTEWORTHY By establishing a very preterm rabbit model with 26-day gestation (term 31 days), optimal survival length for 50% of animals in groups was achieved by comparing regimens of combined antenatal glucocorticoids, postnatal surfactant and inhaled nitric oxide, with a low tidal volume ventilation strategy. The efficacies of pharmacotherapeutic action were associated with significantly improved lung mechanics, ameliorated lung injury and pneumothorax, and enhanced surfactant phospholipid metabolism, along with variable mRNA expression profiles characterizing the response patterns.

The Role of Pulmonary Surfactant Phospholipids in Fibrotic Lung Diseases

Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no known cause, is devastating and has no cure. Chronic lesion of alveolar type II (ATII) cells represents a key mechanism for the development of IPF. ATII cells are specialized in the biosynthesis and secretion of pulmonary surfactant (PS), a lipid-protein complex that reduces surface tension and minimizes breathing effort. Some differences in PS composition have been reported between patients with idiopathic pulmonary disease and healthy individuals, especially regarding some specific proteins in the PS; however, few reports have been conducted on the lipid components. This review focuses on the mechanisms by which phospholipids (PLs) could be involved in the development of the fibroproliferative response.

Lung surfactant negatively affects the photodynamic inactivation of bacteria—in vitro and molecular dynamic simulation analyses

In the context of the rapid increase of antibiotic-resistant infections, in particular of pneumonia, antimicrobial photodynamic therapy (aPDT), the microbiological application of photodynamic therapy (PDT), comes in as a promising treatment alternative since the induced damage and resultant death are not dependent on a specific biomolecule or cellular pathway. The applicability of aPDT using the photosensitizer indocyanine green with infrared light has been successfully demonstrated for different bacterial agents invitro, and the combination of pulmonary delivery using nebulization and external light activation has been shown to be feasible. However, there has been little progress in obtaining sufficient invivo efficacy results. This study reports the lung surfactant as a significant suppressor of aPDT in the lungs. In vitro, the clinical surfactant Survanta® reduced the aPDT effect of indocyanine green, Photodithazine®, bacteriochlorin-trizma, and protoporphyrin IX against Streptococcus pneumoniae. The absorbance and fluorescence spectra, as well as the photobleaching profile, suggested that the decrease in efficacy is not a result of singlet oxygen quenching, while a molecular dynamics simulation showed an affinity for the polar head groups of the surfactant phospholipids that likely impacts uptake of the photosensitizers by the bacteria. Methylene blue is the exception, likely because its high water solubility confers a higher mobility when interacting with the surfactant layer. We propose that the interaction between lung surfactant and photosensitizer must be taken into account when developing pulmonary aPDT protocols.

The influence of a biomimetic pulmonary surfactant modification on the in vivo fate of nanoparticles in the lung

Direct biomimetic modification of nanoparticles (NPs) with endogenous surfactants is helpful to improve the biocompatibility of NPs and avoid damage to the physiological function of the lung. Therefore, the objective of this study is to investigate the influence of biomimetic endogenous pulmonary surfactant phospholipid modification on the in vivo fate of NPs after lung delivery. Here, two neutral phospholipids (dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylamine (DPPE)) and two negatively charged phospholipids (dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS)) were selected to modify paclitaxel (PTX)-loaded PLGA NPs with different molar ratio. DPPC, DPPE, and DPPG improved mucoadhesion, in contrast, DPPS improved the mucus permeability of the NPs. Neutral DPPC and DPPE reduced, but negatively charged DPPS and DPPG increased the uptake by alveolar macrophages, all types of phospholipid increased the uptake by lung epithelial cells and increased PTX retention in the whole lung. Whereas, DPPC, DPPE, and DPPG promoted PTX retention in bronchoalveolar lavage fluid (BALF), while DPPS promoted PTX absorption in the lung tissue. Only DPPS-PLGA (1:1) NPs remarkably increased PTX systemic exposure. A good correlation between PTX percentage in the supernatant of BALF and PTX concentration in plasma was established, implying PTX entered the system circulation mainly in molecular form. Phospholipid modification had no effect on extrapulmonary organ distribution of PTX. Taken together, our study disclosed that different phospholipid modification can endow the NPs mucoadhesive or mucus penetration and cellular uptake properties, with tunable retention in BALF and absorption in the lung tissue, providing the scientific background for translational nanocarrier design for inhalation as required. Statement of significanceInhaled nanomedicines will inevitably interact with pulmonary surfactant and form “surfactant corona”. However, the contribution of individual pulmonary surfactant phospholipid on the in vivo fate of nanomedicines is still unclear. In this regard, the most abundant pulmonary surfactant phospholipid dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylamine, and dipalmitoylphosphatidylglycerol and dipalmitoylphosphatidylserine were selected to modify the paclitaxel loaded PLGA nanoparticles and the effect of these pulmonary surfactant phospholipids on their in vivo fate was investigated. It was demonstrated that different phospholipid modification can endow the nanoparticles mucoadhesive or mucus penetration properties, with tunable retention in bronchoalveolar lavage fluid, alveolar macrophages uptake and absorption in the lung tissue. The present study provided a comprehensive understanding for the role of pulmonary surfactant phospholipid on inhaled nanomedicines.

Chronic and Binge Alcohol Ingestion Increases Truncated Oxidized Phosphatidylcholines in Mice Lungs Due to Increased Oxidative Stress.

Heavy alcohol drinking has negative health effects in multiple organs. It predisposes lungs to inflammatory conditions associated with acute lung injury and increased incidence of pneumonia and sepsis, which may lead to death due to acute respiratory distress syndrome in some individuals with alcohol use disorder (AUD). In general, rodent models of alcohol exposure either do not recapitulate multiple organ injuries as seen in humans or require longer duration to establish tissue injury and inflammation. The recently introduced NIAAA model of alcohol-induced liver injury, characterized by a marked increase in steatosis and liver damage with 10 days of a liquid diet containing 5% ethanol followed by a single ethanol binge (5 g/kg). Therefore, we employed this model to explore the status of surfactant phospholipids, oxidative stress, tissue injury markers and inflammatory cytokines in lungs. In lungs of C57BL/6J mice, the alcohol feeding significantly increased levels of the surfactant phospholipid dipalmitoyl phosphatidylcholine (DPPC) as well as the truncated oxidized phosphatidylcholines palmitoyl oxovaleryl phosphatidyl-choline (POVPC), palmitoyl glutaryl phosphatidyl-choline (PGPC), palmitoyl oxo-nonanoyl phosphatidyl-choline (ALDO-PC), and palmitoyl azelaoyl phosphatidyl-choline (PAzePC) at 9 h post-binge. Additionally, gene expression of the enzymes catalyzing lipid oxidation, such as arachidonate 15-lipoxygenase (Alox15), prostaglandin synthase 2 (Ptgs2), Cytochrome P450 2E1 (Cyp2E1) and NADPH oxidase 1 (Nox1) were significantly increased. Furthermore, ethanol increased levels of the inflammatory cytokine Interleukin-17 in bronchoalveolar lavage fluid. In conclusion, the NIAAA alcohol feeding model might be suitable to study alcohol-induced lung injury and inflammation.

Lipid biophysics and/or soft matter-inspired approach for controlling enveloped virus infectivity.

Proven as a natural barrier against viral infection, pulmonary surfactant phospholipids have a biophysical and immunological role within the respiratory system, acting against microorganisms including viruses. Enveloped viruses have, in common, an outer bilayer membrane that forms the underlying structure for viral membrane proteins to function in an optimal way to ensure infectivity. Perturbating the membrane of viruses using exogenous lipids can be envisioned as a generic way to reduce their infectivity. In this context, the potential of exogenous lipids to be used against enveloped virus infectivity would be indicated by the resulting physical stress imposed to the viral membrane, and conical lipids, i.e. lyso-lipids, would be expected to generate stronger biophysical disturbances. We confirm that when treated with lyso-lipids the infectivity three strains of influenza virus (avian H2N3, equine H3N8 or pandemic human influenza H1N1) is reduced by up to 99% in a cell-based model. By contrast, lipids with a similar head group but two aliphatic chains were less effective (reducing infection by only 40–50%). This work opens a new path to merge concepts from different research fields, i.e. ‘soft matter physics' and virology.