-
Cells Apr 2021Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disease with significant neurological and skeletal pathologies. Respiratory dysfunction is a secondary...
Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disease with significant neurological and skeletal pathologies. Respiratory dysfunction is a secondary pathology contributing to mortality in MPS IIIA patients. Pulmonary surfactant is crucial to optimal lung function and has not been investigated in MPS IIIA. We measured heparan sulphate (HS), lipids and surfactant proteins (SP) in pulmonary tissue and bronchoalveolar lavage fluid (BALF), and surfactant activity in healthy and diseased mice (20 weeks of age). Heparan sulphate, ganglioside GM3 and bis(monoacylglycero)phosphate (BMP) were increased in MPS IIIA lung tissue. There was an increase in HS and a decrease in BMP and cholesteryl esters (CE) in MPS IIIA BALF. Phospholipid composition remained unchanged, but BALF total phospholipids were reduced (49.70%) in MPS IIIA. There was a reduction in SP-A, -C and -D mRNA, SP-D protein in tissue and SP-A, -C and -D protein in BALF of MPS IIIA mice. Captive bubble surfactometry showed an increase in minimum and maximum surface tension and percent surface area compression, as well as a higher compressibility and hysteresis in MPS IIIA surfactant upon dynamic cycling. Collectively these biochemical and biophysical changes in alveolar surfactant are likely to be detrimental to lung function in MPS IIIA.
Topics: Animals; Biophysical Phenomena; Bronchoalveolar Lavage Fluid; Cholesterol; Chromatography, Liquid; G(M3) Ganglioside; Gene Expression Regulation; Heparitin Sulfate; Lysophospholipids; Mice, Inbred C57BL; Monoglycerides; Mucopolysaccharidosis III; Phospholipids; Pulmonary Alveoli; Pulmonary Surfactants; Reference Standards; Tandem Mass Spectrometry; Mice
PubMed: 33918094
DOI: 10.3390/cells10040849 -
Drug Delivery Dec 2019Intra-tracheal instillation of budesonide using surfactant as a vehicle significantly decreased the incidence of bronchopulmonary dysplasia or death in preterm infants....
Intra-tracheal instillation of budesonide using surfactant as a vehicle significantly decreased the incidence of bronchopulmonary dysplasia or death in preterm infants. The formularity of surfactant supplemented with budesonide and biophysical and chemical stability of the suspension has not been well reported. The aims are to investigate the biophysical and chemical stability of two surfactant preparations, Survanta and Curosurf, supplemented with budesonide. Biophysical property of the surface tension of Survanta and Survanta/budesonide suspension and of Curosurf and Curosurf/budesonide suspension was conducted by a pulsating bubble surfactometer and by a drop shape tensiometer. Chemical stability of Survanta/budesonide and of Curosurf/budesonide suspensions was tested by high-performance liquid chromatography analysis (HPLC). Pulmonary distribution of Survanta/F-budesonide suspension was examined by a Nano/PET digital scan in rats. The Marangoni effect of Survanta, Curosurf, and budesonide was tested by digital high speed photography. For Survanta supplemented with budesonide, with a concentration ratio of ≥50, the surface tension-lowering activity was minimally affected. Similarly, the surface tension-lowering activity of Curosurf was not significantly affected by addition of budesonide, if the concentration ratio was ≥160. With these concentration ratios of both suspensions, HPLC analysis revealed no new compounds identified. Curosurf as compared to Survanta exhibited a significantly higher Marangoni effect. We conclude that with current dosage recommended for Survanta and Curosurf, both surfactant/budesonide suspensions are biophysically and chemically stable. Both surfactants can act as an effective vehicle for budesonide delivery.
Topics: Animals; Biological Products; Budesonide; Injection, Intratympanic; Lung; Male; Phospholipids; Pulmonary Surfactants; Rats; Rats, Sprague-Dawley; Surface Tension
PubMed: 31204848
DOI: 10.1080/10717544.2019.1618418 -
American Journal of Veterinary Research Jul 2022To perform lipidomic analysis of surfactant and plasma from asthmatic and healthy horses.
OBJECTIVE
To perform lipidomic analysis of surfactant and plasma from asthmatic and healthy horses.
ANIMALS
30 horses with clinical signs of asthma and 30 age-matched control horses.
PROCEDURES
Detailed history, physical examination, CBC, and bronchoalveolar lavage fluid (BALF) cytologies were obtained. Asthmatic horses were grouped based on their BALF inflammatory profile: severe equine asthma (SEA), mild equine asthma with neutrophilic airway inflammation (MEA-N), or mild equine asthma with eosinophilic airway inflammation (MEA-E). Each asthma group was assigned its own age-matched control group. Lipidomic analysis was completed on surfactant and plasma. Surfactant protein D (SP-D) concentrations were measured in serum and BALF.
RESULTS
SEA surfactant was characterized by a phospholipid deficit and altered composition (increased ceramides, decreased phosphatidylglycerol, and increased cyclic phosphatidic acid [cPA]). In comparison, MEA-N surfactant only had a decrease in select phosphatidylglycerol species and increased cPA levels. The plasma lipidomic profile was significantly different in all asthma groups compared to controls. Specifically, all groups had increased plasma phytoceramide. SEA horses had increased plasma cPA and diacylglycerol whereas MEA-N horses only had increased cPA. MEA-E horses had increases in select ceramides and dihydrocermides. Only SEA horses had significantly increased serum SP-D concentrations.
CLINICAL RELEVANCE
The most significant surfactant alterations were present in SEA (altered phospholipid content and composition); only mild changes were observed in MEA-N horses. The plasma lipidomic profile was significantly altered in all groups of asthmatic horses and differed among groups. Data from a larger population of asthmatic horses are needed to assess implications for diagnosis, prognosis, and treatment.
Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Ceramides; Horse Diseases; Horses; Inflammation; Lipidomics; Phosphatidylglycerols; Phospholipids; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Surface-Active Agents
PubMed: 35895773
DOI: 10.2460/ajvr.21.11.0179 -
Seminars in Fetal & Neonatal Medicine Apr 2021Despite important advances in neonatal care, rates of bronchopulmonary dysplasia (BPD) have remained persistently high. Numerous drugs and ventilator strategies are used...
Despite important advances in neonatal care, rates of bronchopulmonary dysplasia (BPD) have remained persistently high. Numerous drugs and ventilator strategies are used for the prevention and treatment of BPD. Some, such as exogenous surfactant, volume targeted ventilation, caffeine, and non-invasive respiratory support, are associated with modest but important reductions in rates of BPD and long-term respiratory morbidities. Many other therapies, such as corticosteroids, diuretics, nitric oxide, bronchodilators and anti-reflux medications, are widely used despite conflicting, limited or no evidence of efficacy and safety. This paper examines the range of therapies used for the prevention or treatment of BPD. They are classified into those supported by evidence of effectiveness, and those which are widely used despite limited evidence or unclear risk to benefit ratios. Finally, the paper explores emerging therapies and approaches which aim to prevent or reduce BPD and long-term respiratory morbidity.
Topics: Adrenal Cortex Hormones; Bronchodilator Agents; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Infant, Premature; Pulmonary Surfactants
PubMed: 33674252
DOI: 10.1016/j.siny.2021.101223 -
Bioscience Reports Aug 2023Patients with COVID-19 exhibit similar symptoms to neonatal respiratory distress syndrome. SARS-CoV-2 spike protein has been shown to target alveolar type 2 lung cells... (Review)
Review
Patients with COVID-19 exhibit similar symptoms to neonatal respiratory distress syndrome. SARS-CoV-2 spike protein has been shown to target alveolar type 2 lung cells which synthesize and secrete endogenous surfactants leading to acute respiratory distress syndrome in some patients. This was proven by post-mortem histopathological findings revealing desquamated alveolar type 2 cells. Surfactant use in patients with COVID-19 respiratory distress syndrome results in marked improvement in respiratory parameters but not mortality which needs further clinical trials comparing surfactant formulas and modes of administration to decrease the mortality. In addition, surfactants could be a promising vehicle for specific drug delivery as a liposomal carrier, which requires more and more challenging efforts. In this review, we highlight the current reviews and two clinical trials on exogenous surfactant therapy in COVID-19-associated respiratory distress in adults, and how surfactant could be a promising drug to help fight the COVID-19 infection.
Topics: Infant, Newborn; Adult; Humans; COVID-19; SARS-CoV-2; Respiratory Distress Syndrome, Newborn; Respiratory Distress Syndrome; Pulmonary Surfactants; Surface-Active Agents
PubMed: 37497603
DOI: 10.1042/BSR20230504 -
European Journal of Pharmaceutics and... Dec 2020RNA interference (RNAi) enables highly specific silencing of potential target genes for treatment of pulmonary pathologies. The intracellular RNAi pathway can be...
RNA interference (RNAi) enables highly specific silencing of potential target genes for treatment of pulmonary pathologies. The intracellular RNAi pathway can be activated by cytosolic delivery of small interfering RNA (siRNA), inducing sequence-specific gene knockdown on the post-transcriptional level. Although siRNA drugs hold many advantages over currently applied therapies, their clinical translation is hampered by inefficient delivery across cellular membranes. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel core (nanogel) coated with Curosurf®, a clinically used pulmonary surfactant (PS). The latter enhances both particle stability as well as intracellular siRNA delivery, which was shown to be governed by the PS-associated surfactant protein B (SP-B). Despite having a proven in vitro and in vivo siRNA delivery potential when prepared ex novo, clinical translation of this liquid nanoparticle suspension requires the identification of a long-term preservation strategy that maintains nanoparticle stability and potency. In addition, to achieve optimal pulmonary deposition of the nanocomposite, its compatibility with state-of-the-art pulmonary administration techniques should be evaluated. Here, we demonstrate that PS-coated nanogels can be lyophilized, reconstituted and subsequently nebulized via a vibrating mesh nebulizer. The particles retain their physicochemical integrity and their ability to deliver siRNA in a human lung epithelial cell line. The latter result suggests that the functional integrity of SP-B in the PS coat towards siRNA delivery might be preserved as well. Of note, successful lyophilization was achieved without the need for stabilizing lyo- or cryoprotectants. Our results demonstrate that PS-coated siRNA-loaded nanogels can be lyophilized, which offers the prospect of long-term storage. In addition, the formulation was demonstrated to be suitable for local administration with a state-of-the-art nebulizer for human use upon reconstitution. Hence, the data presented in this study represent an important step towards clinical application of such nanocomposites for treatment of pulmonary disease.
Topics: Administration, Inhalation; Aerosols; Biological Products; Cell Line; Epithelial Cells; Freeze Drying; Gene Transfer Techniques; Humans; Lung; Nanogels; Nanomedicine; Nebulizers and Vaporizers; Phospholipids; Pulmonary Surfactants; RNA, Small Interfering; RNAi Therapeutics
PubMed: 33022391
DOI: 10.1016/j.ejpb.2020.09.011 -
Lipids Jan 2021The only known compositional change in the phospholipids (PL) of pulmonary surfactant in response to a physiologic stimulus occurs around the time of birth. In most...
The only known compositional change in the phospholipids (PL) of pulmonary surfactant in response to a physiologic stimulus occurs around the time of birth. In most species, the predominant anionic PL changes from phosphatidylinositol (PtdIns) to phosphatidylglycerol (PtdGro). Because prior studies have shown that the change in the headgroup itself is functionally insignificant, we tested the hypothesis that the PtdIns and PtdGro contain different diacyl pairs. Experiments used electrospray-ionization mass spectrometry to determine the molecular species in PtdIns, PtdGro, and phosphatidylcholine (PtdCho) in surfactant from newborn calves and cows. The profiles for the two anionic PL were distinct. The PtdIns contained long, unsaturated fatty acid chains and no disaturated species. The PtdGro more closely resembled the profile from PtdCho. For each headgroup, the molecular species for calf and cow were similar. The differences between the two anionic PL indicate that the switch from PtdIns to PtdGro during maturation involves more than simple substitution of the headgroup, and suggest that the functional significance of the shift may reflect the different pool of diacyl pairs.
Topics: Animals; Anions; Cattle; Phospholipids; Pulmonary Surfactants; Spectrometry, Mass, Electrospray Ionization
PubMed: 32895935
DOI: 10.1002/lipd.12273 -
The Journal of Biological Chemistry Mar 2022Pulmonary surfactant is a lipoprotein complex essential for lung function, and insufficiency or altered surfactant composition is associated with major lung diseases,...
Pulmonary surfactant is a lipoprotein complex essential for lung function, and insufficiency or altered surfactant composition is associated with major lung diseases, such as acute respiratory distress syndromes, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Pulmonary surfactant is primarily composed of phosphatidylcholine (PC) in complex with specialized surfactant proteins and secreted by alveolar type 2 (AT2) cells. Surfactant homeostasis on the alveolar surface is balanced by the rates of synthesis and secretion with reuptake and recycling by AT2 cells, with some degradation by pulmonary macrophages and loss up the bronchial tree. However, whether phospholipid (PL) transporters exist in AT2 cells to mediate reuptake of surfactant PL remains to be identified. Here, we demonstrate that major facilitator superfamily domain containing 2a (Mfsd2a), a sodium-dependent lysophosphatidylcholine (LPC) transporter, is expressed at the apical surface of AT2 cells. A mouse model with inducible AT2 cell-specific deficiency of Mfsd2a exhibited AT2 cell hypertrophy with reduced total surfactant PL levels because of reductions in the most abundant surfactants, PC containing dipalmitic acid, and PC species containing the omega-3 fatty acid docosahexaenoic acid. These changes in surfactant levels and composition were mirrored by similar changes in the AT2 cell lipidome. Mechanistically, direct tracheal instillation of fluorescent LPC and PC probes indicated that Mfsd2a mediates the uptake of LPC generated by pulmonary phospholipase activity in the alveolar space. These studies reveal that Mfsd2a-mediated LPC uptake is quantitatively important in maintaining surfactant homeostasis and identify this lipid transporter as a physiological component of surfactant recycling.
Topics: Animals; Docosahexaenoic Acids; Homeostasis; Lung; Lysophosphatidylcholines; Membrane Transport Proteins; Mice; Phosphatidylcholines; Phospholipids; Pulmonary Surfactants; Symporters
PubMed: 35150739
DOI: 10.1016/j.jbc.2022.101709 -
European Journal of Pharmaceutics and... Nov 2022This work evaluates interaction of pulmonary surfactant (PS) and antimicrobial peptides (AMPs) in order to investigate (i) if PS can be used to transport AMPs, and (ii)...
This work evaluates interaction of pulmonary surfactant (PS) and antimicrobial peptides (AMPs) in order to investigate (i) if PS can be used to transport AMPs, and (ii) to what extent PS interferes with AMP function and vice versa. This, in turn, is motivated by a need to find new strategies to treat bacterial infections in the airways. Low respiratory tract infections (LRTIs) are a leading cause of illness and death worldwide that, together with the problem of multidrug-resistant (MDR) bacteria, bring to light the necessity of developing effective therapies that ensure high bioavailability of the drug at the site of infection and display a potent antimicrobial effect. Here, we propose the combination of AMPs with PS to improve their delivery, exemplified for the hydrophobically end-tagged AMP, GRR10W4 (GRRPRPRPRPWWWW-NH), with previously demonstrated potent antimicrobial activity against a broad spectrum of bacteria under various conditions. Experiments using model systems emulating the respiratory interface and an operating alveolus, based on surface balances and bubble surfactometry, served to demonstrate that a fluorescently labelled version of GRR10W4 (GRR10W4-F), was able to interact and insert into PS membranes without affecting its biophysical function. Therefore, vehiculization of the peptide along air-liquid interfaces was enabled, even for interfaces previously occupied by surfactants layers. Furthermore, breathing-like compression-expansion dynamics promoted the interfacial release of GRR10W4-F after its delivery, which could further allow the peptide to perform its antimicrobial function. PS/GRR10W4-F formulations displayed greater antimicrobial effects and reduced toxicity on cultured airway epithelial cells compared to that of the peptide alone. Taken together, these results open the door to the development of novel delivery strategies for AMPs in order to increase the bioavailability of these molecules at the infection site via inhaled therapies.
Topics: Pulmonary Surfactants; Tryptophan; Antimicrobial Peptides; Anti-Infective Agents; Anti-Bacterial Agents; Adenosine Monophosphate; Microbial Sensitivity Tests
PubMed: 36154903
DOI: 10.1016/j.ejpb.2022.09.018 -
Frontiers in Immunology 2021Pulmonary surfactant is a complex and highly surface-active material. It covers the alveolar epithelium and consists of 90% lipids and 10% proteins. Pulmonary surfactant... (Review)
Review
Pulmonary surfactant is a complex and highly surface-active material. It covers the alveolar epithelium and consists of 90% lipids and 10% proteins. Pulmonary surfactant lipids together with pulmonary surfactant proteins facilitate breathing by reducing surface tension of the air-water interface within the lungs, thereby preventing alveolar collapse and the mechanical work required to breathe. Moreover, pulmonary surfactant lipids, such as phosphatidylglycerol and phosphatidylinositol, and pulmonary surfactant proteins, such as surfactant protein A and D, participate in the pulmonary host defense and modify immune responses. Emerging data have shown that pulmonary surfactant lipids modulate the inflammatory response and antiviral effects in some respiratory viral infections, and pulmonary surfactant lipids have shown promise for therapeutic applications in some respiratory viral infections. Here, we briefly review the composition, antiviral properties, and potential therapeutic applications of pulmonary surfactant lipids in respiratory viral infections.
Topics: Animals; Antiviral Agents; COVID-19; Host-Pathogen Interactions; Humans; Lipids; Lung; Pulmonary Surfactants; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34646269
DOI: 10.3389/fimmu.2021.730022