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Colloids and Surfaces. B, Biointerfaces Feb 2022Pulmonary fungal infections lead to damage of the endogenous lung surfactant system. However, the molecular mechanism underlying surfactant inhibition is unknown....
Pulmonary fungal infections lead to damage of the endogenous lung surfactant system. However, the molecular mechanism underlying surfactant inhibition is unknown. β-D-glucan is the major component of pathogenic fungal cell walls and is also present in organic dust, which increases the risk of respiratory diseases. The objective of this study was to characterize the interaction of this D-glucopyranose polymer with pulmonary surfactant. Our results show that β-D-glucan induced a concentration-dependent inhibition of the surface adsorption, respreading, and surface tension-lowering activity of surfactant preparations containing surfactant proteins SP-B and SP-C. Our data support a new mechanism of surfactant inhibition that consists in the extraction of phospholipid molecules from surfactant membranes by β-D-glucan. As a result, surfactant membranes became more fluid, as demonstrated by fluorescence anisotropy, and showed decreased T and transition enthalpy. Surfactant preparations containing surfactant protein A (SP-A) were more resistant to β-D-glucan inhibition. SP-A bound to different β-D-glucans with high affinity (K = 1.5 ± 0.1 nM), preventing and reverting β-D-glucan inhibitory effects on surfactant interfacial adsorption and partially abrogating β-D-glucan inhibitory effects on surfactant's reduction of surface tension. We conclude that β-D-glucan inhibits the biophysical function of surfactant preparations lacking SP-A by subtraction of phospholipids from surfactant bilayers and monolayers. The increased resistance of SP-A-containing surfactant preparations to β-D-glucan reinforces its use in surfactant replacement therapy.
Topics: Glucans; Phospholipids; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants
PubMed: 34836708
DOI: 10.1016/j.colsurfb.2021.112237 -
International Journal of Molecular... Jul 2023The alveolar epithelium is covered by a non-cellular layer consisting of an aqueous hypophase topped by pulmonary surfactant, a lipo-protein mixture with surface-active... (Review)
Review
The alveolar epithelium is covered by a non-cellular layer consisting of an aqueous hypophase topped by pulmonary surfactant, a lipo-protein mixture with surface-active properties. Exposure to cigarette smoke (CS) affects lung physiology and is linked to the development of several diseases. The macroscopic effects of CS are determined by several types of cell and molecular dysfunction, which, among other consequences, lead to surfactant alterations. The purpose of this review is to summarize the published studies aimed at uncovering the effects of CS on both the lipid and protein constituents of surfactant, discussing the molecular mechanisms involved in surfactant homeostasis that are altered by CS. Although surfactant homeostasis has been the topic of several studies and some molecular pathways can be deduced from an analysis of the literature, it remains evident that many aspects of the mechanisms of action of CS on surfactant homeostasis deserve further investigation.
Topics: Pulmonary Surfactants; Electronic Nicotine Delivery Systems; Surface-Active Agents; Nicotiana; Lung
PubMed: 37511463
DOI: 10.3390/ijms241411702 -
Biomedical Journal Aug 2022The lives of thousands premature babies have been saved along the last thirty years thanks to the establishment and consolidation of pulmonary surfactant replacement... (Review)
Review
The lives of thousands premature babies have been saved along the last thirty years thanks to the establishment and consolidation of pulmonary surfactant replacement therapies (SRT). It took some time to close the gap between the identification of the biophysical and molecular causes of the high mortality associated with respiratory distress syndrome in very premature babies and the development of a proper therapy. Closing the gap required the elucidation of some key questions defining the structure-function relationships in surfactant as well as the particular role of the different molecular components assembled into the surfactant system. On the other hand, the application of SRT as part of treatments targeting other devastating respiratory pathologies, in babies and adults, is depending on further extensive research still required before enough amounts of good humanized clinical surfactants will be available. This review summarizes our current concepts on the compositional and structural determinants defining pulmonary surfactant activity, the principles behind the development of efficient natural animal-derived or recombinant or synthetic therapeutic surfactants, as well as a the most promising lines of research that are already opening new perspectives in the application of tailored surfactant therapies to treat important yet unresolved respiratory pathologies.
Topics: Animals; Humans; Infant, Newborn; Pulmonary Surfactants; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Surface-Active Agents
PubMed: 35272060
DOI: 10.1016/j.bj.2022.03.001 -
Biomedical Journal Dec 2021The knowledge about surfactant biology is now deeper and recent research has allowed to clarify its role in several human lung disorders. The balance between surfactant... (Review)
Review
The knowledge about surfactant biology is now deeper and recent research has allowed to clarify its role in several human lung disorders. The balance between surfactant production and consumption is better known and the same applies to their regulatory mechanisms. This has allowed to hypothesize and investigate several new and original strategies to protect surfactant and enhance its activity. These interventions are potentially useful for several disorders and particularly for acute respiratory distress syndrome. We here highlight the mechanisms regulating surfactant consumption, encompassing surfactant catabolism but also surfactant injury due to other mechanisms, in a physiopathology-driven fashion. We then analyze each corresponding strategy to protect surfactant and enhance its activity. Some of these strategies are more advanced in terms of research & development pathway, some others are still investigational, but all are promising and deserve a joint effort from clinical-academic researchers and the industry.
Topics: Humans; Lung; Pulmonary Surfactants; Respiratory Distress Syndrome; Surface-Active Agents
PubMed: 34365021
DOI: 10.1016/j.bj.2021.07.011 -
Biomedical Journal Dec 2021This issue of the Biomedical Journal provides a comprehensive insight into the role of pulmonary surfactant and influencing its components as well as involved molecules...
This issue of the Biomedical Journal provides a comprehensive insight into the role of pulmonary surfactant and influencing its components as well as involved molecules to treat a variety of respiratory distress disorders. We also discover how epithelial mesenchymal transition (EMT) could be targeted as part of a therapeutic strategy against lung cancer. Furthermore, a method is described to eliminate chemoresistance against gemcitabine, a drug administered to treat pancreatic cancer. We gain an insight into the composition of salivary calcium particles in periodontitis, a technique to circumvent complications in hip surgery, and a potential treatment to accelerate diabetic wound healing. Moreover, we get to know an essential oil that exerts a similar effect as diazepam on the central nervous system. A trial in patients with myofascial pain syndrome demonstrates how laser assisted trigger point therapy leads to immediate relief. Finally, a case study outlines the discovery of a genetic mutation that plays a role in intellectual disability.
Topics: Epithelial-Mesenchymal Transition; Humans; Pancreatic Neoplasms; Pulmonary Surfactants; Wound Healing
PubMed: 34942391
DOI: 10.1016/j.bj.2021.12.003 -
International Journal of Molecular... Dec 2022Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress... (Review)
Review
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.
Topics: Humans; Pulmonary Surfactants; Phospholipids; Lung; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial
PubMed: 36613771
DOI: 10.3390/ijms24010326 -
Human Gene Therapy Oct 2022Genetic disorders of surfactant dysfunction result in significant morbidity and mortality, among infants, children, and adults. Available medical interventions are... (Review)
Review
Genetic disorders of surfactant dysfunction result in significant morbidity and mortality, among infants, children, and adults. Available medical interventions are limited, nonspecific, and generally ineffective. As such, the need for effective therapies remains. Pathogenic variants in the , and genes, each of which encode proteins essential for proper pulmonary surfactant production and function, result in interstitial lung disease in infants, children, and adults, and lead to morbidity and early mortality. Expression of these genes is predominantly limited to the alveolar type 2 (AT2) epithelial cells present in the distal airspaces of the lungs, thus providing an unequivocal cellular origin of disease pathogenesis. While several treatment strategies are under development, a gene-based therapeutic holds great promise as a definitive therapy. Importantly for clinical translation, the genes associated with surfactant dysfunction are both well characterized and amenable to a gene-therapeutic-based strategy. This review focuses on the pathophysiology associated with these genetic disorders of surfactant dysfunction, and also provides an overview of the current state of gene-based therapeutics designed to target and transduce the AT2 cells.
Topics: Infant; Child; Adult; Humans; Pulmonary Surfactants; Lung Diseases, Interstitial; Lung; Epithelial Cells; Mutation; Alveolar Epithelial Cells
PubMed: 36166236
DOI: 10.1089/hum.2022.130 -
Cellular Physiology and Biochemistry :... 2010Pulmonary surfactant has two crucial roles in respiratory function; first, as a biophysical entity it reduces surface tension at the air water interface, facilitating... (Review)
Review
Pulmonary surfactant has two crucial roles in respiratory function; first, as a biophysical entity it reduces surface tension at the air water interface, facilitating gas exchange and alveolar stability during breathing, and, second, as an innate component of the lung's immune system it helps maintain sterility and balance immune reactions in the distal airways. Pulmonary surfactant consists of 90% lipids and 10% protein. There are four surfactant proteins named SP-A, SP-B, SP-C, and SP-D; their distinct interactions with surfactant phospholipids are necessary for the ultra-structural organization, stability, metabolism, and lowering of surface tension. In addition, SP-A and SP-D bind pathogens, inflict damage to microbial membranes, and regulate microbial phagocytosis and activation or deactivation of inflammatory responses by alveolar macrophages. SP-A and SP-D, also known as pulmonary collectins, mediate microbial phagocytosis via SP-A and SP-D receptors and the coordinated induction of other innate receptors. Several receptors (SP-R210, CD91/calreticulin, SIRPalpha, and toll-like receptors) mediate the immunological functions of SP-A and SP-D. However, accumulating evidence indicate that SP-B and SP-C and one or more lipid constituents of surfactant share similar immuno-regulatory properties as SP-A and SP-D. The present review discusses current knowledge on the interaction of surfactant with lung innate host defense.
Topics: Animals; Humans; Immunity, Innate; Lung Diseases; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants
PubMed: 20054141
DOI: 10.1159/000272047 -
Microbes and Infection Jan 2012Pulmonary surfactant is a complex surface-active substance comprised of key phospholipids and proteins that has many essential functions. Surfactant's unique composition... (Review)
Review
Pulmonary surfactant is a complex surface-active substance comprised of key phospholipids and proteins that has many essential functions. Surfactant's unique composition is integrally related to its surface-active properties, its critical role in host defense, and emerging immunomodulatory activities ascribed to surfactant lipids. Together these effector functions provide for lung stability and protection from a barrage of potentially virulent infectious pathogens.
Topics: Animals; Communicable Diseases; Humans; Immunologic Factors; Lung Diseases; Pulmonary Surfactants
PubMed: 21945366
DOI: 10.1016/j.micinf.2011.08.019 -
Cellular & Molecular Biology Letters Nov 2023The pulmonary surfactant that lines the air-liquid surface within alveoli is a protein-lipid mixture essential for gas exchange. Surfactant lipids and proteins are...
BACKGROUND
The pulmonary surfactant that lines the air-liquid surface within alveoli is a protein-lipid mixture essential for gas exchange. Surfactant lipids and proteins are synthesized and stored in the lamellar body (LB) before being secreted from alveolar type II (AT2) cells. The molecular and cellular mechanisms that regulate these processes are incompletely understood. We previously identified an essential role of general control of amino acid synthesis 5 like 1 (GCN5L1) and the biogenesis of lysosome-related organelle complex 1 subunit 1 (BLOS1) in surfactant system development in zebrafish. Here, we explored the role of GCN5L1 in pulmonary surfactant regulation.
METHOD
GCN5L1 knockout cell lines were generated with the CRISPR/Cas9 system. Cell viability was analyzed by MTT assay. Released surfactant proteins were measured by ELISA. Released surfactant lipids were measured based on coupled enzymatic reactions. Gene overexpression was mediated through lentivirus. The RNA levels were detected through RNA-sequencing (RNA-seq) and quantitative reverse transcription (qRT)- polymerase chain reaction (PCR). The protein levels were detected through western blotting. The cellular localization was analyzed by immunofluorescence. Morphology of the lamellar body was analyzed through transmission electron microscopy (TEM), Lysotracker staining, and BODIPY phosphatidylcholine labeling.
RESULTS
Knocking out GCN5L1 in MLE-12 significantly decreased the release of surfactant proteins and lipids. We detected the downregulation of some surfactant-related genes and misregulation of the ROS-Erk-Foxo1-Cebpα axis in mutant cells. Modulating the activity of the axis or reconstructing the mitochondrial expression of GCN5L1 could partially restore the expression of these surfactant-related genes. We further showed that MLE-12 cells contained many LB-like organelles that were lipid enriched and positive for multiple LB markers. These organelles were smaller in size and accumulated in the absence of GCN5L1, indicating both biogenesis and trafficking defects. Accumulated endogenous surfactant protein (SP)-B or exogenously expressed SP-B/SP-C in adenosine triphosphate-binding cassette transporterA3 (ABCA3)-positive organelles was detected in mutant cells. GCN5L1 localized to the mitochondria and LBs. Reconstruction of mitochondrial GCN5L1 expression rescued the organelle morphology but failed to restore the trafficking defect and surfactant release, indicating specific roles associated with different subcellular localizations.
CONCLUSIONS
In summary, our study identified GCN5L1 as a new regulator of pulmonary surfactant that plays a role in the biogenesis and positioning/trafficking of surfactant-containing LBs.
Topics: Animals; Mice; Alveolar Epithelial Cells; Lamellar Bodies; Lipids; Pulmonary Surfactants; RNA; Surface-Active Agents; Zebrafish
PubMed: 37936104
DOI: 10.1186/s11658-023-00506-0