Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.

Détails

ID Serval
serval:BIB_3B4D059A98A6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.
Périodique
American journal of respiratory cell and molecular biology
Auteur⸱e⸱s
Romero M.J., Yue Q., Ahn W.M., Hamacher J., Zaidi Y., Haigh S., Sridhar S., Gonzales J., Hudel M., Huo Y., Verin A.D., Pace B.S., Stansfield B.K., Maishan M., Neptune E.R., Enkhbaatar P., Su Y., Chakraborty T., Gonsalvez G., Hummler E., Davis W.B., Bogdanov V.Y., Fulton DJR, Csanyi G., Matthay M.A., Eaton D.C., Lucas R.
ISSN
1535-4989 (Electronic)
ISSN-L
1044-1549
Statut éditorial
Publié
Date de publication
04/2025
Peer-reviewed
Oui
Volume
72
Numéro
4
Pages
429-440
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NOX2 (nicotinamide adenine dinucleotide phosphate hydrogen [NADPH] oxidase 2), involving the pneumococcal virulence factor PLY (pneumolysin). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of ENaC (epithelial sodium channel) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function-measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans blue dye incorporation in mouse lungs-after infection with pneumococci. PLY-induced hyperpermeability in human lung microvascular endothelial cell monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47 <sup>phox</sup> subunit (Western blotting) in vitro and by colocalization of CD31 and gp91 <sup>phox</sup> in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-α, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-α knockout (enENaC-α knockout) mice develop increased capillary leak upon intratracheal instillation with PLY or pneumococci, compared with wild-type animals. TIP peptide diminishes capillary leak in Streptococcus pneumoniae-infected wild-type mice, without significantly increasing lung bacterial load. Lung slices from S. pneumoniae-infected enENaC-α knockout mice have significantly increased endothelial NOX2 expression, compared with infected cyclization recombination mice. In conclusion, enENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in acute respiratory distress syndrome, without impairing host defense.
Mots-clé
Animals, Oxidative Stress/drug effects, Pneumonia, Pneumococcal/microbiology, Pneumonia, Pneumococcal/metabolism, NADPH Oxidase 2/metabolism, NADPH Oxidase 2/genetics, Epithelial Sodium Channels/metabolism, Humans, Acute Lung Injury/microbiology, Acute Lung Injury/metabolism, Acute Lung Injury/pathology, Lung/microbiology, Lung/pathology, Lung/metabolism, Lung/blood supply, Mice, Endothelial Cells/metabolism, Endothelial Cells/microbiology, Streptolysins/metabolism, Mice, Inbred C57BL, Capillaries/metabolism, Capillaries/pathology, Bacterial Proteins/metabolism, Streptococcus pneumoniae, Mice, Knockout, NOX2, acute respiratory distress syndrome, capillary leak, endothelial ENaC, pneumococcal pneumonia
Pubmed
Création de la notice
25/10/2024 14:38
Dernière modification de la notice
08/04/2025 7:06
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