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Antibiotics-induced release of the pore-forming virulence factor pneumolysin (PLY) in patients with pneumococcal pneumonia results in its presence days after lungs are sterile and is a major factor responsible for the induction of permeability edema. Here we sought to identify major mechanisms mediating PLY-induced endothelial dysfunction. We evaluated PLY-induced endothelial hyperpermeability in human lung microvascular endothelial cells (HL-MVECs) and human lung pulmonary artery endothelial cells in vitro and in mice instilled intratracheally with PLY. PLY increases permeability in endothelial monolayers by reducing stable and dynamic microtubule content and modulating VE-cadherin expression. These events, dependent upon an increased calcium influx, are preceded by protein kinase C (PKC)-α activation, perturbation of the RhoA/Rac1 balance, and an increase in myosin light chain phosphorylation. At later time points, PLY treatment increases the expression and activity of arginase in HL-MVECs. Arginase inhibition abrogates and suppresses PLY-induced endothelial barrier dysfunction by restoring NO generation. Consequently, a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide, which blunts PLY-induced PKC-α activation, are able to prevent activation of arginase in HL-MVECs and to reduce PLY-induced endothelial hyperpermeability in mice. Arginase I (AI)(+/-)/arginase II (AII)(-/-) C57BL/6 mice, displaying a significantly reduced arginase I expression in the lungs, are significantly less sensitive to PLY-induced capillary leak than their wild-type or AI(+/+)/AII(-/-) counterparts, indicating an important role for arginase I in PLY-induced endothelial hyperpermeability. These results identify PKC-α and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction.
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http://dx.doi.org/10.1165/rcmb.2011-0332OC | DOI Listing |
Am J Respir Cell Mol Biol
October 2024
Medical College of Georgia, Vascular Biology Center, Pharmacology and Toxicology, Pulmonary, Critical Care Medicine, Augusta, Georgia, United States;
Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NADPH oxidase 2 (NOX2), involving the pneumococcal virulence factor pneumolysin (PLY). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of the epithelial sodium channel (ENaC) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2.
View Article and Find Full Text PDFMatrix Biol
December 2022
Center for Infection and Genomics of the Lung (CIGL), Universities of Giessen and Marburg Lung Center, Giessen, Germany. Electronic address:
Shedding of hyaluronan (HA), the component of endothelial cell (EC) glycocalyx, has been associated with acute lung injury. HA degradation allows plasma proteins and fluid to penetrate across the vascular wall leading to lung edema formation and leukocyte recruitment. Here, we analyzed sHA levels and size in patients with community-acquired pneumonia (CAP) and acute respiratory distress syndrome (ARDS), correlated them to disease severity, and evaluated the impact of pneumolysin (PLY), the Streptococcus pneumoniae (S.
View Article and Find Full Text PDFFront Immunol
August 2022
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of , a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol.
View Article and Find Full Text PDFFront Immunol
June 2018
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia.
Pneumonia is a leading cause of death in children and the elderly worldwide, accounting for 15% of all deaths of children under 5 years old. is a common and aggressive cause of pneumonia and can also contribute to meningitis and sepsis. Despite the widespread use of antibiotics, mortality rates for pneumonia remain unacceptably high in part due to the release of bacterial toxins.
View Article and Find Full Text PDFCrit Care
November 2017
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Charitéplatz 1, 10117, Berlin, Germany.
Background: Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality worldwide. Despite effective antimicrobial therapy, CAP can induce pulmonary endothelial hyperpermeability resulting in life-threatening lung failure due to an exaggerated host-pathogen interaction. Treatment of acute lung injury is mainly supportive because key elements of inflammation-induced barrier disruption remain undetermined.
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