Related Experiment Video
Updated: Aug 5, 2026
08:27
Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Published on: May 21, 2018
Endothelial-Derived Extracellular Vesicles Impair Human Pulmonary Microvascular Cell Function in an In-Vitro Model of
Maya Cohen1,2,3, Liana Haigis4, Rebecca Blum4
1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Brown University, Providence, Rhode Island, USA.
Summary
Inflammatory extracellular vesicles (EVs) from sepsis-injured lung cells damage healthy cells by disrupting barrier integrity. Targeting EV biogenesis offers a potential therapeutic strategy for sepsis-induced acute respiratory distress syndrome (ARDS).
Area of Science:
- Pulmonary vascular research
- Cellular and molecular biology
- Sepsis and critical care medicine
Background:
- Sepsis-induced acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by high mortality.
- Endothelial dysfunction is a key feature of ARDS, but the underlying mechanisms of pulmonary microvascular injury are not fully understood.
- Extracellular vesicles (EVs) mediate cell-cell communication in inflammation, yet their specific role in ARDS-related endothelial dysfunction requires further investigation.
Purpose of the Study:
- To investigate whether inflammatory EVs (iEVs) derived from lipopolysaccharide (LPS)-treated human pulmonary microvascular endothelial cells (HPMECs) impair the function of naive HPMECs.
- To elucidate the mechanisms by which iEVs affect endothelial barrier integrity and signaling pathways.
- To identify potential therapeutic targets for sepsis-induced ARDS by examining the role of EV biogenesis and TLR4 signaling.
Main Methods:
- Established a human pulmonary microvascular endothelial cell (HPMEC)-based model of sepsis-induced acute lung injury.
- Characterized EVs using nanoparticle tracking analysis, transmission electron microscopy, and immunofluorescence.
- Assessed HPMEC function, including barrier integrity (electric cell-substrate impedance sensing) and cell migration.
- Utilized TLR4 inhibitor (TAK-242) and neutral sphingomyelinase inhibitor (GW4869) to investigate signaling pathways and EV biogenesis.
Main Results:
- Exposure to iEVs significantly reduced HPMEC barrier integrity and increased cell migration, effects partially reversed by TAK-242.
- Inhibition of ceramide-dependent EV biogenesis with GW4869 attenuated the barrier-disrupting effects of iEVs.
- iEV exposure upregulated key inflammatory and adhesion molecules (TLR4, MyD88, IL-6, ICAM-1, VCAM-1, E-selectin, Jag1 mRNA), with TAK-242 reducing IL-6 and ICAM-1 induction.
- EV effects were attributed to altered signaling rather than cell death.
Conclusions:
- Endothelial-derived EVs, particularly those generated through ceramide-dependent pathways, amplify pulmonary vascular injury in sepsis-induced ARDS.
- TLR4-dependent signaling pathways play a crucial role in mediating the detrimental effects of iEVs.
- Targeting EV biogenesis and EV-mediated signaling represents a promising novel therapeutic strategy for sepsis-induced ARDS.
