Mechanical ventilation-induced neutrophil extracellular vesicles as mediators of postoperative pulmonary complications
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Rationale
Postoperative pulmonary complications (PPC) remain a leading cause of perioperative morbidity and mortality, yet the underlying mechanisms are poorly understood. While alveolar stretch from mechanical ventilation is a known driver of lung inflammation, the role of
extracellular vesicles (EVs) is unknown.
Objectives
To characterise the biogenesis of alveolar stretch-induced EVs and determine their role in perioperative alveolar inflammation and PPC development.
Methods
Serial, bilateral bronchoalveolar lavage (BAL) samples were obtained from forty-two patients undergoing esophagectomy and requiring one- and two-lung ventilation. EV subtypes were identified using flow cytometry and correlated with inflammatory mediators and clinical data. Western blotting identified neutrophil-specific inflammatory matrix metalloproteinases (MMP
8/9) within patient-derived BAL neutrophil-EVs (NEV), and their bioactivity was assessed using a primary human alveolar epithelial cell-macrophage coculture. An in vitro alveolar stretch model, comprising epithelial cells and neutrophils, was used to explore mechanisms of NEV biogenesis.
Measurements and Main Results
Unphysiological one-lung ventilation, but not two-lung ventilation, induced a marked increase in NEVs (4.8-fold), which were associated with alveolar inflammation and a greater incidence of PPCs. BAL NEVs contained abundant MMP-8/9, generating pro-inflammatory responses in vitro, which were reduced by MMP inhibition. In vitro, NEV production was induced by
injurious stretch of an epithelial-neutrophil co-culture through an ATP-dependent mechanism.
Conclusions
We identify a novel mechanistic pathway whereby mechanical ventilation induces NEV release, propagating alveolar inflammation via their biologically active cargo, which may be associated with PPCs. This suggests NEVs could become a potential biomarker and therapeutic target for reducing ventilator-induced lung inflammation and PPCs.
Postoperative pulmonary complications (PPC) remain a leading cause of perioperative morbidity and mortality, yet the underlying mechanisms are poorly understood. While alveolar stretch from mechanical ventilation is a known driver of lung inflammation, the role of
extracellular vesicles (EVs) is unknown.
Objectives
To characterise the biogenesis of alveolar stretch-induced EVs and determine their role in perioperative alveolar inflammation and PPC development.
Methods
Serial, bilateral bronchoalveolar lavage (BAL) samples were obtained from forty-two patients undergoing esophagectomy and requiring one- and two-lung ventilation. EV subtypes were identified using flow cytometry and correlated with inflammatory mediators and clinical data. Western blotting identified neutrophil-specific inflammatory matrix metalloproteinases (MMP
8/9) within patient-derived BAL neutrophil-EVs (NEV), and their bioactivity was assessed using a primary human alveolar epithelial cell-macrophage coculture. An in vitro alveolar stretch model, comprising epithelial cells and neutrophils, was used to explore mechanisms of NEV biogenesis.
Measurements and Main Results
Unphysiological one-lung ventilation, but not two-lung ventilation, induced a marked increase in NEVs (4.8-fold), which were associated with alveolar inflammation and a greater incidence of PPCs. BAL NEVs contained abundant MMP-8/9, generating pro-inflammatory responses in vitro, which were reduced by MMP inhibition. In vitro, NEV production was induced by
injurious stretch of an epithelial-neutrophil co-culture through an ATP-dependent mechanism.
Conclusions
We identify a novel mechanistic pathway whereby mechanical ventilation induces NEV release, propagating alveolar inflammation via their biologically active cargo, which may be associated with PPCs. This suggests NEVs could become a potential biomarker and therapeutic target for reducing ventilator-induced lung inflammation and PPCs.
Date Acceptance
2026-08-09
Citation
American Journal of Respiratory and Critical Care Medicine
ISSN
1073-449X
Publisher
American Thoracic Society
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Copyright Statement
Copyright This paper is embargoed until publication. Once published the author’s accepted manuscript will be made available under a CC-BY License in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy).
License URL
Publication Status
Accepted