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Stimulation of Neutrophils in Whole Blood Enhances the Pro‐inflammatory Activity of Neutrophil‐Derived Microvesicles

Acute increases in circulating levels of neutrophil‐derived microvesicles (N‐MVs) during sepsis combined with evidence of enhanced uptake of MVs within the pulmonary microvasculature during endotoxemia in mice, suggests a role for N‐MVs in development of indirect acute lung injury (ALI). However, evidence for the pro‐inflammatory activity of N‐MVs is unclear, with various in vitro studies demonstrating anti‐inflammatory effects. Most in vitro investigations of N‐MV activity involve stimulation of purified neutrophils with single agonists such as formyl‐methionyl‐leucyl‐phenylalanine (fMLP). This reductionist approach excludes the complex in vivo interplay between different stimuli and other vascular cells contributing to neutrophil responses during sepsis. Here we investigated the proinflammatory activities of N‐MVs under more clinically relevant in vitro conditions, treating healthy volunteer whole blood with lipopolysaccharide (LPS) as a sepsis‐relevant inflammatory stimulus and fMLP as an acute N‐MV inducing stimulus. The activities of N‐MVs derived from whole blood as well as isolated neutrophils were evaluated in a monocyte‐neutrophil‐endothelial cell ‘tri‐culture’ model of pulmonary vascular inflammation.