Patients with acute respiratory distress syndrome (ARDS) have an unacceptably high mortality surpassing 40%. Most patients with ARDS die from multi-organ failure rather than respiratory failure, presumably due to systemic propagation of inflammation between the lungs and peripheral organs. Numerous systemic inflammatory mediators have been identified as potential therapeutic targets for ARDS. However, few specific therapies have been successfully developed and treatment remains primarily limited to supportive care.

Microvesicles (MVs) are tiny particles released from cells during cell activation and stress. MVs represent a unique form of inter-cellular communication through their ability to act as ‘biological ferries’ carrying inflammatory mediators as their cargoes in a packaged, lipid-encapsulated environment resistant to neutralisation in the systemic circulation. We hypothesised that leukocyte-derived MVs play a critical role in systemic inflammatory signalling in ARDS.

Through initially focusing on periphery-to-lung signalling, we developed an in vitro bioassay of pulmonary microvascular inflammation and investigated the bioactivity of neutrophil-derived MVs. We found that inflammatory neutrophil-derived MVs induced significant acute pulmonary microvascular inflammation, in a peripheral blood mononuclear cell-dependent manner. We then focused on lung-to-periphery signalling through developing a novel human in vitro model of ventilator-induced pulmonary microvascular inflammation. We found, for the first time, that pathological cyclic stretch induced acute leukocyte activation and release of leukocyte-derived MVs. We developed methodology to separate MV subtypes from the mixed total MV population generated, and demonstrated that these stretch-induced leukocyte-derived MVs are capable of inducing remote organ endothelial injury. Finally, we investigated circulating MV profiles in plasma samples of patients with ARDS. We found significantly increased baseline neutrophil- and endothelial-derived MV levels in patients with hyperinflammatory ARDS.

Our findings suggest MVs play a crucial role in the early phase of ARDS pathophysiology and could represent a paradigm shift in our understanding of systemic inflammatory signalling in ARDS.