Ventilator-induced Lung Injury Promotes Inflammation within the Pleural Cavity.

Mechanical ventilation contributes to the morbidity and mortality of patients in Intensive Care, likely through the exacerbation and dissemination of inflammation. Despite its proximity to the lungs and exposure to physical forces, little attention has been paid to the potential of the pleural cavity as an inflammatory source during ventilation. Here we investigate the pleural cavity as a novel site of inflammation during ventilator-induced lung injury. Mice were subjected to low or high tidal volume ventilation strategies for up to 3 hours. High tidal volume ventilation significantly increased cytokine and total protein levels in bronchoalveolar and pleural lavage fluid. In contrast acid aspiration, explored as an alternative model of injury, only promoted intra-alveolar inflammation with no effect on the pleural space. Resident pleural macrophages demonstrated enhanced activation following injurious ventilation, including upregulated ICAM-1 and interleukin-1β expression, and release of extracellular vesicles. In vivo ventilation and in vitro stretch of pleural mesothelial cells promoted ATP secretion, while purinergic receptor inhibition substantially attenuated extracellular vesicles and cytokine levels in the pleural space. Finally, labelled protein rapidly translocated from the pleural cavity into the circulation during high tidal volume ventilation, to a significantly greater extent than protein translocation from the alveolar space. Overall we conclude that injurious ventilation induces pleural cavity inflammation mediated via purinergic pathway signaling, and likely enhances dissemination of mediators into the vasculature. This previously unidentified consequence of mechanical ventilation potentially implicates the pleural space as a focus of research and novel avenue for intervention in critical care.