Increasing heterogeneity is associated with <i>IL-6</i> expression in the lungs following mechanical ventilation

This study aimed to characterize how peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP) influence regional lung volume heterogeneity as a result of mechanical ventilation and the influence of this heterogeneity on markers of inflammation within the lungs. Four groups of <i>BALB/C</i> mice (<i>n</i> = 7 or 8 per group) were mechanically ventilated for 2 h using low or high (12 cmH₂O or 20 cmH₂O) peak inspiratory pressure (PIP) with or without 2 cmH₂O positive end-expiratory pressure (PEEP). Four-dimensional computed tomography (4-DCT) images were acquired using synchrotron-based radiation source at baseline and after 2 h. Regional tidal volumes were obtained by 4-D cross-correlational X-ray velocimetry, whereas end-expiratory volume was quantified by Hounsfield units. Tissue was harvested from 10 lung regions, and expression of <i>IL-6</i> and monocyte chemo-attractant protein 1 (<i>MCP-1</i>) was quantified using qPCR. We found a significant reduction in specific end-expiratory volume (sEEV) in mice ventilated with low PIP and no PEEP and a reduction in tidal volume in groups without PEEP. End-expiratory volume heterogeneity decreased in the low PIP and no PEEP group, whereas tidal volume heterogeneity decreased in the equivalent high PIP group, potentially due to regional redistribution of lung volumes. We found associations between <i>IL-6</i> expression and tidal volume heterogeneity. In this study, we have demonstrated that changes in PIP and PEEP impact atelectasis, overdistension, and heterogeneity, and that increases in tidal volume heterogeneity may be driving <i>IL-6-</i>mediated biotrauma. These findings highlight the importance of considering the spatial distribution of tidal volumes as a driver of lung injury during mechanical ventilation.<b>NEW & NOTEWORTHY</b> The combination of low inspiratory and expiratory pressure promotes atelectasis but is not associated with markers of injury in the healthy lung during short-term ventilation. High inspiratory pressures promote tidal volume heterogeneity, which is correlated with the expression of genetic markers of lung injury. These data suggest that heterogeneity in tidal volume may be a key driver of biotrauma in the healthy, mechanically ventilated lung.