Spatiotemporal distribution of cellular injury and leukocytes during the progression of ventilator-induced lung injury

Abstract

Supportive mechanical ventilation is a necessary lifesaving treatment for acute respiratory distress syndrome (ARDS). This intervention often leads to injury exacerbation by ventilator-induced lung injury (VILI). Patterns of injury in ARDS and VILI are recognized to be heterogeneous; however, quantification of these injury distributions remains incomplete. Developing a more detailed understanding of injury heterogeneity, particularly how it varies in space and time, can help elucidate the mechanisms of VILI pathogenesis. Ultimately, this knowledge can be used to develop protective ventilation strategies that slow disease progression. To expand existing knowledge of VILI heterogeneity, we document the spatial evolution of cellular injury distribution and leukocyte infiltration, on the micro- and macroscales, during protective and injurious mechanical ventilation. We ventilated naïve mice using either high inspiratory pressure and zero positive end-expiratory pressure ventilation or low tidal volume with positive end-expiratory pressure. Distributions of cellular injury, identified with propidium iodide staining, were microscopically analyzed at three levels of injury severity. Cellular injury initiated in diffuse, quasi-random patterns, and progressed through expansion of high-density regions of injured cells termed “injury clusters.” The density profile of the expanding injury regions suggests that stress shielding occurs, protecting the already injured regions from further damage. Spatial distribution of leukocytes did not correlate with that of cellular injury or ventilation-induced changes in lung function. These results suggest that protective ventilation protocols should protect the interface between healthy and injured regions to stymie injury propagation.