The crucial roles of mononuclear phagocytic cells during ventilator-induced lung injury

Abstract

Acute respiratory distress syndrome remains a significant cause of mortality among intensive care patients. Mechanical ventilation is a crucial component of therapy but can exacerbate injury through overstretch of lung units, known as ventilator-induced lung injury (VILI). The mechanisms by which ventilation triggers the characteristic inflammatory cascade and how this pulmonary inflammation progresses to extrapulmonary organs have not been clearly elucidated. In this work I explored the role of mononuclear phagocytes in the initiation (alveolar macrophages) and subsequent progression (monocytes) of VILI, using in vivo mouse models. Initially, the importance of alveolar macrophages in VILI was clarified by pharmacologically depleting these cells, which substantially attenuated injury. The observation that injurious ventilation led to a decrease in macrophage recoverability led us to hypothesise that adhesive interactions between epithelial cells and macrophages may be important in their activation. To address this, I developed a novel flow cytometric methodology to assess intracellular mitogen activated protein (MAP) kinase phosphorylation in discrete pulmonary cell populations. I was able to demonstrate rapid alveolar macrophage activation, but little epithelial activation, during high stretch ventilation. This potentially indicated that alveolar macrophages directly sense stretch through their adhesive contacts with epithelial cells. I attempted to study this using antibodies to block integrin-mediated interactions, although results were inconclusive. In addition to these experiments, I carried out a preliminary study showing, for the first time, that activated leukocytes marginate to extrapulmonary organs during VILI. This supports the possibility that monocytes and neutrophils play a role in the development of extra-pulmonary organ injury, although this remains undefined. This data shows that mononuclear phagocytic cells are likely to play crucial roles in the pathogenesis of VILI. The findings and methodologies developed provide many possibilities for future research that will enhance our understanding of this iatrogenic injury, ultimately in view of potential therapeutic targets.