Eur J Clin Invest 2012; 42 (12): 1342–1349

Neutrophils are the most abundant circulating white cell in humans and play a crucial role in the innate immune response. Accumulation and activation of neutrophils, together with delayed clearance, have been shown to be a key event in the pathogenesis of acute lung injury. Previously, it has been proposed that there is substantial pooling of neutrophils within the pulmonary vasculature, even under physiological conditions, making the lung especially vulnerable to neutrophil‐mediated tissue injury. However, more recent evidence suggests that only primed neutrophils accumulate in the pulmonary vasculature. This article examines the evidence for these two opposing views and proposes a new two‐step model for the recruitment of neutrophils into the lung. Firstly, neutrophils that become primed, by exposure to a range of inflammatory mediators or physicochemical perturbations, become shape changed and stiff because of alterations in their cytoskeleton, and as a result, accumulate within the pulmonary circulation. In the absence of further stimuli, the healthy pulmonary vasculature is able to selectively retained these primed cells, allow them to ‘de‐prime’ and be released back into the circulation in a quiescent, state. If this pulmonary ‘de‐priming’ mechanism fails, or a second insult occurs, such as ventilator‐associated barotrauma, which causes loss of alveolar integrity, primed neutrophils migrate from the pulmonary vasculature into the interstitial space with resultant lung injury. This canonical ‘two step’ model highlights the importance of neutrophil priming in the genesis of lung injury and the importance of adopting strategies to minimise alveolar injury.