Acute lung injury results from failure of neutrophil de‐priming: a new hypothesis

Abstract

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 ventilatorassociated 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.Keywords De-priming, lung injury, neutrophils. Eur J Clin Invest 2012; 42 (12): 1342-1349Acute De-priming, lung injury Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) comprise a spectrum of diseases characterised by refractory hypoxaemia, diffuse alveolar damage, neutrophilic lung inflammation and protein-rich pulmonary oedema. The incidence of ARDS ⁄ ALI has been reported to be approximately 80 cases per 100 000 person-years in the United States [1] and, despite being first described more than 40 years ago [2], the mortality rate remains unchanged at 30-50% [1,[3][4][5].Clinically, ALI is defined as a condition of acute onset and characterised by bilateral pulmonary infiltrates consistent with pulmonary oedema (see Fig. 1) and impaired gas exchange, with a PaO 2 ⁄ FiO 2 ratio of < 40 KPa, both occurring in the absence of signs of left atrial hypertension [6]. ALI ⁄ ARDS can result from a wide range of either direct pulmonary insults (e.g. pneumonia and lung contusions) or extra-pulmonary conditions (e.g. sepsis, pancreatitis, major trauma, massive blood transfusion and shock from any cause). One of the unifying features of the many seemingly disparate causes of ALI ⁄ ARDS is the occurrence of systemic neutrophil priming and activation.

Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion

“…The pulmonary endothelium plays an active role in regulating the priming of PMNs during their transit through the systemic circulation (Aoyama-Ishikawa, et al 2014, Singh, et al 2012). In the mouse model of sepsis, the pro-inflammatory milieu caused by endotoxin challenge impairs lung-mediated PMN de-priming, resulting in their accumulation, priming, release to the systemic circulation.…”

Pulmonary endothelial activation caused by extracellular histones contributes to neutrophil activation in acute respiratory distress syndrome

“…The healthy pulmonary endothelium instructs the primed cells to ‘de-prime’ and return back to a quiescent state within the vasculature [25]. It is only when neutrophils confront activated markers on the pulmonary endothelium such as P-selectin, ICAM-1, etc., will they adhere to the endothelium and become activated [26].…”

Priming of the neutrophil respiratory burst: role in host defense and inflammation

“…Reversible priming was also shown by priming neutrophils by TNFα and PAF . Summers and colleagues showed that unprimed neutrophils are not or weakly retained in human pulmonary vessels, but primed neutrophils are markedly retained, then deprimed and released into the circulation . Thus, in healthy individuals, neutrophils can be physiologically primed, activated, deactivated, and finally can die by apoptosis ( Fig.…”