Neutrophils play a key role in the elimination of pathogens. They are remarkably short-lived with a circulating half life of 6–8 h and hence are produced at a rate of 5 × 1010–10 × 1010 cells/day. Tight regulation of these cells is vital because they have significant histotoxic capacity and are widely implicated in tissue injury. This review outlines our current understanding of how neutrophils are released from the bone marrow; in particular, the role of the CXC chemokine receptor 4/stromal-derived factor 1 axis, the relative size and role of the freely circulating and marginated (i.e. slowly transiting) pools within the vascular compartment, and the events that result in the uptake and removal of circulating neutrophils. We also review current understanding of how systemic stress and inflammation affect this finely balanced system.

RationaleAcute respiratory distress syndrome (ARDS) affects over 200 000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined.MethodsUsing autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls.Main resultsUnprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis.ConclusionsWe demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then ‘deprime’ and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.

Superior oxygenation in the prone posture in oxygen-dependent premature infants studied before discharge could be explained by higher lung volumes.

Eosinophils are the major cellular effectors of allergic inflammation and represent an important therapeutic target. Although the genesis and activation of eosinophils have been extensively explored, little is known about their intravascular kinetics or physiological fate. This study was designed to determine the intravascular life span of eosinophils, their partitioning between circulating and marginated pools, and sites of disposal in healthy persons. Using autologous, minimally manipulated 111-Indium-labeled leukocytes with blood sampling, we measured the eosinophil intravascular residence time as 25.2 hours (compared with 10.3 hours for neutrophils) and demonstrated a substantial marginated eosinophil pool. ␥ camera imaging studies using purified eosinophils demonstrated initial retention in the lungs, with early redistribution to the liver and spleen, and evidence of recirculation from a hepatic pool. This work provides the first in vivo measurements of eosinophil kinetics in healthy volunteers and shows that 111-Indium-labeled eosinophils can be used to monitor the fate of eosinophils noninvasively. (Blood. 2012;120(19):4068-4071) IntroductionEosinophils play a key role in allergic inflammation 1 and represent an important therapeutic target in asthma and other allergic diseases. They have the capacity to release histotoxic substances, including granule proteins, inflammatory cytokines, and reactive oxygen metabolites, which cause bronchoconstriction, epithelial damage, hyper-responsiveness, and airway remodeling. [2][3][4][5][6] Much is known about the cellular mechanisms regulating the development and maturation of eosinophils, their release from the bone marrow, and the processes involved in their recruitment, activation, and clearance during allergic inflammation. 7-11 By contrast, very little is known about the physiology of circulating eosinophils in humans. Because of the relative scarcity of eosinophils in the blood of healthy persons (range, 0.0-0.4 ϫ 10 9 /L), previous attempts to study eosinophil kinetics have been restricted to patients with hypereosinophilia, 12-14 hampered by label reuse after pulse injection of 3 H-thymidine, 15 or relied on autoradiographs developed Ͼ 500 days. 16 We have used 111-Indiumlabeled mixed leukocytes with postinjection isolation of eosinophils to ascertain their intravascular life span, and subsequently purified 111-Indium-labeled autologous eosinophils with ␥ camera imaging to assess organ-specific trafficking in vivo. We have demonstrated an intravascular lifespan for circulating eosinophils exceeding 24 hours and revealed extensive intravascular margination of these cells, together with evidence of recirculation from a hepatic pool. Methods ParticipantsHealthy male and female adults with normal lung function and eosinophil counts (range, 0.02-0.38 ϫ 10 9 /L) gave written informed consent in accordance with the Declaration of Helsinki. The study was approved by Cambridgeshire Research Ethics Committee (09/H0308/119) and the Administration of Radioactive Substan...

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.