Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) affects over 200000 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. METHODS: Using 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 RESULTS: Unprimed 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. CONCLUSIONS: We 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.This work was supported by the Wellcome Trust, MRC (UK), Papworth Hospital R&D, Intensive Care Society and NIHR Cambridge Biomedical Research Centre.This is the final published version, also available from http://thorax.bmj.com/content/early/2014/04/04/thoraxjnl-2013-204742.full

Incidence and recognition of acute respiratory distress syndrome in a UK intensive care unit.

The reported incidence of ARDS is highly variable (2.5%-19% of intensive care unit (ICU) patients) and varies depending on study patient population used. We undertook a 6-month, prospective study to determine the incidence and outcome of ARDS in a UK adult University Hospital ICU. 344 patients were admitted during the study period, of these 43 (12.5%) were determined to have ARDS. Patients with ARDS had increased mortality at 28 days and 2 years post-diagnosis, and there was under-recognition of ARDS in both medical records and death certificattion. Our findings have implications for critical care resource planning.This is the final version of the article. It first appeared from BMJ Thorax via ://dx.doi.org/10.1136/thoraxjnl-2016-20840

Neutrophil kinetics in health and disease

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 x 10(10)-10 x 10(10) 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

Neutrophil kinetics in health and disease

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 x 10(10)-10 x 10(10) 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

Use of 111-Indium-labelled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects

Eosinophils are the major cellular effectors of allergic inflammation and represent an important therapeutic target. Whilst the genesis and activation of eosinophils has been extensively explored, little is known about their intravascular kinetics or physiological fate. This study was designed to determine the intravascular lifespan of eosinophils, their partitioning between circulating and marginated pools, and sites of disposal in healthy individuals. Using autologous, minimally manipulated 111-Indium-labelled leukocytes with blood sampling, we measured the eosinophil intravascular residence time as 25.2 hours (compared to 10.3 hours for neutrophils) and demonstrated a substantial marginated eosinophil pool. Gamma camera imaging studies using purified eosinophils demonstrated initial retention in the lungs, with early re-distribution to the liver and spleen, and evidence of re-circulation from a hepatic pool. This work provides the first in vivo measurements of eosinophil kinetics in healthy volunteers and shows that 111-Indium-labelled-eosinophils can be used to monitor the fate of eosinophils non-invasively