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

Abstract

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.

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

“…Such a profile could be particularly important in the asthmatic lung, where local concentrations of PGD 2 are likely to vary depending on the numbers of activated mast cells, especially given that PGD 2 release occurs in a matter of minutes after IgE activation (Kawata et al, 1995). Importantly, the transit time of mixed leukocytes across the pulmonary circulation has recently been quantified and is thought to be similar to that of neutrophils measured precisely at 14.2 seconds, only marginally slower than that reported for RBCs (Summers et al, 2014). This implies that sustained CRTh2 blockade will protect against eosinophil recruitment as they transit through areas of high PGD 2 concentration in the lung.…”

Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition

“…In our present study, ARDS blood and ARDS alv PMNs were functionally primed, and such cells have previously been implicated in lung injury (46,47). We previously demonstrated that the pulmonary capillary bed can trap and "de-prime" neutrophils and that this mechanism may fail in ARDS, augmenting the circulating pool of these potentially injurious cells (48). Additional priming signals may be imparted during vascular transmigration (49), and ARDS BALF also primed the oxidative burst of HV blood PMNs.…”

Alteration of Leukocyte Count Correlates With Increased Pulmonary Vascular Permeability and Decreased PaO2

“…Hence it seems that the accumulation of immunocompetent leucocytes in the alveoli is either important in itself or a marker for some other factor related to mortality. Another very recent study on (non-burn) ARDS [34] propose that the retention of activated leucocytes in pulmonary vessels is important to protect the host from the systemic action of these leucocytes. This model may fit with the observation of decreased amount of and decreased level of activation of leucocytes in alveoli of burn nonsurvivors.…”